ATP

cross_nutrient

Magnesium-dependent ATP chemistry is coupled to sodium and potassium handling by the pump; serum magnesium is not the enzyme-site concentration.

experimental_model

Pig-kidney Na/K-ATPase rapid-mixing phosphorylation; Na-containing, K-free medium; varied ATP and MgCl2.

limitations

Kinetic model, not proof of Mg-free catalysis; binding and phosphate transfer are distinct.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Sus scrofa

plain_language

A requirement for magnesium does not prove that only a preformed MgATP molecule can bind.

primary_references

[campos-1992-nka] Effects of magnesium and ATP on pre-steady-state phosphorylation kinetics of the Na+,K(+)-ATPase (1992). https://pubmed.ncbi.nlm.nih.gov/1314673/ DOI: 10.1016/0005-2736(92)90161-e

tissue_or_cell_type

Kidney enzyme

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 783–793

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Pig-kidney Na/K-ATPase rapid-mixing phosphorylation; Na-containing, K-free medium; varied ATP and MgCl2. · source_derived_draft · unverified_draft

### mg-nka-atp-binding-order-boundary The 1992 best-fit model allowed free ATP or MgATP to bind before productive Mg-dependent phosphorylation. Condition category: normal nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: A requirement for magnesium does not prove that only a preformed MgATP molecule can bind. organism: Sus scrofa tissue_or_cell_type: Kidney enzyme experimental_model: Pig-kidney Na/K-ATPase rapid-mixing phosphorylation; Na-containing, K-free medium; varied ATP and MgCl2. limitations: Kinetic model, not proof of Mg-free catalysis; binding and phosphate transfer are distinct. cross_nutrient: Magnesium-dependent ATP chemistry is coupled to sodium and potassium handling by the pump; serum magnesium is not the enzyme-site concentration. [campos-1992-nka] Effects of magnesium and ATP on pre-steady-state phosphorylation kinetics of the Na+,K(+)-ATPase (1992). https://pubmed.ncbi.nlm.nih.gov/1314673/ DOI: 10.1016/0005-2736(92)90161-e

cross_nutrient

Magnesium-dependent ATP chemistry is coupled to sodium and potassium handling by the pump; serum magnesium is not the enzyme-site concentration.

experimental_model

Human red cells and resealed ghosts; ATP/Mg loading, ouabain, sodium-24, potassium-42 and gamma-phosphorus-32 ATP.

limitations

Measured stoichiometry applies to specified ionic conditions; no Mg titration was performed.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Homo sapiens

plain_language

ATP turnover was directly linked to outward sodium pumping in a magnesium-containing preparation.

primary_references

[garrahan-1967-nka] The stoicheiometry of the sodium pump (1967). https://doi.org/10.1113/jphysiol.1967.sp008297 DOI: 10.1113/jphysiol.1967.sp008297

tissue_or_cell_type

Resealed erythrocyte ghosts

transport_direction

Sodium: intracellular ghost compartment to external medium.

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 819–830

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human red cells and resealed ghosts; ATP/Mg loading, ouabain, sodium-24, potassium-42 and gamma-phosphorus-32 ATP. · source_derived_draft · unverified_draft

### mg-nka-isotope-atp-sodium-coupling In Mg-loaded human red-cell ghosts, ouabain-sensitive hydrolysis of one ATP accompanied loss of about three sodium ions. Condition category: normal nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: ATP turnover was directly linked to outward sodium pumping in a magnesium-containing preparation. organism: Homo sapiens tissue_or_cell_type: Resealed erythrocyte ghosts experimental_model: Human red cells and resealed ghosts; ATP/Mg loading, ouabain, sodium-24, potassium-42 and gamma-phosphorus-32 ATP. limitations: Measured stoichiometry applies to specified ionic conditions; no Mg titration was performed. cross_nutrient: Magnesium-dependent ATP chemistry is coupled to sodium and potassium handling by the pump; serum magnesium is not the enzyme-site concentration. transport_direction: Sodium: intracellular ghost compartment to external medium. [garrahan-1967-nka] The stoicheiometry of the sodium pump (1967). https://doi.org/10.1113/jphysiol.1967.sp008297 DOI: 10.1113/jphysiol.1967.sp008297

cross_nutrient

Magnesium and thiamine-derived ThDP intersect at mitochondrial carbon metabolism; purified-enzyme responses do not measure whole-body energy supply.

experimental_model

Isolated pig-heart enzyme complex plus mitochondrial extracts; extract source not resolved in this curation; nucleotide/phosphate/Mg speciation experiments.

limitations

The paper assigns more than one inhibitory mechanism; their in vivo contributions were not measured.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Sus scrofa

plain_language

ATP concentration can alter both free magnesium and nucleotide regulation of the enzyme.

primary_references

[rodriguez-2000-ogdh] Modulation of 2-oxoglutarate dehydrogenase complex by inorganic phosphate, Mg(2+), and other effectors (2000). https://pubmed.ncbi.nlm.nih.gov/10864444/ DOI: 10.1006/abbi.2000.1856

tissue_or_cell_type

Isolated heart enzyme; additional mitochondrial-extract source not resolved

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 711–721

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Isolated pig-heart enzyme complex plus mitochondrial extracts; extract source not resolved in this curation; nucleotide/phosphate/Mg speciation experiments. · source_derived_draft · unverified_draft

### mg-ogdh-atp-chelation-inhibition The 2000 study attributed ATP inhibition to Mg chelation and an inhibitory effect of MgATP. Condition category: normal nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: ATP concentration can alter both free magnesium and nucleotide regulation of the enzyme. organism: Sus scrofa tissue_or_cell_type: Isolated heart enzyme; additional mitochondrial-extract source not resolved experimental_model: Isolated pig-heart enzyme complex plus mitochondrial extracts; extract source not resolved in this curation; nucleotide/phosphate/Mg speciation experiments. limitations: The paper assigns more than one inhibitory mechanism; their in vivo contributions were not measured. cross_nutrient: Magnesium and thiamine-derived ThDP intersect at mitochondrial carbon metabolism; purified-enzyme responses do not measure whole-body energy supply. [rodriguez-2000-ogdh] Modulation of 2-oxoglutarate dehydrogenase complex by inorganic phosphate, Mg(2+), and other effectors (2000). https://pubmed.ncbi.nlm.nih.gov/10864444/ DOI: 10.1006/abbi.2000.1856

compartment_description

Extracellular space

experimental_model

ENPP1-proficient versus deficient cells

limitations

Other ectonucleotidases compete for ATP; PPi is not synonymous with orthophosphate.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Homo sapiens

plain_language

An extracellular enzyme converts exported ATP into a mineralization inhibitor.

primary_references

[szeri2022] The mineralization regulator ANKH mediates cellular efflux of ATP, not pyrophosphate (2022). https://pmc.ncbi.nlm.nih.gov/articles/PMC9098669/ DOI: 10.1002/jbmr.4528

tissue_or_cell_type

HEK293 extracellular medium

Calcium: mechanism-first literature curation (2026-09-17) · lines 1012–1022

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · ENPP1-proficient versus deficient cells · source_derived_draft · unverified_draft

### enpp1-atp-to-pyrophosphate ENPP1 converts extracellular ATP into AMP and PPi; ANKH-expressing cells lacking ENPP1 released ATP without the accompanying PPi accumulation. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: An extracellular enzyme converts exported ATP into a mineralization inhibitor. organism: Homo sapiens tissue_or_cell_type: HEK293 extracellular medium experimental_model: ENPP1-proficient versus deficient cells limitations: Other ectonucleotidases compete for ATP; PPi is not synonymous with orthophosphate. compartment_description: Extracellular space [szeri2022] The mineralization regulator ANKH mediates cellular efflux of ATP, not pyrophosphate (2022). https://pmc.ncbi.nlm.nih.gov/articles/PMC9098669/ DOI: 10.1002/jbmr.4528

cross_nutrient

Mg-dependent ATP chemistry activates B1; it does not imply every later ThDP-binding event consumes ATP.

curation_note

Adds explicit phosphate-transfer/AMP-product detail to the existing magnesium collection.

evidence-scope

Recombinant enzyme

evidence_locator

Abstract

evidence_spans

[{"source_document": "artifacts/thiamine_transport_sources/sambon-2022-tpk1-source-record.json", "source_field": "resultList.result[0].abstractText", "start_char": 0, "end_char": 1689}]

experimental_model

Purified His-tagged human TPK1; ATP/Mg kinetics and mutagenesis.

limitations

Overall chemistry does not resolve substrate-binding order.

nutrient_topic

Thiamine research collection; topical membership is not evidence of a direct dietary effect. · Thiamine (vitamin B1)

organism

Homo sapiens

plain_language

B1 activation uses ATP and releases AMP; it is not an ATP-to-ADP single-phosphate step.

primary_references

[onozuka-2003-tpk1] Steady-state kinetics and mutational studies of recombinant human thiamin pyrophosphokinase (2003). https://pubmed.ncbi.nlm.nih.gov/12953792/ DOI: 10.3177/jnsv.49.156 [sambon-2022-tpk1] Product inhibition of mammalian thiamine pyrophosphokinase is an important mechanism for maintaining thiamine diphosphate homeostasis (2022). https://doi.org/10.1016/j.bbagen.2021.130071 DOI: 10.1016/j.bbagen.2021.130071

reaction

thiamine + ATP -> thiamine diphosphate + AMP

related_existing_claim_keys

["mg-tpk1-thiamine-to-thdp"]

tissue_or_cell_type

Recombinant enzyme

Thiamine: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 339–356

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified His-tagged human TPK1; ATP/Mg kinetics and mutagenesis. · source_derived_draft · unverified_draft

### b1-tpk1-atp-amp-stoichiometry TPK1 activation transfers ATP-derived diphosphoryl to thiamine, yielding ThDP and AMP in a magnesium-dependent reaction. Condition category: normal nutrient_topic: Thiamine research collection; topical membership is not evidence of a direct dietary effect. plain_language: B1 activation uses ATP and releases AMP; it is not an ATP-to-ADP single-phosphate step. organism: Homo sapiens tissue_or_cell_type: Recombinant enzyme experimental_model: Purified His-tagged human TPK1; ATP/Mg kinetics and mutagenesis. limitations: Overall chemistry does not resolve substrate-binding order. cross_nutrient: Mg-dependent ATP chemistry activates B1; it does not imply every later ThDP-binding event consumes ATP. reaction: thiamine + ATP -> thiamine diphosphate + AMP related_existing_claim_keys: ["mg-tpk1-thiamine-to-thdp"] curation_note: Adds explicit phosphate-transfer/AMP-product detail to the existing magnesium collection. evidence_spans: [{"source_document": "artifacts/thiamine_transport_sources/sambon-2022-tpk1-source-record.json", "source_field": "resultList.result[0].abstractText", "start_char": 0, "end_char": 1689}] evidence_locator: Abstract evidence-scope: Recombinant enzyme [onozuka-2003-tpk1] Steady-state kinetics and mutational studies of recombinant human thiamin pyrophosphokinase (2003). https://pubmed.ncbi.nlm.nih.gov/12953792/ DOI: 10.3177/jnsv.49.156 [sambon-2022-tpk1] Product inhibition of mammalian thiamine pyrophosphokinase is an important mechanism for maintaining thiamine diphosphate homeostasis (2022). https://doi.org/10.1016/j.bbagen.2021.130071 DOI: 10.1016/j.bbagen.2021.130071

cross_nutrient

Free ATP must be distinguished from its magnesium complex.

experimental_model

Rat beta-cell inside-out patches.

limitations

Excised patches do not reproduce all intact-cell metabolic regulation.

nutrient_topic

Potassium research collection; topical membership is not evidence of a direct dietary effect. · Potassium

organism

Rat

plain_language

ATP can close the potassium channel through nucleotide regulation.

primary_references

[ashcroft-1989-magnesium] ATP-sensitive K+ channels in rat pancreatic beta-cells: modulation by ATP and Mg2+ ions (1989). https://pmc.ncbi.nlm.nih.gov/articles/PMC1189219/ DOI: 10.1113/jphysiol.1989.sp017765

tissue_or_cell_type

Pancreatic beta-cell membrane

Potassium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 786–796

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat beta-cell inside-out patches. · source_derived_draft · unverified_draft

### k-beta-atp-inhibition Free ATP and nonhydrolyzable ATP analogues inhibited beta-cell KATP channels without requiring phosphorylation. Condition category: normal nutrient_topic: Potassium research collection; topical membership is not evidence of a direct dietary effect. plain_language: ATP can close the potassium channel through nucleotide regulation. organism: Rat tissue_or_cell_type: Pancreatic beta-cell membrane experimental_model: Rat beta-cell inside-out patches. limitations: Excised patches do not reproduce all intact-cell metabolic regulation. cross_nutrient: Free ATP must be distinguished from its magnesium complex. [ashcroft-1989-magnesium] ATP-sensitive K+ channels in rat pancreatic beta-cells: modulation by ATP and Mg2+ ions (1989). https://pmc.ncbi.nlm.nih.gov/articles/PMC1189219/ DOI: 10.1113/jphysiol.1989.sp017765

evidence_span

{"source_cache": "artifacts/citrulline-research/18323623.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "079be80a0ea1a47308efb069d3c9522c96c0aa5923ad1d7ce79ac620b2d9502f", "start_char": 0, "end_char": 840, "text_sha256": "079be80a0ea1a47308efb069d3c9522c96c0aa5923ad1d7ce79ac620b2d9502f"}

experimental_model

Crystal structure and biochemical reaction characterization

exposure

Citrulline and aspartate bound to recombinant enzyme

limitations

Structure and established reaction; no clinical magnesium, aspartate or ATP deficiency threshold is established.

nutrient_topic

Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline

organism

Human ASS1

plain_language

Arginine regeneration has an energy cost.

primary_references

[citrulline-p18323623] Structure of human argininosuccinate synthetase. (2008). https://pubmed.ncbi.nlm.nih.gov/18323623/ DOI: 10.1107/s0907444907067455

tissue_or_cell_type

Cytosolic arginine-regeneration reaction

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 151–162

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Crystal structure and biochemical reaction characterization · source_derived_draft · unverified_draft

### citrulline-ass1-energy The ASS1 reaction uses ATP cleavage to AMP and pyrophosphate. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Arginine regeneration has an energy cost. organism: Human ASS1 tissue_or_cell_type: Cytosolic arginine-regeneration reaction experimental_model: Crystal structure and biochemical reaction characterization limitations: Structure and established reaction; no clinical magnesium, aspartate or ATP deficiency threshold is established. exposure: Citrulline and aspartate bound to recombinant enzyme evidence_span: {"source_cache": "artifacts/citrulline-research/18323623.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "079be80a0ea1a47308efb069d3c9522c96c0aa5923ad1d7ce79ac620b2d9502f", "start_char": 0, "end_char": 840, "text_sha256": "079be80a0ea1a47308efb069d3c9522c96c0aa5923ad1d7ce79ac620b2d9502f"} [citrulline-p18323623] Structure of human argininosuccinate synthetase. (2008). https://pubmed.ncbi.nlm.nih.gov/18323623/ DOI: 10.1107/s0907444907067455

evidence_span

{"source_cache": "artifacts/niacin-precursors-sources/naprt2011.abstract.txt", "locator": "Indexed primary abstract; identified exact passage", "start_char": 645, "end_char": 876, "file_sha256": "c9f4959ad65f0b0621179b3ccf00c460f7f648293bf910209ecc6e7785417deb", "text_sha256": "4c7ca81c7fa47c688d3b609b934e21bddf5bb0501b5bd8b54699ff7761280cb9"}

experimental_model

Purified recombinant human NAPRT kinetic assays and site-directed mutagenesis

exposure

Biochemical or structural assay; no dietary intervention

limitations

Purified-enzyme evidence does not establish dietary intake requirements or clinical outcomes.

nutrient_topic

Niacin research collection; topical membership is not evidence of a direct dietary effect. · Niacin (vitamin B3)

organism

Homo sapiens

plain_language

ATP’s effect on this enzyme depended on the assay conditions.

primary_references

[b3-pre-naprt2011] Characterization of human nicotinate phosphoribosyltransferase: Kinetic studies, structure prediction and functional analysis by site-directed mutagenesis. (2012). https://pubmed.ncbi.nlm.nih.gov/21742010/ DOI: 10.1016/j.biochi.2011.06.033

tissue_or_cell_type

Purified recombinant protein; no intact tissue

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 276–287

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant human NAPRT kinetic assays and site-directed mutagenesis · source_derived_draft · unverified_draft

### b3-pre-naprt-atp-context ATP stimulated or inhibited recombinant human NAPRT depending on low or high substrate saturation in the reported kinetic assays. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: ATP’s effect on this enzyme depended on the assay conditions. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Purified recombinant human NAPRT kinetic assays and site-directed mutagenesis limitations: Purified-enzyme evidence does not establish dietary intake requirements or clinical outcomes. exposure: Biochemical or structural assay; no dietary intervention evidence_span: {"source_cache": "artifacts/niacin-precursors-sources/naprt2011.abstract.txt", "locator": "Indexed primary abstract; identified exact passage", "start_char": 645, "end_char": 876, "file_sha256": "c9f4959ad65f0b0621179b3ccf00c460f7f648293bf910209ecc6e7785417deb", "text_sha256": "4c7ca81c7fa47c688d3b609b934e21bddf5bb0501b5bd8b54699ff7761280cb9"} [b3-pre-naprt2011] Characterization of human nicotinate phosphoribosyltransferase: Kinetic studies, structure prediction and functional analysis by site-directed mutagenesis. (2012). https://pubmed.ncbi.nlm.nih.gov/21742010/ DOI: 10.1016/j.biochi.2011.06.033

evidence_access

Primary abstract

experimental_model

Biochemical concentration titrations.

limitations

This is assay speciation, not evidence that lithium exhausts ATP or that extra magnesium improves clinical outcomes.

nutrient_topic

Lithium collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Lithium

plain_language

ATP and free magnesium must be considered together.

primary_references

Lithium inhibits glycogen synthase kinase-3 by competition for magnesium. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11162580/ · DOI 10.1006/bbrc.2000.4169

Lithium: metal-sensitive enzymes, transport and cross-nutrient mechanisms (2026-09-19) · lines 24–30

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Biochemical concentration titrations. · source_derived_draft · unverified_draft

## lithium-gsk3-atp-magnesium ATP and free magnesium must be considered together. ATP concentrations exceeding magnesium progressively inhibited GSK3 in the assay through free-magnesium chelation. Model: Biochemical concentration titrations. Limitations: This is assay speciation, not evidence that lithium exhausts ATP or that extra magnesium improves clinical outcomes. Evidence access: Primary abstract Lithium inhibits glycogen synthase kinase-3 by competition for magnesium. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11162580/ · DOI 10.1006/bbrc.2000.4169

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/inositol-research/16707555.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "b411ec23aa4b3ee2a861a8a9a99811acb039a03c18015a5954a1f90971d175ef", "start_char": 0, "end_char": 1640, "text_sha256": "b411ec23aa4b3ee2a861a8a9a99811acb039a03c18015a5954a1f90971d175ef"}

experimental_model

Cardiac patch clamp and lipid/ATP manipulation

exposure

ATP withdrawal, analogs and exogenous PIP2

limitations

The current was described as TRPM7-like; this experiment alone does not establish its molecular identity.

nutrient_topic

Inositol research collection; topical membership is not evidence of a direct dietary effect. · Inositol (stereoisomer family)

organism

Pig, rat and guinea pig cardiac cells

plain_language

ATP had to support a chemical reaction, rather than merely occupy a binding site.

primary_references

[ino-p16707555] ATP and PIP2 dependence of the magnesium-inhibited, TRPM7-like cation channel in cardiac myocytes. (2006). https://pubmed.ncbi.nlm.nih.gov/16707555/ DOI: 10.1152/ajpcell.00074.2006

tissue_or_cell_type

Cardiac magnesium-inhibited current

trigger_kind

machinery_impairment Imported condition classification; unverified.

Inositol: synthesis, signaling, mineral interactions and conditional deficiency (2026-09-17) · lines 990–1001

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cardiac patch clamp and lipid/ATP manipulation · source_derived_draft · unverified_draft

### ino-mic-atp Hydrolyzable ATP supported maintenance of cardiac magnesium-inhibited cation current, whereas a nonhydrolyzable ATP analog did not substitute. Condition category: machinery_impairment nutrient_topic: Inositol research collection; topical membership is not evidence of a direct dietary effect. plain_language: ATP had to support a chemical reaction, rather than merely occupy a binding site. organism: Pig, rat and guinea pig cardiac cells tissue_or_cell_type: Cardiac magnesium-inhibited current experimental_model: Cardiac patch clamp and lipid/ATP manipulation limitations: The current was described as TRPM7-like; this experiment alone does not establish its molecular identity. exposure: ATP withdrawal, analogs and exogenous PIP2 evidence_span: {"source_cache": "artifacts/inositol-research/16707555.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "b411ec23aa4b3ee2a861a8a9a99811acb039a03c18015a5954a1f90971d175ef", "start_char": 0, "end_char": 1640, "text_sha256": "b411ec23aa4b3ee2a861a8a9a99811acb039a03c18015a5954a1f90971d175ef"} [ino-p16707555] ATP and PIP2 dependence of the magnesium-inhibited, TRPM7-like cation channel in cardiac myocytes. (2006). https://pubmed.ncbi.nlm.nih.gov/16707555/ DOI: 10.1152/ajpcell.00074.2006

cross_nutrient

Magnesium and ATP support folate interconversion.

experimental_model

Purified liver enzyme

exposure

Controlled enzyme assay with ATP and magnesium.

limitations

Cofactor dependence does not establish a dietary magnesium threshold.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

ATP supplies energy for this magnesium-dependent folate conversion.

primary_references

[bertrand-1987] Human liver methenyltetrahydrofolate synthetase: improved purification and increased affinity for folate polyglutamate substrates (1987). https://pubmed.ncbi.nlm.nih.gov/3801490/ DOI: 10.1016/0167-4838(87)90004-5

tissue_or_cell_type

Liver-derived, cell-free

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1255–1266

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified liver enzyme · source_derived_draft · unverified_draft

### mthfs-atp-magnesium-dependence The purified human liver MTHFS reaction requires ATP and Mg2+ and is an ADP-forming cyclo-ligase reaction. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: ATP supplies energy for this magnesium-dependent folate conversion. organism: Homo sapiens tissue_or_cell_type: Liver-derived, cell-free experimental_model: Purified liver enzyme limitations: Cofactor dependence does not establish a dietary magnesium threshold. exposure: Controlled enzyme assay with ATP and magnesium. cross_nutrient: Magnesium and ATP support folate interconversion. [bertrand-1987] Human liver methenyltetrahydrofolate synthetase: improved purification and increased affinity for folate polyglutamate substrates (1987). https://pubmed.ncbi.nlm.nih.gov/3801490/ DOI: 10.1016/0167-4838(87)90004-5

evidence_span

{"source_cache": "artifacts/biotin-research/17360195.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3ae046490d9657d005d5c39efb1f7439bc015d0cb2190834e3e868de70eaf985", "start_char": 0, "end_char": 1067, "text_sha256": "3ae046490d9657d005d5c39efb1f7439bc015d0cb2190834e3e868de70eaf985"}

experimental_model

Purified recombinant human MCC produced by baculovirus expression

exposure

ATP and methylcrotonyl-CoA kinetics

limitations

Recombinant-enzyme kinetics do not determine human dietary requirements.

nutrient_topic

Biotin research collection; topical membership is not evidence of a direct dietary effect. · Biotin

organism

Homo sapiens

plain_language

The biotin-dependent reaction also requires an energy substrate and the carbon substrate.

primary_references

[b7-p17360195] Expression, purification, characterization of human 3-methylcrotonyl-CoA carboxylase (MCCC). (2007). https://pubmed.ncbi.nlm.nih.gov/17360195/ DOI: 10.1016/j.pep.2007.01.012

tissue_or_cell_type

Purified human MCC complex

Biotin: carboxylases, recycling, deficiency and nutrient interactions (2026-09-17) · lines 780–791

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant human MCC produced by baculovirus expression · source_derived_draft · unverified_draft

### b7-mcc-atp Recombinant human MCC had an ATP Km of 45 ± 11 micromolar and a methylcrotonyl-CoA Km of 74 ± 7 micromolar. Condition category: normal nutrient_topic: Biotin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The biotin-dependent reaction also requires an energy substrate and the carbon substrate. organism: Homo sapiens tissue_or_cell_type: Purified human MCC complex experimental_model: Purified recombinant human MCC produced by baculovirus expression limitations: Recombinant-enzyme kinetics do not determine human dietary requirements. exposure: ATP and methylcrotonyl-CoA kinetics evidence_span: {"source_cache": "artifacts/biotin-research/17360195.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3ae046490d9657d005d5c39efb1f7439bc015d0cb2190834e3e868de70eaf985", "start_char": 0, "end_char": 1067, "text_sha256": "3ae046490d9657d005d5c39efb1f7439bc015d0cb2190834e3e868de70eaf985"} [b7-p17360195] Expression, purification, characterization of human 3-methylcrotonyl-CoA carboxylase (MCCC). (2007). https://pubmed.ncbi.nlm.nih.gov/17360195/ DOI: 10.1016/j.pep.2007.01.012

evidence_span

{"source_cache": "artifacts/coq10-research/29198567.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "4719b64857834d1a9b54316220f3d33aa529dce36938da0a063c74c5a5f30f67", "start_char": 0, "end_char": 1050, "text_sha256": "4719b64857834d1a9b54316220f3d33aa529dce36938da0a063c74c5a5f30f67"}

experimental_model

Biochemistry and chemical genetics

exposure

Cardiolipin-containing membranes and phenolic compounds

limitations

Human ATPase chemistry and yeast inhibition are distinct model components.

nutrient_topic

Coenzyme Q10 research collection; topical membership is not evidence of a direct dietary effect. · Coenzyme Q10 / CoQ10 redox system

organism

Human COQ8A and yeast Coq8

plain_language

A protein once described mainly as kinase-like also uses ATP to support CoQ synthesis.

primary_references

[coq10-p29198567] Conserved Lipid and Small-Molecule Modulation of COQ8 Reveals Regulation of the Ancient Kinase-like UbiB Family. (2018). https://pubmed.ncbi.nlm.nih.gov/29198567/ DOI: 10.1016/j.chembiol.2017.11.001

tissue_or_cell_type

Membrane-regulated ATPase

Coenzyme Q10: biosynthesis, electron transfer, antioxidant recycling and nutrient interactions (2026-09-17) · lines 320–331

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Biochemistry and chemical genetics · source_derived_draft · unverified_draft

### coq10-coq8a-atpase Human COQ8A showed ATPase activity as part of the conserved COQ8 biochemical function. Condition category: normal nutrient_topic: Coenzyme Q10 research collection; topical membership is not evidence of a direct dietary effect. plain_language: A protein once described mainly as kinase-like also uses ATP to support CoQ synthesis. organism: Human COQ8A and yeast Coq8 tissue_or_cell_type: Membrane-regulated ATPase experimental_model: Biochemistry and chemical genetics limitations: Human ATPase chemistry and yeast inhibition are distinct model components. exposure: Cardiolipin-containing membranes and phenolic compounds evidence_span: {"source_cache": "artifacts/coq10-research/29198567.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "4719b64857834d1a9b54316220f3d33aa529dce36938da0a063c74c5a5f30f67", "start_char": 0, "end_char": 1050, "text_sha256": "4719b64857834d1a9b54316220f3d33aa529dce36938da0a063c74c5a5f30f67"} [coq10-p29198567] Conserved Lipid and Small-Molecule Modulation of COQ8 Reveals Regulation of the Ancient Kinase-like UbiB Family. (2018). https://pubmed.ncbi.nlm.nih.gov/29198567/ DOI: 10.1016/j.chembiol.2017.11.001

compartment_description

Cytosol to extracellular medium

experimental_model

ANKH expression with ENPP1 deletion controls

limitations

Cellular export assay; it does not determine purified ANKH transport stoichiometry in every tissue.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Homo sapiens

plain_language

ANKH can provide extracellular ATP for subsequent PPi production.

primary_references

[szeri2022] The mineralization regulator ANKH mediates cellular efflux of ATP, not pyrophosphate (2022). https://pmc.ncbi.nlm.nih.gov/articles/PMC9098669/ DOI: 10.1002/jbmr.4528

tissue_or_cell_type

HEK293 cells

Calcium: mechanism-first literature curation (2026-09-17) · lines 1000–1010

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · ANKH expression with ENPP1 deletion controls · source_derived_draft · unverified_draft

### ankh-atp-export ANKH expression drove ATP release from HEK293 cells even when ENPP1 was absent. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: ANKH can provide extracellular ATP for subsequent PPi production. organism: Homo sapiens tissue_or_cell_type: HEK293 cells experimental_model: ANKH expression with ENPP1 deletion controls limitations: Cellular export assay; it does not determine purified ANKH transport stoichiometry in every tissue. compartment_description: Cytosol to extracellular medium [szeri2022] The mineralization regulator ANKH mediates cellular efflux of ATP, not pyrophosphate (2022). https://pmc.ncbi.nlm.nih.gov/articles/PMC9098669/ DOI: 10.1002/jbmr.4528

cross_nutrient

Mg dependence remains distinct from physiological net reaction direction.

evidence-scope

Recombinant enzyme

evidence_locator

Reaction definition and sections 2.2 and 3.3

evidence_spans

[{"source_document": "artifacts/thiamine_transport_sources/sambon-2022-tpk1-source-record.json", "source_field": "resultList.result[0].abstractText", "start_char": 0, "end_char": 1689}]

experimental_model

Purified recombinant mouse TPK1; forward and reverse reactions.

limitations

High AMP/Mg requirements do not establish meaningful reverse flux in humans.

nutrient_topic

Thiamine research collection; topical membership is not evidence of a direct dietary effect. · Thiamine (vitamin B1)

organism

Mus musculus

plain_language

The activation chemistry can run backward experimentally.

primary_references

[sambon-2022-tpk1] Product inhibition of mammalian thiamine pyrophosphokinase is an important mechanism for maintaining thiamine diphosphate homeostasis (2022). https://doi.org/10.1016/j.bbagen.2021.130071 DOI: 10.1016/j.bbagen.2021.130071

tissue_or_cell_type

Recombinant enzyme

Thiamine: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 373–386

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant mouse TPK1; forward and reverse reactions. · source_derived_draft · unverified_draft

### b1-mouse-tpk1-reverse-reaction Purified mouse TPK1 formed ATP and thiamine from ThDP plus AMP under high-AMP, magnesium-containing conditions. Condition category: normal nutrient_topic: Thiamine research collection; topical membership is not evidence of a direct dietary effect. plain_language: The activation chemistry can run backward experimentally. organism: Mus musculus tissue_or_cell_type: Recombinant enzyme experimental_model: Purified recombinant mouse TPK1; forward and reverse reactions. limitations: High AMP/Mg requirements do not establish meaningful reverse flux in humans. cross_nutrient: Mg dependence remains distinct from physiological net reaction direction. evidence_spans: [{"source_document": "artifacts/thiamine_transport_sources/sambon-2022-tpk1-source-record.json", "source_field": "resultList.result[0].abstractText", "start_char": 0, "end_char": 1689}] evidence_locator: Reaction definition and sections 2.2 and 3.3 evidence-scope: Recombinant enzyme [sambon-2022-tpk1] Product inhibition of mammalian thiamine pyrophosphokinase is an important mechanism for maintaining thiamine diphosphate homeostasis (2022). https://doi.org/10.1016/j.bbagen.2021.130071 DOI: 10.1016/j.bbagen.2021.130071

evidence_span

{"source_cache": "artifacts/hbot-research/15642322.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e3bc035a17e4e19dd92d4fadb1a79f8e3801619dac24fb91dcf985728afaf995", "start_char": 0, "end_char": 2646, "text_sha256": "e3bc035a17e4e19dd92d4fadb1a79f8e3801619dac24fb91dcf985728afaf995"}

experimental_model

Cultured human lens epithelial cells exposed to extreme hyperbaric oxygen with enzyme assays and real-time PCR

exposure

99% oxygen at 50 atmospheres for 3 hours, then normal culture for up to 11 days

limitations

Fifty atmospheres is an extreme experimental exposure far above therapy, chosen to probe which defences matter. The selenoenzyme result is the informative part; the pressure is not clinically relevant.

nutrient_topic

Hyperbaric oxygen research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. · Hyperbaric oxygen therapy

organism

Human cells

plain_language

The damage landed on the mitochondria, and the cell could not make up the energy by fermenting.

primary_references

[hbot-p15642322] Thioredoxin reductase may be essential for the normal growth of hyperbaric oxygen-treated human lens epithelial cells. (2004). https://pubmed.ncbi.nlm.nih.gov/15642322/ DOI: 10.1016/j.exer.2004.07.001

tissue_or_cell_type

Lens epithelium

Hyperbaric oxygen: the exposure, its reactive species, the signals they carry, and the nutrient-dependent enzymes that handle them (2026-09-19) · lines 413–424

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cultured human lens epithelial cells exposed to extreme hyperbaric oxygen with enzyme assays and real-time PCR · source_derived_draft · unverified_draft

### hbot-mito-damage-and-atp Cell death appeared to be caused by loss of ATP, with a 31% decrease immediately after exposure despite a 46% increase in lactate production, and damage occurred primarily in the mitochondria rather than the cytoplasm. Condition category: normal nutrient_topic: Hyperbaric oxygen research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. plain_language: The damage landed on the mitochondria, and the cell could not make up the energy by fermenting. organism: Human cells tissue_or_cell_type: Lens epithelium experimental_model: Cultured human lens epithelial cells exposed to extreme hyperbaric oxygen with enzyme assays and real-time PCR limitations: Fifty atmospheres is an extreme experimental exposure far above therapy, chosen to probe which defences matter. The selenoenzyme result is the informative part; the pressure is not clinically relevant. exposure: 99% oxygen at 50 atmospheres for 3 hours, then normal culture for up to 11 days evidence_span: {"source_cache": "artifacts/hbot-research/15642322.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e3bc035a17e4e19dd92d4fadb1a79f8e3801619dac24fb91dcf985728afaf995", "start_char": 0, "end_char": 2646, "text_sha256": "e3bc035a17e4e19dd92d4fadb1a79f8e3801619dac24fb91dcf985728afaf995"} [hbot-p15642322] Thioredoxin reductase may be essential for the normal growth of hyperbaric oxygen-treated human lens epithelial cells. (2004). https://pubmed.ncbi.nlm.nih.gov/15642322/ DOI: 10.1016/j.exer.2004.07.001

evidence_access

Primary full text

experimental_model

Candida membrane-permeability assay; ATP release followed over time.

limitations

ATP leakage indicates microbial membrane damage, not increased host ATP production.

nutrient_topic

Fulvic acid collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Fulvic acid (heterogeneous humic fraction)

plain_language

Cell contents escaped after membrane injury.

primary_references

Carbohydrate Derived Fulvic Acid: An in vitro Investigation of a Novel Membrane Active Antiseptic Agent Against Candida albicans Biofilms. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22479260/ · DOI 10.3389/fmicb.2012.00116

Fulvic acid: mixture identity, mineral chemistry, signaling and cross-nutrient mechanisms (2026-09-19) · lines 132–138

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Candida membrane-permeability assay; ATP release followed over time. · source_derived_draft · unverified_draft

## fulvic-acid-fungal-atp Cell contents escaped after membrane injury. CHD-FA exposure caused extracellular ATP leakage from Candida cells. Model: Candida membrane-permeability assay; ATP release followed over time. Limitations: ATP leakage indicates microbial membrane damage, not increased host ATP production. Evidence access: Primary full text Carbohydrate Derived Fulvic Acid: An in vitro Investigation of a Novel Membrane Active Antiseptic Agent Against Candida albicans Biofilms. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22479260/ · DOI 10.3389/fmicb.2012.00116

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/iron-research/30660387.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ea84d16e2c32450b285c269acb4a5343a8af27b49d8d1827afd3ad1961b8a61e", "start_char": 0, "end_char": 1625, "text_sha256": "ea84d16e2c32450b285c269acb4a5343a8af27b49d8d1827afd3ad1961b8a61e"}

experimental_model

Patient-derived cell biochemistry and variant structural analysis

exposure

Compound-heterozygous GLRX5 variants

limitations

One patient; reduced succinyl-CoA contribution to ALAS2 dysfunction was proposed, not definitively isolated.

nutrient_topic

Iron research collection; topical membership is not evidence of a direct dietary effect. · Iron

organism

Human GLRX5-deficient patient

plain_language

The defect extended beyond red-cell pigment to mitochondrial energy handling.

primary_references

[iron-p30660387] GLRX5 mutations impair heme biosynthetic enzymes ALA synthase 2 and ferrochelatase in Human congenital sideroblastic anemia. (2019). https://pubmed.ncbi.nlm.nih.gov/30660387/ DOI: 10.1016/j.ymgme.2018.12.012

tissue_or_cell_type

Lymphoblastoid and CD34-positive cells

trigger_kind

machinery_impairment Imported condition classification; unverified.

Iron: absorption, trafficking, iron-dependent enzymes and nutrient interactions (2026-09-17) · lines 1096–1107

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Patient-derived cell biochemistry and variant structural analysis · source_derived_draft · unverified_draft

### iron-glrx5-energy Patient-derived cells showed reduced glutathione and aconitase activity, damaged/depleted mitochondrial DNA, lower complex I/IV activities and lower ATP content. Condition category: machinery_impairment nutrient_topic: Iron research collection; topical membership is not evidence of a direct dietary effect. plain_language: The defect extended beyond red-cell pigment to mitochondrial energy handling. organism: Human GLRX5-deficient patient tissue_or_cell_type: Lymphoblastoid and CD34-positive cells experimental_model: Patient-derived cell biochemistry and variant structural analysis limitations: One patient; reduced succinyl-CoA contribution to ALAS2 dysfunction was proposed, not definitively isolated. exposure: Compound-heterozygous GLRX5 variants evidence_span: {"source_cache": "artifacts/iron-research/30660387.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ea84d16e2c32450b285c269acb4a5343a8af27b49d8d1827afd3ad1961b8a61e", "start_char": 0, "end_char": 1625, "text_sha256": "ea84d16e2c32450b285c269acb4a5343a8af27b49d8d1827afd3ad1961b8a61e"} [iron-p30660387] GLRX5 mutations impair heme biosynthetic enzymes ALA synthase 2 and ferrochelatase in Human congenital sideroblastic anemia. (2019). https://pubmed.ncbi.nlm.nih.gov/30660387/ DOI: 10.1016/j.ymgme.2018.12.012

cross_nutrient

false

experimental_model

Recombinant human PPCS, PPCDC and COASY expressed in Escherichia coli; coupled enzyme assays and HPLC reconstitution

exposure

1 mM ATP versus 1 mM CTP, with 1.5 mM phosphopantothenate and 5 mM cysteine; 37°C.

limitations

Reported relative assay efficiency, not a universal kinetic constant; the paper contrasts the stronger CTP preference of E. coli PPCS.

nutrient_topic

Pantothenic acid (vitamin B5) research collection; topical membership is not evidence of a direct dietary effect. · Pantothenate (vitamin B5)

organism

Homo sapiens

plain_language

Human PPCS favors ATP; bacterial nucleotide preferences should not be substituted for the human result.

primary_references

[b5-bio-daugherty2002] Complete reconstitution of the human coenzyme A biosynthetic pathway via comparative genomics. (2002). https://pubmed.ncbi.nlm.nih.gov/11923312/ DOI: 10.1074/jbc.m201708200

tissue_or_cell_type

Purified recombinant protein; no intact tissue

Pantothenic acid (vitamin B5): coenzyme A, deficiency and nutrient interactions (2026-09-17) · lines 535–546

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human PPCS, PPCDC and COASY expressed in Escherichia coli; coupled enzyme assays and HPLC reconstitution · source_derived_draft · unverified_draft

### b5-bio-ppcs-atp-preference Under the reported coupled-assay conditions, human PPCS activated substrate with ATP about four times more efficiently than with CTP. Condition category: normal nutrient_topic: Pantothenic acid (vitamin B5) research collection; topical membership is not evidence of a direct dietary effect. plain_language: Human PPCS favors ATP; bacterial nucleotide preferences should not be substituted for the human result. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Recombinant human PPCS, PPCDC and COASY expressed in Escherichia coli; coupled enzyme assays and HPLC reconstitution limitations: Reported relative assay efficiency, not a universal kinetic constant; the paper contrasts the stronger CTP preference of E. coli PPCS. exposure: 1 mM ATP versus 1 mM CTP, with 1.5 mM phosphopantothenate and 5 mM cysteine; 37°C. cross_nutrient: false [b5-bio-daugherty2002] Complete reconstitution of the human coenzyme A biosynthetic pathway via comparative genomics. (2002). https://pubmed.ncbi.nlm.nih.gov/11923312/ DOI: 10.1074/jbc.m201708200

evidence_span

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experimental_model

Cryo-EM of endogenous and recombinant human ACC1 filaments

exposure

Inactive substrate-containing and dephosphorylated/citrate-treated states

limitations

Filament presence alone does not mean enzyme activation; the paper resolved both active and inactive arrangements.

nutrient_topic

Biotin research collection; topical membership is not evidence of a direct dietary effect. · Biotin

organism

Homo sapiens

plain_language

ACC1 makes a building block used in fatty-acid synthesis.

primary_references

[b7-p39383219] Filament structures unveil the dynamic organization of human acetyl-CoA carboxylase. (2024). https://pubmed.ncbi.nlm.nih.gov/39383219/ DOI: 10.1126/sciadv.ado4880

tissue_or_cell_type

Purified human ACC1

Biotin: carboxylases, recycling, deficiency and nutrient interactions (2026-09-17) · lines 637–648

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cryo-EM of endogenous and recombinant human ACC1 filaments · source_derived_draft · unverified_draft

### b7-acc1-reaction Human ACC1 uses biotin-dependent carboxylation of acetyl-CoA to generate malonyl-CoA. Condition category: normal nutrient_topic: Biotin research collection; topical membership is not evidence of a direct dietary effect. plain_language: ACC1 makes a building block used in fatty-acid synthesis. organism: Homo sapiens tissue_or_cell_type: Purified human ACC1 experimental_model: Cryo-EM of endogenous and recombinant human ACC1 filaments limitations: Filament presence alone does not mean enzyme activation; the paper resolved both active and inactive arrangements. exposure: Inactive substrate-containing and dephosphorylated/citrate-treated states evidence_span: {"source_cache": "artifacts/biotin-research/39383219.fulltext.txt", "locator": "Exact primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5f7d3cd6a5865a03b8dc9c510f60249ee2c9f6516773780e5d7b4aef0a9b2db8", "start_char": 0, "end_char": 309, "text_sha256": "b094342ce091c8f919d065311ecd04ddd0c6b9b2824ba8adedd5768424a81a71"} [b7-p39383219] Filament structures unveil the dynamic organization of human acetyl-CoA carboxylase. (2024). https://pubmed.ncbi.nlm.nih.gov/39383219/ DOI: 10.1126/sciadv.ado4880

evidence_span

{"source_cache": "artifacts/biotin-research/19236960.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "bedd791235b10ff5942ef7177b54bca5b2243883da02fb24572691aaf5975be5", "start_char": 0, "end_char": 896, "text_sha256": "bedd791235b10ff5942ef7177b54bca5b2243883da02fb24572691aaf5975be5"}

experimental_model

Steady-state kinetics of purified recombinant human ACC2; LC-MS/MS malonyl-CoA assay

exposure

Bicarbonate, ATP, acetyl-CoA and citrate concentration matrices

limitations

Kinetic constants are assay properties; they do not define a dietary biotin or B5 threshold.

nutrient_topic

Biotin research collection; topical membership is not evidence of a direct dietary effect. · Biotin

organism

Homo sapiens

plain_language

Citrate affects both enzyme speed and effective substrate use.

primary_references

[b7-p19236960] Characterization of recombinant human acetyl-CoA carboxylase-2 steady-state kinetics. (2009). https://pubmed.ncbi.nlm.nih.gov/19236960/ DOI: 10.1016/j.bbapap.2009.02.004

tissue_or_cell_type

Purified human ACC2

Biotin: carboxylases, recycling, deficiency and nutrient interactions (2026-09-17) · lines 689–700

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Steady-state kinetics of purified recombinant human ACC2; LC-MS/MS malonyl-CoA assay · source_derived_draft · unverified_draft

### b7-acc2-citrate Citrate increased recombinant human ACC2 kcat and kcat/Km for ATP and acetyl-CoA. Condition category: normal nutrient_topic: Biotin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Citrate affects both enzyme speed and effective substrate use. organism: Homo sapiens tissue_or_cell_type: Purified human ACC2 experimental_model: Steady-state kinetics of purified recombinant human ACC2; LC-MS/MS malonyl-CoA assay limitations: Kinetic constants are assay properties; they do not define a dietary biotin or B5 threshold. exposure: Bicarbonate, ATP, acetyl-CoA and citrate concentration matrices evidence_span: {"source_cache": "artifacts/biotin-research/19236960.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "bedd791235b10ff5942ef7177b54bca5b2243883da02fb24572691aaf5975be5", "start_char": 0, "end_char": 896, "text_sha256": "bedd791235b10ff5942ef7177b54bca5b2243883da02fb24572691aaf5975be5"} [b7-p19236960] Characterization of recombinant human acetyl-CoA carboxylase-2 steady-state kinetics. (2009). https://pubmed.ncbi.nlm.nih.gov/19236960/ DOI: 10.1016/j.bbapap.2009.02.004

evidence_span

{"source_cache": "artifacts/biotin-research/19236960.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "bedd791235b10ff5942ef7177b54bca5b2243883da02fb24572691aaf5975be5", "start_char": 0, "end_char": 896, "text_sha256": "bedd791235b10ff5942ef7177b54bca5b2243883da02fb24572691aaf5975be5"}

experimental_model

Steady-state kinetics of purified recombinant human ACC2; LC-MS/MS malonyl-CoA assay

exposure

Bicarbonate, ATP, acetyl-CoA and citrate concentration matrices

limitations

Kinetic constants are assay properties; they do not define a dietary biotin or B5 threshold.

nutrient_topic

Biotin research collection; topical membership is not evidence of a direct dietary effect. · Biotin

organism

Homo sapiens

plain_language

ACC2 makes the same carbon product as ACC1 but serves a distinct enzyme context.

primary_references

[b7-p19236960] Characterization of recombinant human acetyl-CoA carboxylase-2 steady-state kinetics. (2009). https://pubmed.ncbi.nlm.nih.gov/19236960/ DOI: 10.1016/j.bbapap.2009.02.004

tissue_or_cell_type

Purified human ACC2

Biotin: carboxylases, recycling, deficiency and nutrient interactions (2026-09-17) · lines 676–687

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Steady-state kinetics of purified recombinant human ACC2; LC-MS/MS malonyl-CoA assay · source_derived_draft · unverified_draft

### b7-acc2-reaction Purified human ACC2 formed malonyl-CoA from acetyl-CoA in assays varying bicarbonate and ATP. Condition category: normal nutrient_topic: Biotin research collection; topical membership is not evidence of a direct dietary effect. plain_language: ACC2 makes the same carbon product as ACC1 but serves a distinct enzyme context. organism: Homo sapiens tissue_or_cell_type: Purified human ACC2 experimental_model: Steady-state kinetics of purified recombinant human ACC2; LC-MS/MS malonyl-CoA assay limitations: Kinetic constants are assay properties; they do not define a dietary biotin or B5 threshold. exposure: Bicarbonate, ATP, acetyl-CoA and citrate concentration matrices evidence_span: {"source_cache": "artifacts/biotin-research/19236960.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "bedd791235b10ff5942ef7177b54bca5b2243883da02fb24572691aaf5975be5", "start_char": 0, "end_char": 896, "text_sha256": "bedd791235b10ff5942ef7177b54bca5b2243883da02fb24572691aaf5975be5"} [b7-p19236960] Characterization of recombinant human acetyl-CoA carboxylase-2 steady-state kinetics. (2009). https://pubmed.ncbi.nlm.nih.gov/19236960/ DOI: 10.1016/j.bbapap.2009.02.004

evidence_span

{"source_cache": "artifacts/biotin-research/19740736.fulltext.txt", "locator": "Exact primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d785655901465bc9798378986d954b87111e3bd73d6877d9d60ae3d95cac0a37", "start_char": 2587, "end_char": 3080, "text_sha256": "fa0ec838311a45e8ccebf38a73e340a46417eae6bc300064c1165a4a0b711889"}

experimental_model

Purified full-length and residue-58 human HLCS isoforms expressed in E. coli

exposure

Biotin/ATP activation and single-turnover biotin transfer

limitations

Minimal-substrate kinetics do not prove a universal tissue allocation hierarchy; expression host is not the protein species.

nutrient_topic

Biotin research collection; topical membership is not evidence of a direct dietary effect. · Biotin

organism

Homo sapiens

plain_language

Biotin must first be activated before it can be attached to an enzyme.

primary_references

[b7-p19740736] Distinct amino termini of two human HCS isoforms influence biotin acceptor substrate recognition. (2009). https://pubmed.ncbi.nlm.nih.gov/19740736/ DOI: 10.1074/jbc.m109.046201

tissue_or_cell_type

Purified proteins and minimal biotin-accepting substrate

Biotin: carboxylases, recycling, deficiency and nutrient interactions (2026-09-17) · lines 351–362

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified full-length and residue-58 human HLCS isoforms expressed in E. coli · source_derived_draft · unverified_draft

### b7-hlcs-adenylation HLCS activates biotin with ATP to form enzyme-bound biotinyl-5-prime-AMP before transferring biotin to a carboxylase acceptor. Condition category: normal nutrient_topic: Biotin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Biotin must first be activated before it can be attached to an enzyme. organism: Homo sapiens tissue_or_cell_type: Purified proteins and minimal biotin-accepting substrate experimental_model: Purified full-length and residue-58 human HLCS isoforms expressed in E. coli limitations: Minimal-substrate kinetics do not prove a universal tissue allocation hierarchy; expression host is not the protein species. exposure: Biotin/ATP activation and single-turnover biotin transfer evidence_span: {"source_cache": "artifacts/biotin-research/19740736.fulltext.txt", "locator": "Exact primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d785655901465bc9798378986d954b87111e3bd73d6877d9d60ae3d95cac0a37", "start_char": 2587, "end_char": 3080, "text_sha256": "fa0ec838311a45e8ccebf38a73e340a46417eae6bc300064c1165a4a0b711889"} [b7-p19740736] Distinct amino termini of two human HCS isoforms influence biotin acceptor substrate recognition. (2009). https://pubmed.ncbi.nlm.nih.gov/19740736/ DOI: 10.1074/jbc.m109.046201

evidence_span

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experimental_model

Time-resolved cryo-EM and biochemical analysis of human PC

exposure

Pyruvate, ATP and acetyl-CoA catalytic conditions

limitations

Purified-enzyme regulation is not evidence that consuming B5 or biotin stimulates this pathway in every tissue.

nutrient_topic

Biotin research collection; topical membership is not evidence of a direct dietary effect. · Biotin

organism

Homo sapiens

plain_language

The biotin-carrying enzyme coordinates two reaction stations rather than performing one isolated chemical step.

primary_references

[b7-p36283412] Mechanistic insight into allosteric activation of human pyruvate carboxylase by acetyl-CoA. (2022). https://pubmed.ncbi.nlm.nih.gov/36283412/ DOI: 10.1016/j.molcel.2022.09.033

tissue_or_cell_type

Purified human pyruvate carboxylase

Biotin: carboxylases, recycling, deficiency and nutrient interactions (2026-09-17) · lines 572–583

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Time-resolved cryo-EM and biochemical analysis of human PC · source_derived_draft · unverified_draft

### b7-pc-communication Acetyl-CoA-dependent stabilization of human PC triggered ATP hydrolysis and communication between its two reaction centers. Condition category: normal nutrient_topic: Biotin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The biotin-carrying enzyme coordinates two reaction stations rather than performing one isolated chemical step. organism: Homo sapiens tissue_or_cell_type: Purified human pyruvate carboxylase experimental_model: Time-resolved cryo-EM and biochemical analysis of human PC limitations: Purified-enzyme regulation is not evidence that consuming B5 or biotin stimulates this pathway in every tissue. exposure: Pyruvate, ATP and acetyl-CoA catalytic conditions evidence_span: {"source_cache": "artifacts/biotin-research/36283412.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2a5fb8ec1c27e243b8c8ba158f2c58ab1592d9895eecf16438175b2a5778de15", "start_char": 0, "end_char": 1060, "text_sha256": "2a5fb8ec1c27e243b8c8ba158f2c58ab1592d9895eecf16438175b2a5778de15"} [b7-p36283412] Mechanistic insight into allosteric activation of human pyruvate carboxylase by acetyl-CoA. (2022). https://pubmed.ncbi.nlm.nih.gov/36283412/ DOI: 10.1016/j.molcel.2022.09.033

evidence_span

{"source_cache": "artifacts/biotin-research/36283412.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2a5fb8ec1c27e243b8c8ba158f2c58ab1592d9895eecf16438175b2a5778de15", "start_char": 0, "end_char": 1060, "text_sha256": "2a5fb8ec1c27e243b8c8ba158f2c58ab1592d9895eecf16438175b2a5778de15"}

experimental_model

Time-resolved cryo-EM and biochemical analysis of human PC

exposure

Pyruvate, ATP and acetyl-CoA catalytic conditions

limitations

Purified-enzyme regulation is not evidence that consuming B5 or biotin stimulates this pathway in every tissue.

nutrient_topic

Biotin research collection; topical membership is not evidence of a direct dietary effect. · Biotin

organism

Homo sapiens

plain_language

PC replenishes a key carbon molecule used by several metabolic pathways.

primary_references

[b7-p36283412] Mechanistic insight into allosteric activation of human pyruvate carboxylase by acetyl-CoA. (2022). https://pubmed.ncbi.nlm.nih.gov/36283412/ DOI: 10.1016/j.molcel.2022.09.033

tissue_or_cell_type

Purified human pyruvate carboxylase

Biotin: carboxylases, recycling, deficiency and nutrient interactions (2026-09-17) · lines 546–557

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Time-resolved cryo-EM and biochemical analysis of human PC · source_derived_draft · unverified_draft

### b7-pc-reaction Human PC catalyzes two-step pyruvate carboxylation to oxaloacetate. Condition category: normal nutrient_topic: Biotin research collection; topical membership is not evidence of a direct dietary effect. plain_language: PC replenishes a key carbon molecule used by several metabolic pathways. organism: Homo sapiens tissue_or_cell_type: Purified human pyruvate carboxylase experimental_model: Time-resolved cryo-EM and biochemical analysis of human PC limitations: Purified-enzyme regulation is not evidence that consuming B5 or biotin stimulates this pathway in every tissue. exposure: Pyruvate, ATP and acetyl-CoA catalytic conditions evidence_span: {"source_cache": "artifacts/biotin-research/36283412.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2a5fb8ec1c27e243b8c8ba158f2c58ab1592d9895eecf16438175b2a5778de15", "start_char": 0, "end_char": 1060, "text_sha256": "2a5fb8ec1c27e243b8c8ba158f2c58ab1592d9895eecf16438175b2a5778de15"} [b7-p36283412] Mechanistic insight into allosteric activation of human pyruvate carboxylase by acetyl-CoA. (2022). https://pubmed.ncbi.nlm.nih.gov/36283412/ DOI: 10.1016/j.molcel.2022.09.033

evidence_span

{"source_cache": "artifacts/biotin-research/20725044.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "825bf28b9f35a8d45f8d08d883fa200bd430336b0558db035ce4fd1c5ef19053", "start_char": 0, "end_char": 1921, "text_sha256": "825bf28b9f35a8d45f8d08d883fa200bd430336b0558db035ce4fd1c5ef19053"}

experimental_model

Bacterial PCC crystallography and separate 15-angstrom human PCC cryo-EM reconstruction

exposure

Structural analysis

limitations

Atomic bacterial positions are not high-resolution human measurements. Human cryo-EM establishes the overall assembly at lower resolution.

nutrient_topic

Biotin research collection; topical membership is not evidence of a direct dietary effect. · Biotin

organism

Homo sapiens; bacterial PCC comparison

plain_language

The alpha subunit handles biotin loading with the carboxyl group and carries that group onward.

primary_references

[b7-p20725044] Crystal structure of the alpha(6)beta(6) holoenzyme of propionyl-coenzyme A carboxylase. (2010). https://pubmed.ncbi.nlm.nih.gov/20725044/ DOI: 10.1038/nature09302

tissue_or_cell_type

Purified PCC complexes

Biotin: carboxylases, recycling, deficiency and nutrient interactions (2026-09-17) · lines 598–609

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Bacterial PCC crystallography and separate 15-angstrom human PCC cryo-EM reconstruction · source_derived_draft · unverified_draft

### b7-pcc-pcca PCCA contains the biotin-carboxylase and biotin-carrier domains of human PCC. Condition category: normal nutrient_topic: Biotin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The alpha subunit handles biotin loading with the carboxyl group and carries that group onward. organism: Homo sapiens; bacterial PCC comparison tissue_or_cell_type: Purified PCC complexes experimental_model: Bacterial PCC crystallography and separate 15-angstrom human PCC cryo-EM reconstruction limitations: Atomic bacterial positions are not high-resolution human measurements. Human cryo-EM establishes the overall assembly at lower resolution. exposure: Structural analysis evidence_span: {"source_cache": "artifacts/biotin-research/20725044.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "825bf28b9f35a8d45f8d08d883fa200bd430336b0558db035ce4fd1c5ef19053", "start_char": 0, "end_char": 1921, "text_sha256": "825bf28b9f35a8d45f8d08d883fa200bd430336b0558db035ce4fd1c5ef19053"} [b7-p20725044] Crystal structure of the alpha(6)beta(6) holoenzyme of propionyl-coenzyme A carboxylase. (2010). https://pubmed.ncbi.nlm.nih.gov/20725044/ DOI: 10.1038/nature09302

evidence_access

Primary full text

experimental_model

Human IARS1/tRNA assays and primary human fibroblasts.

limitations

Reaction role is distinct from the study-specific shortage substitution experiments.

nutrient_topic

L-Isoleucine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Isoleucine

plain_language

A charging enzyme links free isoleucine to protein synthesis.

primary_references

Isoleucine-to-valine substitutions support cellular physiology during isoleucine deprivation. · 2025 · https://pubmed.ncbi.nlm.nih.gov/39657787/ · DOI 10.1093/nar/gkae1184

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 106–112

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human IARS1/tRNA assays and primary human fibroblasts. · source_derived_draft · unverified_draft

## isoleucine-iars-charging A charging enzyme links free isoleucine to protein synthesis. Human IARS1 aminoacylates tRNA-Ile with isoleucine for cytosolic translation; purified-protein aminoacylation assays were used to study this reaction. Model: Human IARS1/tRNA assays and primary human fibroblasts. Limitations: Reaction role is distinct from the study-specific shortage substitution experiments. Evidence access: Primary full text Isoleucine-to-valine substitutions support cellular physiology during isoleucine deprivation. · 2025 · https://pubmed.ncbi.nlm.nih.gov/39657787/ · DOI 10.1093/nar/gkae1184

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human patient lymphocytes and IARS2-knockdown HEK293T cells with genetic rescue.

limitations

No dietary isoleucine rescue was demonstrated. Protein replacement is not equivalent to substrate supplementation.

nutrient_topic

L-Isoleucine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Isoleucine

plain_language

Mitochondria need their own isoleucine-charging machinery.

primary_references

IARS2 mutations lead to Leigh syndrome with a combined oxidative phosphorylation deficiency. · 2024 · https://pubmed.ncbi.nlm.nih.gov/39169373/ · DOI 10.1186/s13023-024-03310-x

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 154–160

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human patient lymphocytes and IARS2-knockdown HEK293T cells with genetic rescue. · source_derived_draft · unverified_draft

## isoleucine-iars2-respiration Mitochondria need their own isoleucine-charging machinery. IARS2 knockdown and patient variants impaired respiratory complexes I and III; wild-type, but not tested mutant, IARS2 rescued respiration and ATP in knockdown cells. Model: Human patient lymphocytes and IARS2-knockdown HEK293T cells with genetic rescue. Limitations: No dietary isoleucine rescue was demonstrated. Protein replacement is not equivalent to substrate supplementation. Evidence access: Primary abstract IARS2 mutations lead to Leigh syndrome with a combined oxidative phosphorylation deficiency. · 2024 · https://pubmed.ncbi.nlm.nih.gov/39169373/ · DOI 10.1186/s13023-024-03310-x

cross_nutrient

Magnesium availability supports vitamin B1 activation or cofactor use in the specified preparation; this does not establish a dietary threshold or universal treatment failure.

experimental_model

Purified recombinant mouse TPK1; forward and reverse reaction kinetics.

limitations

ATP concentration shifted the optimum; in vitro values are not intake targets.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Mus musculus

plain_language

More magnesium did not continuously increase B1 activation in this assay.

primary_references

[sambon-2022-tpk1] Product inhibition of mammalian thiamine pyrophosphokinase is an important mechanism for maintaining thiamine diphosphate homeostasis (2022). https://doi.org/10.1016/j.bbagen.2021.130071 DOI: 10.1016/j.bbagen.2021.130071

tissue_or_cell_type

Purified recombinant enzyme

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 517–527

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant mouse TPK1; forward and reverse reaction kinetics. · source_derived_draft · unverified_draft

### mg-mouse-tpk-nonmonotonic Recombinant mouse TPK1 showed an Mg optimum followed by inhibition as Mg was increased at fixed ATP. Condition category: normal nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: More magnesium did not continuously increase B1 activation in this assay. organism: Mus musculus tissue_or_cell_type: Purified recombinant enzyme experimental_model: Purified recombinant mouse TPK1; forward and reverse reaction kinetics. limitations: ATP concentration shifted the optimum; in vitro values are not intake targets. cross_nutrient: Magnesium availability supports vitamin B1 activation or cofactor use in the specified preparation; this does not establish a dietary threshold or universal treatment failure. [sambon-2022-tpk1] Product inhibition of mammalian thiamine pyrophosphokinase is an important mechanism for maintaining thiamine diphosphate homeostasis (2022). https://doi.org/10.1016/j.bbagen.2021.130071 DOI: 10.1016/j.bbagen.2021.130071

cross_nutrient

Magnesium-dependent ATP chemistry is coupled to sodium and potassium handling by the pump; serum magnesium is not the enzyme-site concentration.

experimental_model

Shark rectal-gland pump membrane fragments; stopped-flow RH421 fluorescence under Na-rich conditions.

limitations

Conclusion concerns E1-ATP; other pump conformations or Mg sites can behave differently.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Shark

plain_language

The ATP-associated magnesium supports phosphorylation; free ATP can compete for that magnesium.

primary_references

[pilotelle-2009-nka] Mechanism of Mg2+ binding in the Na+,K+-ATPase (2009). https://pmc.ncbi.nlm.nih.gov/articles/PMC2711396/ DOI: 10.1016/j.bpj.2009.01.042

tissue_or_cell_type

Rectal-gland enzyme membrane fragments

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 795–805

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Shark rectal-gland pump membrane fragments; stopped-flow RH421 fluorescence under Na-rich conditions. · source_derived_draft · unverified_draft

### mg-nka-atp-dominates-mg-binding Shark-pump kinetic fits assigned E1-ATP Mg affinity mainly to ATP coordination, after accounting for free ATP competition. Condition category: normal nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: The ATP-associated magnesium supports phosphorylation; free ATP can compete for that magnesium. organism: Shark tissue_or_cell_type: Rectal-gland enzyme membrane fragments experimental_model: Shark rectal-gland pump membrane fragments; stopped-flow RH421 fluorescence under Na-rich conditions. limitations: Conclusion concerns E1-ATP; other pump conformations or Mg sites can behave differently. cross_nutrient: Magnesium-dependent ATP chemistry is coupled to sodium and potassium handling by the pump; serum magnesium is not the enzyme-site concentration. [pilotelle-2009-nka] Mechanism of Mg2+ binding in the Na+,K+-ATPase (2009). https://pmc.ncbi.nlm.nih.gov/articles/PMC2711396/ DOI: 10.1016/j.bpj.2009.01.042

cross_nutrient

Magnesium-dependent ATP chemistry is coupled to sodium and potassium handling by the pump; serum magnesium is not the enzyme-site concentration.

experimental_model

Partially purified pig-kidney pump; sodium-22 occlusion, EGCg quench-flow, ATP/Mg manipulations.

limitations

Equilibrium and Na-ATPase conditions; full Na/K exchange and systemic Mg deficiency were not tested.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Sus scrofa

plain_language

Magnesium can oppose sodium binding as well as support ATP chemistry.

primary_references

[faraj-2023-nka] Measurements of Na+-occluded intermediates during the catalytic cycle of the Na+/K+-ATPase provide novel insights into the mechanism of Na+ transport (2023). https://pmc.ncbi.nlm.nih.gov/articles/PMC9860123/ DOI: 10.1016/j.jbc.2022.102811

tissue_or_cell_type

Kidney enzyme membrane preparation

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 857–867

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Partially purified pig-kidney pump; sodium-22 occlusion, EGCg quench-flow, ATP/Mg manipulations. · source_derived_draft · unverified_draft

### mg-nka-free-mg-sodium-occlusion Free Mg reduced apparent sodium affinity in pig-kidney pump sodium-22 occlusion experiments. Condition category: normal nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Magnesium can oppose sodium binding as well as support ATP chemistry. organism: Sus scrofa tissue_or_cell_type: Kidney enzyme membrane preparation experimental_model: Partially purified pig-kidney pump; sodium-22 occlusion, EGCg quench-flow, ATP/Mg manipulations. limitations: Equilibrium and Na-ATPase conditions; full Na/K exchange and systemic Mg deficiency were not tested. cross_nutrient: Magnesium-dependent ATP chemistry is coupled to sodium and potassium handling by the pump; serum magnesium is not the enzyme-site concentration. [faraj-2023-nka] Measurements of Na+-occluded intermediates during the catalytic cycle of the Na+/K+-ATPase provide novel insights into the mechanism of Na+ transport (2023). https://pmc.ncbi.nlm.nih.gov/articles/PMC9860123/ DOI: 10.1016/j.jbc.2022.102811

cross_nutrient

Magnesium-dependent ATP chemistry is coupled to sodium and potassium handling by the pump; serum magnesium is not the enzyme-site concentration.

experimental_model

Human red cells and resealed ghosts; ATP/Mg loading, ouabain, sodium-24, potassium-42 and gamma-phosphorus-32 ATP.

limitations

This experiment found unequal fluxes but did not itself measure an exact 3:2 ratio.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Homo sapiens

plain_language

The pump moves the two nutrient ions in opposite directions.

primary_references

[garrahan-1967-nka] The stoicheiometry of the sodium pump (1967). https://doi.org/10.1113/jphysiol.1967.sp008297 DOI: 10.1113/jphysiol.1967.sp008297

tissue_or_cell_type

Erythrocytes

transport_direction

Sodium outward; potassium inward.

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 832–843

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human red cells and resealed ghosts; ATP/Mg loading, ouabain, sodium-24, potassium-42 and gamma-phosphorus-32 ATP. · source_derived_draft · unverified_draft

### mg-nka-isotope-opposed-flux Sodium-24 and potassium-42 experiments demonstrated ouabain-sensitive sodium efflux and potassium influx in human red cells. Condition category: normal nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: The pump moves the two nutrient ions in opposite directions. organism: Homo sapiens tissue_or_cell_type: Erythrocytes experimental_model: Human red cells and resealed ghosts; ATP/Mg loading, ouabain, sodium-24, potassium-42 and gamma-phosphorus-32 ATP. limitations: This experiment found unequal fluxes but did not itself measure an exact 3:2 ratio. cross_nutrient: Magnesium-dependent ATP chemistry is coupled to sodium and potassium handling by the pump; serum magnesium is not the enzyme-site concentration. transport_direction: Sodium outward; potassium inward. [garrahan-1967-nka] The stoicheiometry of the sodium pump (1967). https://doi.org/10.1113/jphysiol.1967.sp008297 DOI: 10.1113/jphysiol.1967.sp008297

cross_nutrient

Magnesium-dependent ATP chemistry is coupled to sodium and potassium handling by the pump; serum magnesium is not the enzyme-site concentration.

experimental_model

Pig-kidney Na/K-ATPase rapid-mixing phosphorylation; Na-containing, K-free medium; varied ATP and MgCl2.

limitations

Na-containing, K-free assay; not the full physiological transport cycle.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Sus scrofa

plain_language

Magnesium enables the ATP-driven phosphate-transfer step of the sodium pump.

primary_references

[campos-1992-nka] Effects of magnesium and ATP on pre-steady-state phosphorylation kinetics of the Na+,K(+)-ATPase (1992). https://pubmed.ncbi.nlm.nih.gov/1314673/ DOI: 10.1016/0005-2736(92)90161-e

tissue_or_cell_type

Kidney enzyme

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 771–781

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Pig-kidney Na/K-ATPase rapid-mixing phosphorylation; Na-containing, K-free medium; varied ATP and MgCl2. · source_derived_draft · unverified_draft

### mg-nka-phosphorylation-requirement Pre-steady-state pig-kidney pump experiments identified Mg as an essential activator of ATP-dependent phosphorylation. Condition category: normal nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Magnesium enables the ATP-driven phosphate-transfer step of the sodium pump. organism: Sus scrofa tissue_or_cell_type: Kidney enzyme experimental_model: Pig-kidney Na/K-ATPase rapid-mixing phosphorylation; Na-containing, K-free medium; varied ATP and MgCl2. limitations: Na-containing, K-free assay; not the full physiological transport cycle. cross_nutrient: Magnesium-dependent ATP chemistry is coupled to sodium and potassium handling by the pump; serum magnesium is not the enzyme-site concentration. [campos-1992-nka] Effects of magnesium and ATP on pre-steady-state phosphorylation kinetics of the Na+,K(+)-ATPase (1992). https://pubmed.ncbi.nlm.nih.gov/1314673/ DOI: 10.1016/0005-2736(92)90161-e

cross_nutrient

Magnesium-dependent ATP chemistry is coupled to sodium and potassium handling by the pump; serum magnesium is not the enzyme-site concentration.

experimental_model

Pig-kidney enzyme stopped-flow RH421 fluorescence; sequential ATP then KCl mixing.

limitations

Stopped-flow assay; no dietary or magnesium-depletion intervention.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Sus scrofa

plain_language

Potassium promotes the phosphate-removal part of the pump cycle.

primary_references

[kane-1998-nka] Dephosphorylation kinetics of pig kidney Na+,K+-ATPase (1998). https://pubmed.ncbi.nlm.nih.gov/9521778/ DOI: 10.1021/bi972813e

tissue_or_cell_type

Kidney enzyme

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 807–817

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Pig-kidney enzyme stopped-flow RH421 fluorescence; sequential ATP then KCl mixing. · source_derived_draft · unverified_draft

### mg-nka-potassium-dephosphorylation Adding KCl after ATP phosphorylation accelerated dephosphorylation of pig-kidney Na/K-ATPase. Condition category: normal nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Potassium promotes the phosphate-removal part of the pump cycle. organism: Sus scrofa tissue_or_cell_type: Kidney enzyme experimental_model: Pig-kidney enzyme stopped-flow RH421 fluorescence; sequential ATP then KCl mixing. limitations: Stopped-flow assay; no dietary or magnesium-depletion intervention. cross_nutrient: Magnesium-dependent ATP chemistry is coupled to sodium and potassium handling by the pump; serum magnesium is not the enzyme-site concentration. [kane-1998-nka] Dephosphorylation kinetics of pig kidney Na+,K+-ATPase (1998). https://pubmed.ncbi.nlm.nih.gov/9521778/ DOI: 10.1021/bi972813e

cross_nutrient

Magnesium availability supports vitamin B1 activation or cofactor use in the specified preparation; this does not establish a dietary threshold or universal treatment failure.

experimental_model

Purified recombinant mouse TPK1; forward and reverse reaction kinetics.

limitations

Product inhibition is a separate limit from Mg shortage.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Mus musculus

plain_language

B1 activation has product feedback even when ATP and magnesium are supplied.

primary_references

[sambon-2022-tpk1] Product inhibition of mammalian thiamine pyrophosphokinase is an important mechanism for maintaining thiamine diphosphate homeostasis (2022). https://doi.org/10.1016/j.bbagen.2021.130071 DOI: 10.1016/j.bbagen.2021.130071

tissue_or_cell_type

Purified recombinant enzyme

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 529–539

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant mouse TPK1; forward and reverse reaction kinetics. · source_derived_draft · unverified_draft

### mg-thdp-feedback-on-tpk Accumulated ThDP inhibited the forward reaction of purified mouse TPK1. Condition category: normal nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: B1 activation has product feedback even when ATP and magnesium are supplied. organism: Mus musculus tissue_or_cell_type: Purified recombinant enzyme experimental_model: Purified recombinant mouse TPK1; forward and reverse reaction kinetics. limitations: Product inhibition is a separate limit from Mg shortage. cross_nutrient: Magnesium availability supports vitamin B1 activation or cofactor use in the specified preparation; this does not establish a dietary threshold or universal treatment failure. [sambon-2022-tpk1] Product inhibition of mammalian thiamine pyrophosphokinase is an important mechanism for maintaining thiamine diphosphate homeostasis (2022). https://doi.org/10.1016/j.bbagen.2021.130071 DOI: 10.1016/j.bbagen.2021.130071

cross_nutrient

Magnesium availability supports vitamin B1 activation or cofactor use in the specified preparation; this does not establish a dietary threshold or universal treatment failure.

experimental_model

Purified His-tagged recombinant human TPK1, steady-state kinetics and mutations.

limitations

Total concentrations and speciation must be distinguished; no human Mg cutoff follows.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Homo sapiens

plain_language

The balance between ATP-bound and available magnesium affects activation of B1.

primary_references

[onozuka-2003-tpk1] Steady-state kinetics and mutational studies of recombinant human thiamin pyrophosphokinase (2003). https://pubmed.ncbi.nlm.nih.gov/12953792/ DOI: 10.3177/jnsv.49.156

tissue_or_cell_type

Purified recombinant enzyme

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 493–503

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified His-tagged recombinant human TPK1, steady-state kinetics and mutations. · source_derived_draft · unverified_draft

### mg-tpk1-free-mg-restores-activity Mg2+ in excess over ATP restored human TPK1 activity at low MgATP concentrations compared with a 1:1 total Mg:ATP ratio. Condition category: normal nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: The balance between ATP-bound and available magnesium affects activation of B1. organism: Homo sapiens tissue_or_cell_type: Purified recombinant enzyme experimental_model: Purified His-tagged recombinant human TPK1, steady-state kinetics and mutations. limitations: Total concentrations and speciation must be distinguished; no human Mg cutoff follows. cross_nutrient: Magnesium availability supports vitamin B1 activation or cofactor use in the specified preparation; this does not establish a dietary threshold or universal treatment failure. [onozuka-2003-tpk1] Steady-state kinetics and mutational studies of recombinant human thiamin pyrophosphokinase (2003). https://pubmed.ncbi.nlm.nih.gov/12953792/ DOI: 10.3177/jnsv.49.156

cross_nutrient

Magnesium availability supports vitamin B1 activation or cofactor use in the specified preparation; this does not establish a dietary threshold or universal treatment failure.

experimental_model

Purified His-tagged recombinant human TPK1, steady-state kinetics and mutations.

limitations

Assay chemistry; no clinical response measured.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Homo sapiens

plain_language

The enzyme uses ATP to convert vitamin B1 into its diphosphate cofactor.

primary_references

[onozuka-2003-tpk1] Steady-state kinetics and mutational studies of recombinant human thiamin pyrophosphokinase (2003). https://pubmed.ncbi.nlm.nih.gov/12953792/ DOI: 10.3177/jnsv.49.156

tissue_or_cell_type

Purified recombinant enzyme

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 481–491

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified His-tagged recombinant human TPK1, steady-state kinetics and mutations. · source_derived_draft · unverified_draft

### mg-tpk1-thiamine-to-thdp Recombinant human TPK1 catalyzes thiamine diphosphorylation with ATP and Mg2+. Condition category: normal nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: The enzyme uses ATP to convert vitamin B1 into its diphosphate cofactor. organism: Homo sapiens tissue_or_cell_type: Purified recombinant enzyme experimental_model: Purified His-tagged recombinant human TPK1, steady-state kinetics and mutations. limitations: Assay chemistry; no clinical response measured. cross_nutrient: Magnesium availability supports vitamin B1 activation or cofactor use in the specified preparation; this does not establish a dietary threshold or universal treatment failure. [onozuka-2003-tpk1] Steady-state kinetics and mutational studies of recombinant human thiamin pyrophosphokinase (2003). https://pubmed.ncbi.nlm.nih.gov/12953792/ DOI: 10.3177/jnsv.49.156

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Germ-free mouse colonocytes and ex-vivo substrate addition.

limitations

Germ-free status removes many microbial functions; rescue supports a butyrate contribution without making every change a specific deficiency effect.

nutrient_topic

Butyrate collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Butyrate

plain_language

Removing the microbiota deprived colon cells of an important fuel; adding it back restored respiration.

primary_references

The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21531334/ · DOI 10.1016/j.cmet.2011.02.018

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Butyrate: microbial production, fuel use, signaling and nutrient interactions (2026-09-19) · lines 166–172

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Germ-free mouse colonocytes and ex-vivo substrate addition. · source_derived_draft · unverified_draft

## butyrate-germfree-energy Removing the microbiota deprived colon cells of an important fuel; adding it back restored respiration. Germ-free mouse colonocytes had reduced NADH/NAD+, oxidative phosphorylation and ATP; adding butyrate rescued mitochondrial respiration. Model: Germ-free mouse colonocytes and ex-vivo substrate addition. Limitations: Germ-free status removes many microbial functions; rescue supports a butyrate contribution without making every change a specific deficiency effect. Evidence access: Primary abstract The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21531334/ · DOI 10.1016/j.cmet.2011.02.018

evidence_access

Primary full text

experimental_model

Recombinant enzyme and human gastric cancer cell experiments.

limitations

This is an enzyme connection, not proof that adding L-alanine promotes or inhibits lactylation. Beta-alanine inhibitor findings must not be transferred to L-alanine.

nutrient_topic

L-Alanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Alanine

plain_language

The alanine-handling enzyme also has a separate lactate-driven signaling activity.

primary_references

The alanyl-tRNA synthetase AARS1 moonlights as a lactyltransferase to promote YAP signaling in gastric cancer. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38512451/ · DOI 10.1172/JCI174587

L-Alanine: carbon, nitrogen, protein synthesis and cross-nutrient mechanisms (2026-09-19) · lines 72–78

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Recombinant enzyme and human gastric cancer cell experiments. · source_derived_draft · unverified_draft

## alanine-aars-lactylation The alanine-handling enzyme also has a separate lactate-driven signaling activity. Human AARS1 used lactate and ATP for protein lactylation; the study identified YAP K90 and TEAD1 K108 modification and activation in gastric cancer models. Model: Recombinant enzyme and human gastric cancer cell experiments. Limitations: This is an enzyme connection, not proof that adding L-alanine promotes or inhibits lactylation. Beta-alanine inhibitor findings must not be transferred to L-alanine. Evidence access: Primary full text The alanyl-tRNA synthetase AARS1 moonlights as a lactyltransferase to promote YAP signaling in gastric cancer. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38512451/ · DOI 10.1172/JCI174587

evidence_access

Primary full text

experimental_model

Rat H4IIE cells; acute millimolar alanine exposure.

limitations

Phosphorylation in culture is not proof of clinical benefit or a universal response to dietary alanine.

nutrient_topic

L-Alanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Alanine

plain_language

Alanine metabolism can generate an energy-stress signal in this experimental setting.

primary_references

l-Alanine activates hepatic AMP-activated protein kinase and modulates systemic glucose metabolism. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30190193/ · DOI 10.1016/j.molmet.2018.08.002

L-Alanine: carbon, nitrogen, protein synthesis and cross-nutrient mechanisms (2026-09-19) · lines 248–254

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat H4IIE cells; acute millimolar alanine exposure. · source_derived_draft · unverified_draft

## alanine-ampk-acute Alanine metabolism can generate an energy-stress signal in this experimental setting. Acute alanine treatment increased AMPK and downstream ACC phosphorylation in rat H4IIE liver cells over the tested 0.25–10 mM range. Model: Rat H4IIE cells; acute millimolar alanine exposure. Limitations: Phosphorylation in culture is not proof of clinical benefit or a universal response to dietary alanine. Evidence access: Primary full text l-Alanine activates hepatic AMP-activated protein kinase and modulates systemic glucose metabolism. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30190193/ · DOI 10.1016/j.molmet.2018.08.002

evidence_access

Primary full text

experimental_model

Rat H4IIE experiments; 2–5 mM ammonium chloride comparison.

limitations

Mimicry is not proof that ammonia is the sole mediator of alanine effects or that urea-cycle ATP use accounts for them.

nutrient_topic

L-Alanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Alanine

plain_language

A nitrogen-handling byproduct may contribute to the energy signal.

primary_references

l-Alanine activates hepatic AMP-activated protein kinase and modulates systemic glucose metabolism. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30190193/ · DOI 10.1016/j.molmet.2018.08.002

L-Alanine: carbon, nitrogen, protein synthesis and cross-nutrient mechanisms (2026-09-19) · lines 280–286

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat H4IIE experiments; 2–5 mM ammonium chloride comparison. · source_derived_draft · unverified_draft

## alanine-ampk-ammonia A nitrogen-handling byproduct may contribute to the energy signal. Ammonium chloride exposure reproduced increases in AMP/ATP and AMPK/ACC phosphorylation, and pyruvate attenuated these responses. Model: Rat H4IIE experiments; 2–5 mM ammonium chloride comparison. Limitations: Mimicry is not proof that ammonia is the sole mediator of alanine effects or that urea-cycle ATP use accounts for them. Evidence access: Primary full text l-Alanine activates hepatic AMP-activated protein kinase and modulates systemic glucose metabolism. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30190193/ · DOI 10.1016/j.molmet.2018.08.002

evidence_access

Primary full text

experimental_model

Rat H4IIE nutrient-addition experiments.

limitations

A biochemical rescue does not establish a supplement combination for humans.

nutrient_topic

L-Alanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Alanine

plain_language

Providing usable carbon changed the signaling response to alanine.

primary_references

l-Alanine activates hepatic AMP-activated protein kinase and modulates systemic glucose metabolism. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30190193/ · DOI 10.1016/j.molmet.2018.08.002

L-Alanine: carbon, nitrogen, protein synthesis and cross-nutrient mechanisms (2026-09-19) · lines 272–278

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat H4IIE nutrient-addition experiments. · source_derived_draft · unverified_draft

## alanine-ampk-carbon-rescue Providing usable carbon changed the signaling response to alanine. Pyruvate or TCA-intermediate supplementation restored ATP and attenuated alanine-induced AMPK phosphorylation in the tested liver-cell experiments. Model: Rat H4IIE nutrient-addition experiments. Limitations: A biochemical rescue does not establish a supplement combination for humans. Evidence access: Primary full text l-Alanine activates hepatic AMP-activated protein kinase and modulates systemic glucose metabolism. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30190193/ · DOI 10.1016/j.molmet.2018.08.002

evidence_access

Primary full text

experimental_model

Acute rat H4IIE metabolomics; AMP/ATP approximately 1.5-fold higher at 15 minutes.

limitations

Pool sizes are not flux measurements; increased ATP-consuming urea synthesis was proposed rather than directly proven.

nutrient_topic

L-Alanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Alanine

plain_language

Moving amino nitrogen changed the cell’s carbon pools and energy balance.

primary_references

l-Alanine activates hepatic AMP-activated protein kinase and modulates systemic glucose metabolism. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30190193/ · DOI 10.1016/j.molmet.2018.08.002

L-Alanine: carbon, nitrogen, protein synthesis and cross-nutrient mechanisms (2026-09-19) · lines 264–270

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Acute rat H4IIE metabolomics; AMP/ATP approximately 1.5-fold higher at 15 minutes. · source_derived_draft · unverified_draft

## alanine-ampk-pools Moving amino nitrogen changed the cell’s carbon pools and energy balance. Alanine increased the AMP/ATP ratio and glutamate while decreasing 2-oxoglutarate and other TCA intermediate pools in rat H4IIE cells. Model: Acute rat H4IIE metabolomics; AMP/ATP approximately 1.5-fold higher at 15 minutes. Limitations: Pool sizes are not flux measurements; increased ATP-consuming urea synthesis was proposed rather than directly proven. Evidence access: Primary full text l-Alanine activates hepatic AMP-activated protein kinase and modulates systemic glucose metabolism. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30190193/ · DOI 10.1016/j.molmet.2018.08.002

evidence_access

Primary abstract

experimental_model

Rat BRIN-BD11 tracing and protein measurements.

limitations

Concurrent changes are not a direct demonstration that PDK loss caused the ATP or secretion phenotype.

nutrient_topic

L-Alanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Alanine

plain_language

More flux through one metabolic step did not mean more stored ATP or stronger insulin release.

primary_references

Prolonged L-alanine exposure induces changes in metabolism, Ca(2+) handling and desensitization of insulin secretion in clonal pancreatic beta-cells. · 2009 · https://pubmed.ncbi.nlm.nih.gov/18702613/ · DOI 10.1042/CS20080138

L-Alanine: carbon, nitrogen, protein synthesis and cross-nutrient mechanisms (2026-09-19) · lines 416–422

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat BRIN-BD11 tracing and protein measurements. · source_derived_draft · unverified_draft

## alanine-beta-chronic-pdh More flux through one metabolic step did not mean more stored ATP or stronger insulin release. Prolonged alanine culture increased NMR-inferred pyruvate-dehydrogenase flux while reducing PDK2/PDK4 protein and cellular ATP. Model: Rat BRIN-BD11 tracing and protein measurements. Limitations: Concurrent changes are not a direct demonstration that PDK loss caused the ATP or secretion phenotype. Evidence access: Primary abstract Prolonged L-alanine exposure induces changes in metabolism, Ca(2+) handling and desensitization of insulin secretion in clonal pancreatic beta-cells. · 2009 · https://pubmed.ncbi.nlm.nih.gov/18702613/ · DOI 10.1042/CS20080138

availability_state

machinery_impairment Imported condition classification; unverified.

experimental_model

Purified human PDXK; crystallography and inhibition kinetics

exposure

2.15 angstrom ternary crystal structure.

limitations

Binding in a purified protein does not establish brain concentrations.

nutrient_topic

Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6

organism

Homo sapiens

plain_language

The structure directly locates the competing toxin.

primary_references

[gandhi-2012-pdxk-inhibitors] Crystal Structures of Human Pyridoxal Kinase in Complex with the Neurotoxins, Ginkgotoxin and Theophylline: Insights into Pyridoxal Kinase Inhibition (2012). https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0040954 DOI: 10.1371/journal.pone.0040954

tissue_or_cell_type

Purified recombinant protein; no intact tissue

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1208–1218

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human PDXK; crystallography and inhibition kinetics · source_derived_draft · unverified_draft

### b6-neuro-ginkgotoxin-binding Human PDXK crystallography placed ginkgotoxin at the pyridoxal-binding site alongside MgATP. Condition category: machinery_impairment nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The structure directly locates the competing toxin. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Purified human PDXK; crystallography and inhibition kinetics limitations: Binding in a purified protein does not establish brain concentrations. exposure: 2.15 angstrom ternary crystal structure. [gandhi-2012-pdxk-inhibitors] Crystal Structures of Human Pyridoxal Kinase in Complex with the Neurotoxins, Ginkgotoxin and Theophylline: Insights into Pyridoxal Kinase Inhibition (2012). https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0040954 DOI: 10.1371/journal.pone.0040954

experimental_model

Purified recombinant human PDXK; HPLC and kinetic competition assays

exposure

HPLC product identification at 37 C, pH 6.2.

limitations

Purified-enzyme substrate recognition does not establish a whole-body toxicity threshold.

nutrient_topic

Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6

organism

Homo sapiens

plain_language

The toxin can use the B6-activating enzyme.

primary_references

[kastner-2007-ginkgotoxin] The human pyridoxal kinase, a plausible target for ginkgotoxin from Ginkgo biloba (2007). https://doi.org/10.1111/j.1742-4658.2007.05654.x DOI: 10.1111/j.1742-4658.2007.05654.x

tissue_or_cell_type

Purified recombinant protein; no intact tissue

Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1184–1194

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant human PDXK; HPLC and kinetic competition assays · source_derived_draft · unverified_draft

### b6-neuro-ginkgotoxin-phosphorylation Purified human PDXK converted ginkgotoxin to its 5-prime-phosphate in an ATP-dependent assay. Condition category: normal nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The toxin can use the B6-activating enzyme. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Purified recombinant human PDXK; HPLC and kinetic competition assays limitations: Purified-enzyme substrate recognition does not establish a whole-body toxicity threshold. exposure: HPLC product identification at 37 C, pH 6.2. [kastner-2007-ginkgotoxin] The human pyridoxal kinase, a plausible target for ginkgotoxin from Ginkgo biloba (2007). https://doi.org/10.1111/j.1742-4658.2007.05654.x DOI: 10.1111/j.1742-4658.2007.05654.x

cross_nutrient

Magnesium-B6 activation chemistry.

evidence_location

Indexed abstract and publisher abstract; human enzyme findings only

experimental_model

Purified recombinant human and E. coli pyridoxal kinases.

exposure

MgATP versus ZnATP kinetic comparisons.

limitations

Metal preference depends on assay conditions and does not prove magnesium supplementation improves B6 status.

nutrient_topic

Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6

organism

Homo sapiens

plain_language

Magnesium helps supply ATP to B6 activation.

primary_references

[disalvo2004] Expression, purification, and kinetic constants for human and Escherichia coli pyridoxal kinases. (2004). https://pubmed.ncbi.nlm.nih.gov/15249053/ DOI: 10.1016/j.pep.2004.04.021

tissue_or_cell_type

Purified human enzyme

Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 189–201

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant human and E. coli pyridoxal kinases. · source_derived_draft · unverified_draft

### b6-transport-pdxk-mgatp Kinase kinetic experiments identified MgATP as the preferred phosphate-donor complex under the reported physiological assay conditions. Condition category: normal nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Magnesium helps supply ATP to B6 activation. organism: Homo sapiens tissue_or_cell_type: Purified human enzyme experimental_model: Purified recombinant human and E. coli pyridoxal kinases. limitations: Metal preference depends on assay conditions and does not prove magnesium supplementation improves B6 status. exposure: MgATP versus ZnATP kinetic comparisons. evidence_location: Indexed abstract and publisher abstract; human enzyme findings only cross_nutrient: Magnesium-B6 activation chemistry. [disalvo2004] Expression, purification, and kinetic constants for human and Escherichia coli pyridoxal kinases. (2004). https://pubmed.ncbi.nlm.nih.gov/15249053/ DOI: 10.1016/j.pep.2004.04.021

evidence_location

Indexed abstract and publisher abstract; human enzyme findings only

experimental_model

Purified recombinant human and E. coli pyridoxal kinases.

exposure

Purified-enzyme substrate kinetics.

limitations

Model-specific evidence; no dietary threshold or treatment benefit established.

nutrient_topic

Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6

organism

Homo sapiens

plain_language

PDXK adds phosphate to this B6 precursor.

primary_references

[disalvo2004] Expression, purification, and kinetic constants for human and Escherichia coli pyridoxal kinases. (2004). https://pubmed.ncbi.nlm.nih.gov/15249053/ DOI: 10.1016/j.pep.2004.04.021

tissue_or_cell_type

Purified human enzyme

Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 176–187

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant human and E. coli pyridoxal kinases. · source_derived_draft · unverified_draft

### b6-transport-pdxk-pm Purified recombinant human PDXK phosphorylated pyridoxamine to its corresponding 5-prime phosphate. Condition category: normal nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: PDXK adds phosphate to this B6 precursor. organism: Homo sapiens tissue_or_cell_type: Purified human enzyme experimental_model: Purified recombinant human and E. coli pyridoxal kinases. limitations: Model-specific evidence; no dietary threshold or treatment benefit established. exposure: Purified-enzyme substrate kinetics. evidence_location: Indexed abstract and publisher abstract; human enzyme findings only [disalvo2004] Expression, purification, and kinetic constants for human and Escherichia coli pyridoxal kinases. (2004). https://pubmed.ncbi.nlm.nih.gov/15249053/ DOI: 10.1016/j.pep.2004.04.021

evidence_location

Indexed abstract and publisher abstract; human enzyme findings only

experimental_model

Purified recombinant human and E. coli pyridoxal kinases.

exposure

Purified-enzyme substrate kinetics.

limitations

Model-specific evidence; no dietary threshold or treatment benefit established.

nutrient_topic

Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6

organism

Homo sapiens

plain_language

PDXK adds phosphate to this B6 precursor.

primary_references

[disalvo2004] Expression, purification, and kinetic constants for human and Escherichia coli pyridoxal kinases. (2004). https://pubmed.ncbi.nlm.nih.gov/15249053/ DOI: 10.1016/j.pep.2004.04.021

tissue_or_cell_type

Purified human enzyme

Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 163–174

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant human and E. coli pyridoxal kinases. · source_derived_draft · unverified_draft

### b6-transport-pdxk-pn Purified recombinant human PDXK phosphorylated pyridoxine to its corresponding 5-prime phosphate. Condition category: normal nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: PDXK adds phosphate to this B6 precursor. organism: Homo sapiens tissue_or_cell_type: Purified human enzyme experimental_model: Purified recombinant human and E. coli pyridoxal kinases. limitations: Model-specific evidence; no dietary threshold or treatment benefit established. exposure: Purified-enzyme substrate kinetics. evidence_location: Indexed abstract and publisher abstract; human enzyme findings only [disalvo2004] Expression, purification, and kinetic constants for human and Escherichia coli pyridoxal kinases. (2004). https://pubmed.ncbi.nlm.nih.gov/15249053/ DOI: 10.1016/j.pep.2004.04.021

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Isolated membrane-vesicle cofactor-dependence experiments.

limitations

Cofactor removal is experimental machinery impairment, not proof that dietary magnesium deficiency changes human strontium retention by a specified amount.

nutrient_topic

Strontium collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Strontium

plain_language

The pump needs both its energy source and magnesium.

primary_references

A Comparison Between Calcium and Strontium Transport by the (Ca2+ + Mg2+)ATPase of the Basolateral Plasma Membrane of Renal Proximal Convoluted Tubules. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40277992/ · DOI 10.3390/membranes15040122

trigger_kind

machinery_impairment Imported condition classification; unverified.

Strontium: calcium interactions, cellular mechanisms and mineralization (2026-09-19) · lines 38–44

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Isolated membrane-vesicle cofactor-dependence experiments. · source_derived_draft · unverified_draft

## strontium-renal-cofactor-loss The pump needs both its energy source and magnesium. Omission of ATP or magnesium prevented strontium uptake in the tested renal membrane preparation; other tested nucleotides did not substitute for ATP. Model: Isolated membrane-vesicle cofactor-dependence experiments. Limitations: Cofactor removal is experimental machinery impairment, not proof that dietary magnesium deficiency changes human strontium retention by a specified amount. Evidence access: Primary full text A Comparison Between Calcium and Strontium Transport by the (Ca2+ + Mg2+)ATPase of the Basolateral Plasma Membrane of Renal Proximal Convoluted Tubules. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40277992/ · DOI 10.3390/membranes15040122

evidence_access

Primary full text

experimental_model

Isolated renal membrane vesicles; 90Sr and 45Ca tracers; ATP/Mg uptake assays.

limitations

Accessed methods refer to a prior preparation protocol without resolving species or ATP2B isoform. The assay measures ion transport, not radiation injury or net human renal clearance.

nutrient_topic

Strontium collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Strontium

plain_language

A calcium-handling membrane preparation can also pump strontium.

primary_references

A Comparison Between Calcium and Strontium Transport by the (Ca2+ + Mg2+)ATPase of the Basolateral Plasma Membrane of Renal Proximal Convoluted Tubules. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40277992/ · DOI 10.3390/membranes15040122

transport_effect

depends Membrane vesicles accumulated strontium in the assay, while the basolateral pump's role in the intact cell is extrusion toward blood; the two pools move opposite ways.

transport_pool

the proximal-tubule cell interior Membrane vesicles accumulated strontium in the assay, while the basolateral pump's role in the intact cell is extrusion toward blood; the two pools move opposite ways.

Strontium: calcium interactions, cellular mechanisms and mineralization (2026-09-19) · lines 14–20

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Isolated renal membrane vesicles; 90Sr and 45Ca tracers; ATP/Mg uptake assays. · source_derived_draft · unverified_draft

## strontium-renal-uptake A calcium-handling membrane preparation can also pump strontium. Basolateral proximal-tubule membrane vesicles accumulated radiolabeled strontium in an ATP- and Mg2+-dependent transport assay. Model: Isolated renal membrane vesicles; 90Sr and 45Ca tracers; ATP/Mg uptake assays. Limitations: Accessed methods refer to a prior preparation protocol without resolving species or ATP2B isoform. The assay measures ion transport, not radiation injury or net human renal clearance. Evidence access: Primary full text A Comparison Between Calcium and Strontium Transport by the (Ca2+ + Mg2+)ATPase of the Basolateral Plasma Membrane of Renal Proximal Convoluted Tubules. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40277992/ · DOI 10.3390/membranes15040122

evidence_access

Primary full text; Figure 4A

experimental_model

Human recombinant kinases; radiolabeled ATP and TLC; annelid taurocyamine kinase positive control.

limitations

The experimental result does not exclude every reaction at other conditions, but does not support replacing creatine.

nutrient_topic

Agmatine Sulfate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Agmatine Sulfate

plain_language

Related guanidino compounds are not automatically interchangeable energy buffers.

primary_references

Guanidino acid hydrolysis by the human enzyme annotated as agmatinase. · 2022 · https://pubmed.ncbi.nlm.nih.gov/36543883/ · DOI 10.1038/s41598-022-26655-4

Agmatine Sulfate: transport, guanidino metabolism, ion channels and cross-nutrient mechanisms (2026-09-20) · lines 212–218

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human recombinant kinases; radiolabeled ATP and TLC; annelid taurocyamine kinase positive control. · source_derived_draft · unverified_draft

## agmatine-sulfate-creatine-specificity Related guanidino compounds are not automatically interchangeable energy buffers. Four purified human creatine-kinase isoforms phosphorylated creatine but not taurocyamine, guanidinobutyrate or guanidinopropionate at 10 mM test substrate. Model: Human recombinant kinases; radiolabeled ATP and TLC; annelid taurocyamine kinase positive control. Limitations: The experimental result does not exclude every reaction at other conditions, but does not support replacing creatine. Evidence access: Primary full text; Figure 4A Guanidino acid hydrolysis by the human enzyme annotated as agmatinase. · 2022 · https://pubmed.ncbi.nlm.nih.gov/36543883/ · DOI 10.1038/s41598-022-26655-4

evidence_access

Primary abstract

experimental_model

Recombinant human alpha-prime plus beta; radiolabeled ATP transfer.

limitations

Assay potency is not an oral therapeutic concentration.

nutrient_topic

Luteolin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Luteolin / 3′,4′,5,7-tetrahydroxyflavone

plain_language

A measured kinase effect uses a defined human subunit combination.

primary_references

Structure-activity relationship of 7 flavonoids on recombinant human protein kinase CK2 holoenzyme. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19197122/

Luteolin: metabolism, immune signaling, redox chemistry and cross-nutrient mechanisms (2026-09-19) · lines 332–338

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Recombinant human alpha-prime plus beta; radiolabeled ATP transfer. · source_derived_draft · unverified_draft

## luteolin-ck2-human A measured kinase effect uses a defined human subunit combination. Luteolin inhibited reconstituted human CK2 alpha-prime/beta holoenzyme, IC50 0.86 micromolar. Model: Recombinant human alpha-prime plus beta; radiolabeled ATP transfer. Limitations: Assay potency is not an oral therapeutic concentration. Evidence access: Primary abstract Structure-activity relationship of 7 flavonoids on recombinant human protein kinase CK2 holoenzyme. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19197122/

evidence_access

Primary abstract

experimental_model

CK2 inhibitor kinetics and maize catalytic-subunit crystal structure.

limitations

Do not relabel the crystal as human CK2.

nutrient_topic

Luteolin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Luteolin / 3′,4′,5,7-tetrahydroxyflavone

plain_language

The structural experiment used a plant enzyme.

primary_references

Inhibition of protein kinase CK2 by flavonoids and tyrphostins. A structural insight. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22794353/ · DOI 10.1021/bi300531c

Luteolin: metabolism, immune signaling, redox chemistry and cross-nutrient mechanisms (2026-09-19) · lines 340–346

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · CK2 inhibitor kinetics and maize catalytic-subunit crystal structure. · source_derived_draft · unverified_draft

## luteolin-ck2-plant-structure The structural experiment used a plant enzyme. Crystallography located luteolin in the catalytic pocket of Zea mays CK2; kinase inhibition was ATP-competitive. Model: CK2 inhibitor kinetics and maize catalytic-subunit crystal structure. Limitations: Do not relabel the crystal as human CK2. Evidence access: Primary abstract Inhibition of protein kinase CK2 by flavonoids and tyrphostins. A structural insight. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22794353/ · DOI 10.1021/bi300531c

evidence_span

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experimental_model

Human choline kinase alpha1 and pathogen-enzyme biochemical comparison

exposure

ATP-dependent choline phosphorylation in magnesium-containing assays

limitations

The shared enzyme requirement is not a clinical magnesium threshold or proof of a general supplement rescue.

nutrient_topic

Choline research collection; topical membership is not evidence of a direct dietary effect. · Choline

organism

Human alpha1 isoform; pathogen comparators remain separate

plain_language

Choline enters membrane synthesis through an ATP-powered phosphorylation step.

primary_references

[choline-p25515750] Choline kinase active site provides features for designing versatile inhibitors. (2014). https://pubmed.ncbi.nlm.nih.gov/25515750/ DOI: 10.2174/1568026614666141216093337

tissue_or_cell_type

Purified choline kinase active site

Choline: metabolism, signaling and nutrient connections (2026-09-17) · lines 698–709

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human choline kinase alpha1 and pathogen-enzyme biochemical comparison · source_derived_draft · unverified_draft

### choline-chka-phosphocholine Human choline kinase alpha1 catalyzes ATP-dependent phosphorylation of choline, producing phosphocholine and ADP in magnesium-containing conditions. Condition category: normal nutrient_topic: Choline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Choline enters membrane synthesis through an ATP-powered phosphorylation step. organism: Human alpha1 isoform; pathogen comparators remain separate tissue_or_cell_type: Purified choline kinase active site experimental_model: Human choline kinase alpha1 and pathogen-enzyme biochemical comparison limitations: The shared enzyme requirement is not a clinical magnesium threshold or proof of a general supplement rescue. exposure: ATP-dependent choline phosphorylation in magnesium-containing assays evidence_span: {"source_cache": "artifacts/choline-research/25515750.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "742dc604629df5eae2bb6cfc0ef0a13cbd69f5e318a2f3292e98f2e707958aeb", "start_char": 0, "end_char": 1321, "text_sha256": "742dc604629df5eae2bb6cfc0ef0a13cbd69f5e318a2f3292e98f2e707958aeb"} [choline-p25515750] Choline kinase active site provides features for designing versatile inhibitors. (2014). https://pubmed.ncbi.nlm.nih.gov/25515750/ DOI: 10.2174/1568026614666141216093337

evidence_access

Primary abstract

experimental_model

Rat liver F1 crystallography.

limitations

A captured structure is not proof that a given oral dose suppresses mitochondrial ATP production.

nutrient_topic

Vanadium collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Vanadium

plain_language

Another ATP-handling enzyme can bind the phosphate analogue.

primary_references

Mitochondrial ATP synthase. Crystal structure of the catalytic F1 unit in a vanadate-induced transition-like state and implications for mechanism. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16531409/ · DOI 10.1074/jbc.M513369200

Vanadium: speciation, phosphate-sensitive enzymes and cross-nutrient mechanisms (2026-09-19) · lines 262–268

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat liver F1 crystallography. · source_derived_draft · unverified_draft

## vanadium-f1-transition Another ATP-handling enzyme can bind the phosphate analogue. Vanadate crystallization of rat-liver F1 ATP synthase captured an ADP–vanadate–Mg transition-like state with remodeling of the catalytic P-loop region. Model: Rat liver F1 crystallography. Limitations: A captured structure is not proof that a given oral dose suppresses mitochondrial ATP production. Evidence access: Primary abstract Mitochondrial ATP synthase. Crystal structure of the catalytic F1 unit in a vanadate-induced transition-like state and implications for mechanism. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16531409/ · DOI 10.1074/jbc.M513369200

evidence_access

Primary abstract and RCSB PDB 5A3Q author deposition

experimental_model

Rabbit SERCA structure, deposition 5A3Q; primary abstract plus author-deposited structure identity.

limitations

Structure used nucleotide analogues and thapsigargin; not a measured human intracellular calcium effect.

nutrient_topic

Vanadium collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Vanadium

plain_language

A phosphate analogue can trap a calcium pump in a catalytic state.

primary_references

Crystal Structure of the Vanadate-Inhibited Ca(2+)-ATPase. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27050689/ · DOI 10.1016/j.str.2016.02.018

Vanadium: speciation, phosphate-sensitive enzymes and cross-nutrient mechanisms (2026-09-19) · lines 254–260

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rabbit SERCA structure, deposition 5A3Q; primary abstract plus author-deposited structure identity. · source_derived_draft · unverified_draft

## vanadium-serca-transition A phosphate analogue can trap a calcium pump in a catalytic state. Vanadate occupied the catalytic site of calcium-free SERCA as planar VO3 with water and magnesium in a dephosphorylation-transition-like conformation. Model: Rabbit SERCA structure, deposition 5A3Q; primary abstract plus author-deposited structure identity. Limitations: Structure used nucleotide analogues and thapsigargin; not a measured human intracellular calcium effect. Evidence access: Primary abstract and RCSB PDB 5A3Q author deposition Crystal Structure of the Vanadate-Inhibited Ca(2+)-ATPase. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27050689/ · DOI 10.1016/j.str.2016.02.018

evidence_span

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experimental_model

Reconstructed-protein biochemistry, crystallography and mutagenesis

exposure

ATP-dependent pocket gating; excess final CoQ product

limitations

2026 reconstructed system using short-chain intermediates; do not assign all kinetics directly to intact human mitochondria.

nutrient_topic

Coenzyme Q10 research collection; topical membership is not evidence of a direct dietary effect. · Coenzyme Q10 / CoQ10 redox system

organism

Ancestral tetrapod COQ8A/COQ8B and COQ metabolon

plain_language

The helper moves intermediates between synthesis enzymes rather than simply adding more raw material.

primary_references

[coq10-p42525751] COQ8 chaperones coenzyme Q lipid intermediates through ATP-driven structural gating. (2026). https://pubmed.ncbi.nlm.nih.gov/42525751/ DOI: 10.1126/sciadv.aeg1124

tissue_or_cell_type

Lipid-intermediate delivery

Coenzyme Q10: biosynthesis, electron transfer, antioxidant recycling and nutrient interactions (2026-09-17) · lines 346–357

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Reconstructed-protein biochemistry, crystallography and mutagenesis · source_derived_draft · unverified_draft

### coq10-coq8a-chaperone Reconstructed COQ8A promoted CoQ production through ATPase-linked handling of insoluble pathway intermediates. Condition category: normal nutrient_topic: Coenzyme Q10 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The helper moves intermediates between synthesis enzymes rather than simply adding more raw material. organism: Ancestral tetrapod COQ8A/COQ8B and COQ metabolon tissue_or_cell_type: Lipid-intermediate delivery experimental_model: Reconstructed-protein biochemistry, crystallography and mutagenesis limitations: 2026 reconstructed system using short-chain intermediates; do not assign all kinetics directly to intact human mitochondria. exposure: ATP-dependent pocket gating; excess final CoQ product evidence_span: {"source_cache": "artifacts/coq10-research/42525751.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "b7a49b25f09323a11c782afbdbff069e95429ed28e0ce2da5519abcbaa76c632", "start_char": 0, "end_char": 1058, "text_sha256": "b7a49b25f09323a11c782afbdbff069e95429ed28e0ce2da5519abcbaa76c632"} [coq10-p42525751] COQ8 chaperones coenzyme Q lipid intermediates through ATP-driven structural gating. (2026). https://pubmed.ncbi.nlm.nih.gov/42525751/ DOI: 10.1126/sciadv.aeg1124

evidence_span

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experimental_model

Reconstructed-protein biochemistry, crystallography and mutagenesis

exposure

ATP-dependent pocket gating; excess final CoQ product

limitations

2026 reconstructed system using short-chain intermediates; do not assign all kinetics directly to intact human mitochondria.

nutrient_topic

Coenzyme Q10 research collection; topical membership is not evidence of a direct dietary effect. · Coenzyme Q10 / CoQ10 redox system

organism

Ancestral tetrapod COQ8A/COQ8B and COQ metabolon

plain_language

The helper moves intermediates between synthesis enzymes rather than simply adding more raw material.

primary_references

[coq10-p42525751] COQ8 chaperones coenzyme Q lipid intermediates through ATP-driven structural gating. (2026). https://pubmed.ncbi.nlm.nih.gov/42525751/ DOI: 10.1126/sciadv.aeg1124

tissue_or_cell_type

Lipid-intermediate delivery

Coenzyme Q10: biosynthesis, electron transfer, antioxidant recycling and nutrient interactions (2026-09-17) · lines 359–370

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Reconstructed-protein biochemistry, crystallography and mutagenesis · source_derived_draft · unverified_draft

### coq10-coq8b-chaperone Reconstructed COQ8B promoted CoQ production through ATPase-linked handling of insoluble pathway intermediates. Condition category: normal nutrient_topic: Coenzyme Q10 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The helper moves intermediates between synthesis enzymes rather than simply adding more raw material. organism: Ancestral tetrapod COQ8A/COQ8B and COQ metabolon tissue_or_cell_type: Lipid-intermediate delivery experimental_model: Reconstructed-protein biochemistry, crystallography and mutagenesis limitations: 2026 reconstructed system using short-chain intermediates; do not assign all kinetics directly to intact human mitochondria. exposure: ATP-dependent pocket gating; excess final CoQ product evidence_span: {"source_cache": "artifacts/coq10-research/42525751.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "b7a49b25f09323a11c782afbdbff069e95429ed28e0ce2da5519abcbaa76c632", "start_char": 0, "end_char": 1058, "text_sha256": "b7a49b25f09323a11c782afbdbff069e95429ed28e0ce2da5519abcbaa76c632"} [coq10-p42525751] COQ8 chaperones coenzyme Q lipid intermediates through ATP-driven structural gating. (2026). https://pubmed.ncbi.nlm.nih.gov/42525751/ DOI: 10.1126/sciadv.aeg1124

evidence_access

Primary full text

experimental_model

Human MRS/MARS1 biochemical and HeLa-cell experiments.

limitations

Baseline charging and stress-related mistranslation are separate observations.

nutrient_topic

L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine

plain_language

A dedicated enzyme attaches methionine to the translation machinery.

primary_references

Promiscuous methionyl-tRNA synthetase mediates adaptive mistranslation to protect cells against oxidative stress. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25097229/ · DOI 10.1242/jcs.152470

L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 60–66

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human MRS/MARS1 biochemical and HeLa-cell experiments. · source_derived_draft · unverified_draft

## methionine-mars-charging A dedicated enzyme attaches methionine to the translation machinery. Human MARS1 catalyzes methionylation of cognate tRNA; the study compared this activity with stress-induced charging of non-cognate tRNAs. Model: Human MRS/MARS1 biochemical and HeLa-cell experiments. Limitations: Baseline charging and stress-related mistranslation are separate observations. Evidence access: Primary full text Promiscuous methionyl-tRNA synthetase mediates adaptive mistranslation to protect cells against oxidative stress. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25097229/ · DOI 10.1242/jcs.152470

evidence_access

Primary abstract

experimental_model

Established enzyme role described in the human MARS2 disease study.

limitations

This role statement is distinct from the patient-cell respiratory measurements.

nutrient_topic

L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine

plain_language

Mitochondria need their own charging enzyme.

primary_references

Novel, compound heterozygous, single-nucleotide variants in MARS2 associated with developmental delay, poor growth, and sensorineural hearing loss. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25754315/ · DOI 10.1002/humu.22781

L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 92–98

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Established enzyme role described in the human MARS2 disease study. · source_derived_draft · unverified_draft

## methionine-mars2-charging Mitochondria need their own charging enzyme. MARS2 is the mitochondrial methionyl-tRNA synthetase, connecting methionine to organelle translation. Model: Established enzyme role described in the human MARS2 disease study. Limitations: This role statement is distinct from the patient-cell respiratory measurements. Evidence access: Primary abstract Novel, compound heterozygous, single-nucleotide variants in MARS2 associated with developmental delay, poor growth, and sensorineural hearing loss. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25754315/ · DOI 10.1002/humu.22781

evidence_access

Primary abstract

experimental_model

Human MAT2A structure with nonhydrolyzable imidotriphosphate and methylthioadenosine.

limitations

Inhibitor-bound structural contacts are not a dietary magnesium dose-response.

nutrient_topic

L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine

plain_language

SAM-making chemistry depends on correctly organized metal/phosphate contacts.

primary_references

Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33656855/ · DOI 10.1021/acs.biochem.0c00998

L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 132–138

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human MAT2A structure with nonhydrolyzable imidotriphosphate and methylthioadenosine. · source_derived_draft · unverified_draft

## methionine-mat-magnesium SAM-making chemistry depends on correctly organized metal/phosphate contacts. The human MAT2A inhibitor-bound structure contained two magnesium ions coordinating phosphate groups at the catalytic site. Model: Human MAT2A structure with nonhydrolyzable imidotriphosphate and methylthioadenosine. Limitations: Inhibitor-bound structural contacts are not a dietary magnesium dose-response. Evidence access: Primary abstract Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33656855/ · DOI 10.1021/acs.biochem.0c00998

evidence_access

Primary abstract

experimental_model

Purified human MAT2A crystallography and kinetic study.

limitations

Does not show that extra potassium increases methylation in potassium-replete humans.

nutrient_topic

L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine

plain_language

Potassium participates directly in the enzyme chemistry.

primary_references

Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33656855/ · DOI 10.1021/acs.biochem.0c00998

L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 140–146

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Purified human MAT2A crystallography and kinetic study. · source_derived_draft · unverified_draft

## methionine-mat-potassium Potassium participates directly in the enzyme chemistry. An essential potassium ion contacted the beta-phosphoryl oxygen in the human MAT2A catalytic-site ligand structure. Model: Purified human MAT2A crystallography and kinetic study. Limitations: Does not show that extra potassium increases methylation in potassium-replete humans. Evidence access: Primary abstract Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33656855/ · DOI 10.1021/acs.biochem.0c00998

evidence_access

Primary abstract

experimental_model

Human MAT1A disease cohort; established isoenzyme chemistry.

limitations

MAT1A and MAT2A retain separate identities.

nutrient_topic

L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine

plain_language

The liver has distinct enzyme assemblies for activating methionine.

primary_references

Mudd's disease (MAT I/III deficiency): a survey of data for MAT1A homozygotes and compound heterozygotes. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26289392/ · DOI 10.1186/s13023-015-0321-y

L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 148–154

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human MAT1A disease cohort; established isoenzyme chemistry. · source_derived_draft · unverified_draft

## methionine-mat1-isoenzymes The liver has distinct enzyme assemblies for activating methionine. MAT1A supplies subunits of tetrameric MAT I and dimeric MAT III, which convert methionine and ATP to SAM. Model: Human MAT1A disease cohort; established isoenzyme chemistry. Limitations: MAT1A and MAT2A retain separate identities. Evidence access: Primary abstract Mudd's disease (MAT I/III deficiency): a survey of data for MAT1A homozygotes and compound heterozygotes. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26289392/ · DOI 10.1186/s13023-015-0321-y

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Engineered yeast; 13C labeling and metabolic/enzyme assays.

limitations

Not a phenotype demonstrated for common human MTHFR polymorphisms.

nutrient_topic

L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine

plain_language

Removing a feedback brake can waste energy rather than improve the pathway.

primary_references

Allosteric inhibition of MTHFR prevents futile SAM cycling and maintains nucleotide pools in one-carbon metabolism. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32934008/ · DOI 10.1074/jbc.RA120.015129

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 220–226

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Engineered yeast; 13C labeling and metabolic/enzyme assays. · source_derived_draft · unverified_draft

## methionine-mthfr-feedback-loss Removing a feedback brake can waste energy rather than improve the pathway. Feedback-insensitive yeast MTHFR mutants underwent excessive methionine/SAM cycling with ATP and nucleotide depletion and poor growth in methionine-containing medium. Model: Engineered yeast; 13C labeling and metabolic/enzyme assays. Limitations: Not a phenotype demonstrated for common human MTHFR polymorphisms. Evidence access: Primary abstract Allosteric inhibition of MTHFR prevents futile SAM cycling and maintains nucleotide pools in one-carbon metabolism. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32934008/ · DOI 10.1074/jbc.RA120.015129

compartment_description

Cytosolic kinase complex

experimental_model

Purified mammalian brain CaMKII; phosphorylation and substrate-kinase assays

limitations

Autonomy depends on phosphorylation conditions; not all self-phosphorylation activates and persistence in living cells is not quantified.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Mammalia

plain_language

After activation, CaMKII can retain activity beyond the calcium pulse.

primary_references

[ca-miller1986] Regulation of brain type II Ca2+/calmodulin-dependent protein kinase by autophosphorylation: a Ca2+-triggered molecular switch (1986). https://pubmed.ncbi.nlm.nih.gov/3006921/ DOI: 10.1016/0092-8674(86)90008-5

research_relationship_category

protein_modification

tissue_or_cell_type

Brain enzyme preparation

Calcium: mechanism-first literature curation (2026-09-17) · lines 451–462

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified mammalian brain CaMKII; phosphorylation and substrate-kinase assays · source_derived_draft · unverified_draft

### ca-camkii-autonomous-activity Partial autophosphorylation generates CaMKII activity that persists in the absence of calcium in the purified assay. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: After activation, CaMKII can retain activity beyond the calcium pulse. organism: Mammalia tissue_or_cell_type: Brain enzyme preparation experimental_model: Purified mammalian brain CaMKII; phosphorylation and substrate-kinase assays limitations: Autonomy depends on phosphorylation conditions; not all self-phosphorylation activates and persistence in living cells is not quantified. research_relationship_category: protein_modification compartment_description: Cytosolic kinase complex [ca-miller1986] Regulation of brain type II Ca2+/calmodulin-dependent protein kinase by autophosphorylation: a Ca2+-triggered molecular switch (1986). https://pubmed.ncbi.nlm.nih.gov/3006921/ DOI: 10.1016/0092-8674(86)90008-5

compartment_description

Cytosolic kinase complex

experimental_model

Purified mammalian brain CaMKII; phosphorylation and substrate-kinase assays

limitations

Brain holoenzyme assay; does not identify every isoform or phosphorylation site.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Mammalia

plain_language

Calcium-bound calmodulin starts CaMKII self-phosphorylation.

primary_references

[ca-miller1986] Regulation of brain type II Ca2+/calmodulin-dependent protein kinase by autophosphorylation: a Ca2+-triggered molecular switch (1986). https://pubmed.ncbi.nlm.nih.gov/3006921/ DOI: 10.1016/0092-8674(86)90008-5

research_relationship_category

regulation

tissue_or_cell_type

Brain enzyme preparation

Calcium: mechanism-first literature curation (2026-09-17) · lines 438–449

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified mammalian brain CaMKII; phosphorylation and substrate-kinase assays · source_derived_draft · unverified_draft

### ca-camkii-calmodulin-activation Calcium/calmodulin stimulates autophosphorylation of purified brain CaMKII. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium-bound calmodulin starts CaMKII self-phosphorylation. organism: Mammalia tissue_or_cell_type: Brain enzyme preparation experimental_model: Purified mammalian brain CaMKII; phosphorylation and substrate-kinase assays limitations: Brain holoenzyme assay; does not identify every isoform or phosphorylation site. research_relationship_category: regulation compartment_description: Cytosolic kinase complex [ca-miller1986] Regulation of brain type II Ca2+/calmodulin-dependent protein kinase by autophosphorylation: a Ca2+-triggered molecular switch (1986). https://pubmed.ncbi.nlm.nih.gov/3006921/ DOI: 10.1016/0092-8674(86)90008-5

compartment_description

Cytosolic regulatory regions of ER channel

experimental_model

Recombinant human ITPR3; cryo-EM in ligand-bound gating states

limitations

Structural populations do not define a universal calcium threshold or prove all calcium-bound channels are active.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Homo sapiens

plain_language

Calcium helps control ITPR3 opening; binding does not guarantee that the channel stays open.

primary_references

[ca-schmitz2022] Structural basis for activation and gating of IP3 receptors (2022). https://pubmed.ncbi.nlm.nih.gov/35301323/ DOI: 10.1038/s41467-022-29073-2

research_relationship_category

regulation

tissue_or_cell_type

Recombinant ITPR3

Calcium: mechanism-first literature curation (2026-09-17) · lines 492–503

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human ITPR3; cryo-EM in ligand-bound gating states · source_derived_draft · unverified_draft

### ca-itpr3-calcium-coactivation Calcium binding participates in ITPR3 gating after IP3/ATP priming, with both active and inactive calcium-bound conformations resolved. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium helps control ITPR3 opening; binding does not guarantee that the channel stays open. organism: Homo sapiens tissue_or_cell_type: Recombinant ITPR3 experimental_model: Recombinant human ITPR3; cryo-EM in ligand-bound gating states limitations: Structural populations do not define a universal calcium threshold or prove all calcium-bound channels are active. research_relationship_category: regulation compartment_description: Cytosolic regulatory regions of ER channel [ca-schmitz2022] Structural basis for activation and gating of IP3 receptors (2022). https://pubmed.ncbi.nlm.nih.gov/35301323/ DOI: 10.1038/s41467-022-29073-2

compartment_description

ER membrane

experimental_model

Recombinant human ITPR3; cryo-EM in ligand-bound gating states

limitations

Structure specifies ITPR3; it must not be relabeled as ITPR1 or a measurement of every receptor subtype.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Homo sapiens

plain_language

ITPR3 provides a route for calcium to leave the ER.

primary_references

[ca-schmitz2022] Structural basis for activation and gating of IP3 receptors (2022). https://pubmed.ncbi.nlm.nih.gov/35301323/ DOI: 10.1038/s41467-022-29073-2

research_relationship_category

transport

tissue_or_cell_type

Recombinant ITPR3

transport_effect

raises A calcium-release channel: the recorded direction is ER lumen to cytosol.

transport_or_reaction_direction

ER lumen to cytosol

transport_pool

cytosolic calcium A calcium-release channel: the recorded direction is ER lumen to cytosol.

Calcium: mechanism-first literature curation (2026-09-17) · lines 478–490

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human ITPR3; cryo-EM in ligand-bound gating states · source_derived_draft · unverified_draft

### ca-itpr3-er-calcium-channel Human ITPR3 forms a calcium-release channel with an open pore in the IP3/ATP/Ca2+-bound structural state. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: ITPR3 provides a route for calcium to leave the ER. organism: Homo sapiens tissue_or_cell_type: Recombinant ITPR3 experimental_model: Recombinant human ITPR3; cryo-EM in ligand-bound gating states limitations: Structure specifies ITPR3; it must not be relabeled as ITPR1 or a measurement of every receptor subtype. research_relationship_category: transport transport_or_reaction_direction: ER lumen to cytosol compartment_description: ER membrane [ca-schmitz2022] Structural basis for activation and gating of IP3 receptors (2022). https://pubmed.ncbi.nlm.nih.gov/35301323/ DOI: 10.1038/s41467-022-29073-2

compartment_description

Plasma membrane

experimental_model

Purified human PMCA1-neuroplastin complex; cryo-EM and ATPase assays

limitations

This study combines structure and ATPase assays; it does not quantify whole-tissue extrusion flux.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Homo sapiens

plain_language

PMCA1 uses ATP to clear calcium from the cytosol.

primary_references

[ca-gong2018] Structure of the human plasma membrane Ca2+-ATPase 1 in complex with its obligatory subunit neuroplastin (2018). https://pubmed.ncbi.nlm.nih.gov/30190470/ DOI: 10.1038/s41467-018-06075-7

research_relationship_category

transport

tissue_or_cell_type

Purified recombinant pump

transport_effect

lowers Recorded as an ATP-driven plasma-membrane calcium extrusion pump.

transport_or_reaction_direction

Cytosol to extracellular fluid

transport_pool

cytosolic calcium Recorded as an ATP-driven plasma-membrane calcium extrusion pump.

Calcium: mechanism-first literature curation (2026-09-17) · lines 585–597

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human PMCA1-neuroplastin complex; cryo-EM and ATPase assays · source_derived_draft · unverified_draft

### ca-pmca1-extrusion Human PMCA1 is an ATP-driven plasma-membrane calcium extrusion pump characterized structurally with neuroplastin. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: PMCA1 uses ATP to clear calcium from the cytosol. organism: Homo sapiens tissue_or_cell_type: Purified recombinant pump experimental_model: Purified human PMCA1-neuroplastin complex; cryo-EM and ATPase assays limitations: This study combines structure and ATPase assays; it does not quantify whole-tissue extrusion flux. research_relationship_category: transport transport_or_reaction_direction: Cytosol to extracellular fluid compartment_description: Plasma membrane [ca-gong2018] Structure of the human plasma membrane Ca2+-ATPase 1 in complex with its obligatory subunit neuroplastin (2018). https://pubmed.ncbi.nlm.nih.gov/30190470/ DOI: 10.1038/s41467-018-06075-7

compartment_description

Cytosolic channel-regulatory region

experimental_model

Purified rabbit skeletal-muscle RyR1 with calstabin2; cryo-EM and planar-bilayer recordings

limitations

Calcium is both a transported ion and a ligand; caffeine-assisted structures do not imply caffeine is required physiologically.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Oryctolagus cuniculus

plain_language

Calcium helps regulate the RyR1 gate.

primary_references

[ca-desgeorges2016] Structural Basis for Gating and Activation of RyR1 (2016). https://pubmed.ncbi.nlm.nih.gov/27662087/ DOI: 10.1016/j.cell.2016.08.075

research_relationship_category

regulation

tissue_or_cell_type

Skeletal-muscle channel preparation

Calcium: mechanism-first literature curation (2026-09-17) · lines 666–677

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified rabbit skeletal-muscle RyR1 with calstabin2; cryo-EM and planar-bilayer recordings · source_derived_draft · unverified_draft

### ca-ryr1-calcium-gating Calcium binds an activating RyR1 site and primes gating; ATP and caffeine increase open-state representation in the experimental preparation. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium helps regulate the RyR1 gate. organism: Oryctolagus cuniculus tissue_or_cell_type: Skeletal-muscle channel preparation experimental_model: Purified rabbit skeletal-muscle RyR1 with calstabin2; cryo-EM and planar-bilayer recordings limitations: Calcium is both a transported ion and a ligand; caffeine-assisted structures do not imply caffeine is required physiologically. research_relationship_category: regulation compartment_description: Cytosolic channel-regulatory region [ca-desgeorges2016] Structural Basis for Gating and Activation of RyR1 (2016). https://pubmed.ncbi.nlm.nih.gov/27662087/ DOI: 10.1016/j.cell.2016.08.075

compartment_description

ER membrane

experimental_model

Purified recombinant human SERCA2b; cryo-EM and ATPase characterization

limitations

Evidence specifies ATP2A2 splice isoform SERCA2b; kinetic properties should not be assigned to every SERCA isoform.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Homo sapiens

plain_language

SERCA2b uses ATP to refill ER calcium stores.

primary_references

[ca-zhang2020] Cryo-EM structures of SERCA2b reveal the mechanism of regulation by the luminal extension tail (2020). https://pubmed.ncbi.nlm.nih.gov/32851169/ DOI: 10.1126/sciadv.abb0147

research_relationship_category

transport

tissue_or_cell_type

Recombinant SERCA2b

transport_effect

lowers Recorded as sequestration of cytosolic calcium into the ER.

transport_or_reaction_direction

Cytosol to ER lumen

transport_pool

cytosolic calcium Recorded as sequestration of cytosolic calcium into the ER.

Calcium: mechanism-first literature curation (2026-09-17) · lines 571–583

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant human SERCA2b; cryo-EM and ATPase characterization · source_derived_draft · unverified_draft

### ca-serca2b-er-uptake Human SERCA2b couples its ATPase cycle to sequestration of cytosolic calcium into the ER. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: SERCA2b uses ATP to refill ER calcium stores. organism: Homo sapiens tissue_or_cell_type: Recombinant SERCA2b experimental_model: Purified recombinant human SERCA2b; cryo-EM and ATPase characterization limitations: Evidence specifies ATP2A2 splice isoform SERCA2b; kinetic properties should not be assigned to every SERCA isoform. research_relationship_category: transport transport_or_reaction_direction: Cytosol to ER lumen compartment_description: ER membrane [ca-zhang2020] Cryo-EM structures of SERCA2b reveal the mechanism of regulation by the luminal extension tail (2020). https://pubmed.ncbi.nlm.nih.gov/32851169/ DOI: 10.1126/sciadv.abb0147

evidence_span

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experimental_model

X-ray structure of a creatine kinase transition-state analogue complex

exposure

ADP, magnesium, nitrate and creatine complex at 2.1 angstrom resolution

limitations

Nitrate models the transferring phosphoryl group; it is not declared a physiological substrate. Structural magnesium dependence does not establish benefit from extra oral magnesium.

nutrient_topic

Creatine research collection; topical membership is not evidence of a direct dietary effect. · Creatine

organism

Torpedo californica enzyme

plain_language

Creatine can temporarily hold a phosphate group and return it to ADP when ATP must be regenerated.

primary_references

[creatine-p12437342] The 2.1 A structure of Torpedo californica creatine kinase complexed with the ADP-Mg(2+)-NO(3)(-)-creatine transition-state analogue complex. (2002). https://pubmed.ncbi.nlm.nih.gov/12437342/ DOI: 10.1021/bi026655p

tissue_or_cell_type

Purified creatine kinase

Creatine: synthesis, transport, phosphocreatine energetics and nutrient interactions (2026-09-17) · lines 334–345

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · X-ray structure of a creatine kinase transition-state analogue complex · source_derived_draft · unverified_draft

### creatine-ck-reversible-phosphate Creatine kinase catalyzes reversible phosphoryl transfer between ATP and creatine to form ADP and phosphocreatine. Condition category: normal nutrient_topic: Creatine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Creatine can temporarily hold a phosphate group and return it to ADP when ATP must be regenerated. organism: Torpedo californica enzyme tissue_or_cell_type: Purified creatine kinase experimental_model: X-ray structure of a creatine kinase transition-state analogue complex limitations: Nitrate models the transferring phosphoryl group; it is not declared a physiological substrate. Structural magnesium dependence does not establish benefit from extra oral magnesium. exposure: ADP, magnesium, nitrate and creatine complex at 2.1 angstrom resolution evidence_span: {"source_cache": "artifacts/creatine-research/12437342.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "291edd82015566452fe1b1321454a1df644a4c6da705fda90e8e369ea6ab53a1", "start_char": 0, "end_char": 1625, "text_sha256": "291edd82015566452fe1b1321454a1df644a4c6da705fda90e8e369ea6ab53a1"} [creatine-p12437342] The 2.1 A structure of Torpedo californica creatine kinase complexed with the ADP-Mg(2+)-NO(3)(-)-creatine transition-state analogue complex. (2002). https://pubmed.ncbi.nlm.nih.gov/12437342/ DOI: 10.1021/bi026655p

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

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experimental_model

Magnetic-resonance spectroscopy and contraction experiment with kinetic modeling

exposure

5 Hz stimulation, including the first 2 seconds and an 80-second steady state

limitations

Measured metabolite changes are distinguished from model-inferred ADP and oxidative activation; knockout compensation is possible.

nutrient_topic

Creatine research collection; topical membership is not evidence of a direct dietary effect. · Creatine

organism

Ckm-knockout and wild-type mice

plain_language

A normal resting energy measurement did not guarantee normal rapid buffering.

primary_references

[creatine-p12419710] Phosphocreatine kinetics at the onset of contractions in skeletal muscle of MM creatine kinase knockout mice. (2002). https://pubmed.ncbi.nlm.nih.gov/12419710/ DOI: 10.1152/ajpcell.00210.2002

tissue_or_cell_type

Gastrocnemius muscle

trigger_kind

machinery_impairment Imported condition classification; unverified.

Creatine: synthesis, transport, phosphocreatine energetics and nutrient interactions (2026-09-17) · lines 399–410

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Magnetic-resonance spectroscopy and contraction experiment with kinetic modeling · source_derived_draft · unverified_draft

### creatine-ckm-loss-resting-markers Resting PCr/ATP and pH did not differ, and no ATP change was detected at 2 seconds despite altered early phosphocreatine depletion. Condition category: machinery_impairment nutrient_topic: Creatine research collection; topical membership is not evidence of a direct dietary effect. plain_language: A normal resting energy measurement did not guarantee normal rapid buffering. organism: Ckm-knockout and wild-type mice tissue_or_cell_type: Gastrocnemius muscle experimental_model: Magnetic-resonance spectroscopy and contraction experiment with kinetic modeling limitations: Measured metabolite changes are distinguished from model-inferred ADP and oxidative activation; knockout compensation is possible. exposure: 5 Hz stimulation, including the first 2 seconds and an 80-second steady state evidence_span: {"source_cache": "artifacts/creatine-research/12419710.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e27a7cfa46bbfc4a05cb51ba54832614c64b750471ee2ea564c8232addb4bd68", "start_char": 0, "end_char": 1400, "text_sha256": "e27a7cfa46bbfc4a05cb51ba54832614c64b750471ee2ea564c8232addb4bd68"} [creatine-p12419710] Phosphocreatine kinetics at the onset of contractions in skeletal muscle of MM creatine kinase knockout mice. (2002). https://pubmed.ncbi.nlm.nih.gov/12419710/ DOI: 10.1152/ajpcell.00210.2002

evidence_span

{"source_cache": "artifacts/creatine-research/8692275.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "dca64c2f8e71d91a83ba9bbcc8cc320c7c87e2239de6f07111efe0560ac061c6", "start_char": 0, "end_char": 1125, "text_sha256": "dca64c2f8e71d91a83ba9bbcc8cc320c7c87e2239de6f07111efe0560ac061c6"}

experimental_model

Mitochondrial creatine kinase crystal structure

exposure

Octamer architecture and electrostatic surface analysis

limitations

The abstract does not specify the organism; no human-specific structural assignment is made. Membrane binding interpretation accompanies structural data.

nutrient_topic

Creatine research collection; topical membership is not evidence of a direct dietary effect. · Creatine

organism

Mitochondrial creatine kinase preparation in the primary study

plain_language

Mitochondrial creatine kinase can load the phosphate carrier near the site of ATP production.

primary_references

[creatine-p8692275] Structure of mitochondrial creatine kinase. (1996). https://pubmed.ncbi.nlm.nih.gov/8692275/ DOI: 10.1038/381341a0

tissue_or_cell_type

Purified protein; mitochondrial membrane interface interpretation

Creatine: synthesis, transport, phosphocreatine energetics and nutrient interactions (2026-09-17) · lines 360–371

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mitochondrial creatine kinase crystal structure · source_derived_draft · unverified_draft

### creatine-mitochondrial-ck-organization The mitochondrial creatine kinase structure supported an octameric enzyme positioned to convert mitochondrially generated ATP into phosphocreatine. Condition category: normal nutrient_topic: Creatine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Mitochondrial creatine kinase can load the phosphate carrier near the site of ATP production. organism: Mitochondrial creatine kinase preparation in the primary study tissue_or_cell_type: Purified protein; mitochondrial membrane interface interpretation experimental_model: Mitochondrial creatine kinase crystal structure limitations: The abstract does not specify the organism; no human-specific structural assignment is made. Membrane binding interpretation accompanies structural data. exposure: Octamer architecture and electrostatic surface analysis evidence_span: {"source_cache": "artifacts/creatine-research/8692275.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "dca64c2f8e71d91a83ba9bbcc8cc320c7c87e2239de6f07111efe0560ac061c6", "start_char": 0, "end_char": 1125, "text_sha256": "dca64c2f8e71d91a83ba9bbcc8cc320c7c87e2239de6f07111efe0560ac061c6"} [creatine-p8692275] Structure of mitochondrial creatine kinase. (1996). https://pubmed.ncbi.nlm.nih.gov/8692275/ DOI: 10.1038/381341a0

evidence_span

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experimental_model

Oral loading with muscle biopsies

exposure

5 g creatine four to six times daily for two or more days

limitations

Loading study, not evidence that everyone is deficient; the indexed abstract is truncated and no unreported exercise effect is extracted.

nutrient_topic

Creatine research collection; topical membership is not evidence of a direct dietary effect. · Creatine

organism

17 human participants

plain_language

More creatine expanded the phosphate reserve without simply raising resting ATP.

primary_references

[creatine-p1327657] Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation. (1992). https://pubmed.ncbi.nlm.nih.gov/1327657/ DOI: 10.1042/cs0830367

tissue_or_cell_type

Skeletal muscle and blood

Creatine: synthesis, transport, phosphocreatine energetics and nutrient interactions (2026-09-17) · lines 945–956

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Oral loading with muscle biopsies · source_derived_draft · unverified_draft

### creatine-pcr-versus-atp-loading Approximately 20% or more of the creatine taken up was recovered as phosphocreatine, while muscle ATP concentration did not change. Condition category: normal nutrient_topic: Creatine research collection; topical membership is not evidence of a direct dietary effect. plain_language: More creatine expanded the phosphate reserve without simply raising resting ATP. organism: 17 human participants tissue_or_cell_type: Skeletal muscle and blood experimental_model: Oral loading with muscle biopsies limitations: Loading study, not evidence that everyone is deficient; the indexed abstract is truncated and no unreported exercise effect is extracted. exposure: 5 g creatine four to six times daily for two or more days evidence_span: {"source_cache": "artifacts/creatine-research/1327657.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3ae0516c0f0465293ac00446b6a863fa2d791a750258a11b532c1247fdb47bd6", "start_char": 0, "end_char": 1573, "text_sha256": "3ae0516c0f0465293ac00446b6a863fa2d791a750258a11b532c1247fdb47bd6"} [creatine-p1327657] Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation. (1992). https://pubmed.ncbi.nlm.nih.gov/1327657/ DOI: 10.1042/cs0830367

evidence_span

{"source_cache": "artifacts/creatine-research/38418482.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "b6dad9388eb7cb8986f1873e6ba9f8dd36924c7a9aa7c661059cde1012f1e3a8", "start_char": 0, "end_char": 1364, "text_sha256": "b6dad9388eb7cb8986f1873e6ba9f8dd36924c7a9aa7c661059cde1012f1e3a8"}

experimental_model

Placebo comparison with repeated phosphorus/proton MRS and cognition

exposure

Single creatine monohydrate dose 0.35 g/kg during approximately 21 hours of sleep deprivation

limitations

Acute high-dose, sleep-deprivation setting; not an everyday dose recommendation or proof of benefit in well-rested people.

nutrient_topic

Creatine research collection; topical membership is not evidence of a direct dietary effect. · Creatine

organism

Human participants during sleep deprivation

plain_language

The experiment detected changes in brain energy-related measurements under acute sleep stress.

primary_references

[creatine-p38418482] Single dose creatine improves cognitive performance and induces changes in cerebral high energy phosphates during sleep deprivation. (2024). https://pubmed.ncbi.nlm.nih.gov/38418482/ DOI: 10.1038/s41598-024-54249-9

tissue_or_cell_type

Brain spectroscopy and cognitive performance

Creatine: synthesis, transport, phosphocreatine energetics and nutrient interactions (2026-09-17) · lines 1049–1060

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Placebo comparison with repeated phosphorus/proton MRS and cognition · source_derived_draft · unverified_draft

### creatine-sleep-deprivation-phosphates Creatine altered PCr/Pi, ATP and total-creatine/total-NAA measures and prevented the observed fall in brain pH during sleep deprivation. Condition category: normal nutrient_topic: Creatine research collection; topical membership is not evidence of a direct dietary effect. plain_language: The experiment detected changes in brain energy-related measurements under acute sleep stress. organism: Human participants during sleep deprivation tissue_or_cell_type: Brain spectroscopy and cognitive performance experimental_model: Placebo comparison with repeated phosphorus/proton MRS and cognition limitations: Acute high-dose, sleep-deprivation setting; not an everyday dose recommendation or proof of benefit in well-rested people. exposure: Single creatine monohydrate dose 0.35 g/kg during approximately 21 hours of sleep deprivation evidence_span: {"source_cache": "artifacts/creatine-research/38418482.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "b6dad9388eb7cb8986f1873e6ba9f8dd36924c7a9aa7c661059cde1012f1e3a8", "start_char": 0, "end_char": 1364, "text_sha256": "b6dad9388eb7cb8986f1873e6ba9f8dd36924c7a9aa7c661059cde1012f1e3a8"} [creatine-p38418482] Single dose creatine improves cognitive performance and induces changes in cerebral high energy phosphates during sleep deprivation. (2024). https://pubmed.ncbi.nlm.nih.gov/38418482/ DOI: 10.1038/s41598-024-54249-9

evidence_span

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experimental_model

Human enzyme mutagenesis, kinetics and molecular dynamics

exposure

S-loop variants; established biosynthetic reactions described in the introduction

limitations

Reaction descriptions are background chemistry in a primary enzyme paper, not evidence that sulforaphane corrects inherited GSS deficiency.

nutrient_topic

Sulforaphane research collection; topical membership is not evidence of a direct dietary effect. · Sulforaphane / SFN, stereochemistry specified per study

organism

Human GSS

plain_language

The induced glutathione pathway still depends on ordinary enzyme cofactors.

primary_references

[sulforaphane-p30581542] Genetic Mutations in the S-loop of Human Glutathione Synthetase: Links Between Substrate Binding, Active Site Structure and Allostery. (2019). https://pubmed.ncbi.nlm.nih.gov/30581542/ DOI: 10.1016/j.csbj.2018.11.008

tissue_or_cell_type

Glutathione synthesis and substrate binding

Sulforaphane: formation, electrophile sensing and nutrient connections (2026-09-17) · lines 866–877

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human enzyme mutagenesis, kinetics and molecular dynamics · source_derived_draft · unverified_draft

### sulforaphane-gss-magnesium The human GSS active sites bind ATP and associated magnesium for peptide-bond formation. Condition category: normal nutrient_topic: Sulforaphane research collection; topical membership is not evidence of a direct dietary effect. plain_language: The induced glutathione pathway still depends on ordinary enzyme cofactors. organism: Human GSS tissue_or_cell_type: Glutathione synthesis and substrate binding experimental_model: Human enzyme mutagenesis, kinetics and molecular dynamics limitations: Reaction descriptions are background chemistry in a primary enzyme paper, not evidence that sulforaphane corrects inherited GSS deficiency. exposure: S-loop variants; established biosynthetic reactions described in the introduction evidence_span: {"source_cache": "artifacts/sulforaphane-research/30581542.fulltext.txt", "locator": "Primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "77cf6674cf9b9bc140a228588a53c937966fd3a67397c1c4970221c5cc58a0b1", "start_char": 1428, "end_char": 1604, "text_sha256": "a5d33b10162adea5e60fcff380eabf7e272963711914ea0e8e7091ad8c79df21"} [sulforaphane-p30581542] Genetic Mutations in the S-loop of Human Glutathione Synthetase: Links Between Substrate Binding, Active Site Structure and Allostery. (2019). https://pubmed.ncbi.nlm.nih.gov/30581542/ DOI: 10.1016/j.csbj.2018.11.008

evidence_span

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experimental_model

Human enzyme mutagenesis, kinetics and molecular dynamics

exposure

S-loop variants; established biosynthetic reactions described in the introduction

limitations

Reaction descriptions are background chemistry in a primary enzyme paper, not evidence that sulforaphane corrects inherited GSS deficiency.

nutrient_topic

Sulforaphane research collection; topical membership is not evidence of a direct dietary effect. · Sulforaphane / SFN, stereochemistry specified per study

organism

Human GSS

plain_language

A second enzyme, glycine and energy complete the molecule.

primary_references

[sulforaphane-p30581542] Genetic Mutations in the S-loop of Human Glutathione Synthetase: Links Between Substrate Binding, Active Site Structure and Allostery. (2019). https://pubmed.ncbi.nlm.nih.gov/30581542/ DOI: 10.1016/j.csbj.2018.11.008

tissue_or_cell_type

Glutathione synthesis and substrate binding

Sulforaphane: formation, electrophile sensing and nutrient connections (2026-09-17) · lines 853–864

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human enzyme mutagenesis, kinetics and molecular dynamics · source_derived_draft · unverified_draft

### sulforaphane-gss-second-step Human GSS joins gamma-glutamylcysteine and glycine in an ATP-dependent reaction to form glutathione. Condition category: normal nutrient_topic: Sulforaphane research collection; topical membership is not evidence of a direct dietary effect. plain_language: A second enzyme, glycine and energy complete the molecule. organism: Human GSS tissue_or_cell_type: Glutathione synthesis and substrate binding experimental_model: Human enzyme mutagenesis, kinetics and molecular dynamics limitations: Reaction descriptions are background chemistry in a primary enzyme paper, not evidence that sulforaphane corrects inherited GSS deficiency. exposure: S-loop variants; established biosynthetic reactions described in the introduction evidence_span: {"source_cache": "artifacts/sulforaphane-research/30581542.fulltext.txt", "locator": "Primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "77cf6674cf9b9bc140a228588a53c937966fd3a67397c1c4970221c5cc58a0b1", "start_char": 923, "end_char": 1092, "text_sha256": "bed9ef1323b513b1e31b65277f28b935ddf0c9b0c83cbe9ee9f827f97806846c"} [sulforaphane-p30581542] Genetic Mutations in the S-loop of Human Glutathione Synthetase: Links Between Substrate Binding, Active Site Structure and Allostery. (2019). https://pubmed.ncbi.nlm.nih.gov/30581542/ DOI: 10.1016/j.csbj.2018.11.008

cross_nutrient

B1 cleavage is sequentially coupled to B5-derived CoA activation and B3-related NAD oxidation.

evidence

[{"paper_key": "foulon-2005-hacl1", "source_bundle": "artifacts/thiamine_metabolism_sources.json", "passage_ids": ["abstract"], "locator": "Primary publication abstract", "preservation": "Exact text retained in the source bundle; full source document retained when openly retrievable."}]

experimental_model

Intact/permeabilized rat hepatocytes and liver preparations.

limitations

Whole-pathway requirements cannot all be assigned to the isolated lyase.

nutrient

Thiamine (vitamin B1) · Thiamine (vitamin B1)

nutrient_topic

Thiamine research collection; topical membership is not evidence of a direct dietary effect. · Thiamine (vitamin B1)

organism

Rattus norvegicus

plain_language

ATP activates the fatty acid upstream, while NAD supports later oxidation. Listing all pathway cofactors does not mean HACL itself consumes ATP or NAD.

primary_references

[foulon-2005-hacl1] Breakdown of 2-hydroxylated straight chain fatty acids via peroxisomal 2-hydroxyphytanoyl-CoA lyase: a revised pathway for the alpha-oxidation of straight chain fatty acids (2005). https://pubmed.ncbi.nlm.nih.gov/15644336/ DOI: 10.1074/jbc.m413362200

tissue_or_cell_type

Liver

Thiamine: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1003–1015

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Intact/permeabilized rat hepatocytes and liver preparations. · source_derived_draft · unverified_draft

### b1-alpha-oxidation-activation-before-cleavage Rat liver/hepatocyte pathway experiments supported activation of 2-hydroxy-fatty acid to its CoA ester before ThDP-dependent cleavage; whole-pathway assays required ATP, CoA, Mg2+, ThDP and NAD+. Condition category: normal nutrient_topic: Thiamine research collection; topical membership is not evidence of a direct dietary effect. plain_language: ATP activates the fatty acid upstream, while NAD supports later oxidation. Listing all pathway cofactors does not mean HACL itself consumes ATP or NAD. organism: Rattus norvegicus tissue_or_cell_type: Liver experimental_model: Intact/permeabilized rat hepatocytes and liver preparations. limitations: Whole-pathway requirements cannot all be assigned to the isolated lyase. evidence: [{"paper_key": "foulon-2005-hacl1", "source_bundle": "artifacts/thiamine_metabolism_sources.json", "passage_ids": ["abstract"], "locator": "Primary publication abstract", "preservation": "Exact text retained in the source bundle; full source document retained when openly retrievable."}] cross_nutrient: B1 cleavage is sequentially coupled to B5-derived CoA activation and B3-related NAD oxidation. nutrient: Thiamine (vitamin B1) [foulon-2005-hacl1] Breakdown of 2-hydroxylated straight chain fatty acids via peroxisomal 2-hydroxyphytanoyl-CoA lyase: a revised pathway for the alpha-oxidation of straight chain fatty acids (2005). https://pubmed.ncbi.nlm.nih.gov/15644336/ DOI: 10.1074/jbc.m413362200

evidence

[{"paper_key": "li-2004-bckdh", "source_bundle": "artifacts/thiamine_metabolism_sources.json", "passage_ids": ["abstract"], "locator": "Primary publication abstract", "preservation": "Exact text retained in the source bundle; full source document retained when openly retrievable."}]

experimental_model

Human E1b/E2b with recombinant rat BCKD kinase.

limitations

Mixed-species assay; kinase accessibility, not clinical thiamine responsiveness.

nutrient

Thiamine (vitamin B1) · Thiamine (vitamin B1)

nutrient_topic

Thiamine research collection; topical membership is not evidence of a direct dietary effect. · Thiamine (vitamin B1)

organism

Homo sapiens E1/E2; Rattus norvegicus kinase

plain_language

Cofactor occupancy also affected access to a regulatory site. The result depends on an intact loop and does not show that every genetic BCKDH defect responds to B1.

primary_references

[li-2004-bckdh] Cross-talk between thiamin diphosphate binding and phosphorylation loop conformation in human branched-chain alpha-keto acid decarboxylase/dehydrogenase (2004). https://pubmed.ncbi.nlm.nih.gov/15166214/ DOI: 10.1074/jbc.m403611200

tissue_or_cell_type

Purified mixed-species assay

Thiamine: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 801–812

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human E1b/E2b with recombinant rat BCKD kinase. · source_derived_draft · unverified_draft

### b1-bckdh-cofactor-limits-phosphorylation ThDP reduced kinase-mediated phosphorylation of wild-type human E1b; loop-network mutations abolished this protection in the reconstituted assay. Condition category: normal nutrient_topic: Thiamine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Cofactor occupancy also affected access to a regulatory site. The result depends on an intact loop and does not show that every genetic BCKDH defect responds to B1. organism: Homo sapiens E1/E2; Rattus norvegicus kinase tissue_or_cell_type: Purified mixed-species assay experimental_model: Human E1b/E2b with recombinant rat BCKD kinase. limitations: Mixed-species assay; kinase accessibility, not clinical thiamine responsiveness. evidence: [{"paper_key": "li-2004-bckdh", "source_bundle": "artifacts/thiamine_metabolism_sources.json", "passage_ids": ["abstract"], "locator": "Primary publication abstract", "preservation": "Exact text retained in the source bundle; full source document retained when openly retrievable."}] nutrient: Thiamine (vitamin B1) [li-2004-bckdh] Cross-talk between thiamin diphosphate binding and phosphorylation loop conformation in human branched-chain alpha-keto acid decarboxylase/dehydrogenase (2004). https://pubmed.ncbi.nlm.nih.gov/15166214/ DOI: 10.1074/jbc.m403611200

evidence-scope

Brain mitochondria

evidence_locator

Results: ThTP synthesis in isolated mitochondria and energy coupling

evidence_spans

[{"source_document": "artifacts/thiamine_transport_sources/gangolf-2010-thtp-source-record.json", "source_field": "resultList.result[0].abstractText", "start_char": 0, "end_char": 1672}]

experimental_model

Isolated rat brain mitochondria; ThDP/Pi incubation, respiratory substrates and inhibitors.

limitations

Not a demonstrated human signaling function or a TPK1 reaction.

nutrient_topic

Thiamine research collection; topical membership is not evidence of a direct dietary effect. · Thiamine (vitamin B1)

organism

Rattus norvegicus

plain_language

A third phosphate can be added to B1 using respiratory energy in this preparation.

primary_references

[gangolf-2010-thtp] Thiamine Triphosphate Synthesis in Rat Brain Occurs in Mitochondria and Is Coupled to the Respiratory Chain (2010). https://pmc.ncbi.nlm.nih.gov/articles/PMC2804207/ DOI: 10.1074/jbc.M109.054379

reaction

ThDP + Pi <-> ThTP + water; coupled to respiratory energy

tissue_or_cell_type

Brain mitochondria

Thiamine: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 602–615

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Isolated rat brain mitochondria; ThDP/Pi incubation, respiratory substrates and inhibitors. · source_derived_draft · unverified_draft

### b1-brain-thtp-from-thdp-and-pi Rat brain mitochondria formed ThTP from ThDP and inorganic phosphate with respiratory substrates; ATP hydrolysis did not energize synthesis. Condition category: normal nutrient_topic: Thiamine research collection; topical membership is not evidence of a direct dietary effect. plain_language: A third phosphate can be added to B1 using respiratory energy in this preparation. organism: Rattus norvegicus tissue_or_cell_type: Brain mitochondria experimental_model: Isolated rat brain mitochondria; ThDP/Pi incubation, respiratory substrates and inhibitors. limitations: Not a demonstrated human signaling function or a TPK1 reaction. reaction: ThDP + Pi <-> ThTP + water; coupled to respiratory energy evidence_spans: [{"source_document": "artifacts/thiamine_transport_sources/gangolf-2010-thtp-source-record.json", "source_field": "resultList.result[0].abstractText", "start_char": 0, "end_char": 1672}] evidence_locator: Results: ThTP synthesis in isolated mitochondria and energy coupling evidence-scope: Brain mitochondria [gangolf-2010-thtp] Thiamine Triphosphate Synthesis in Rat Brain Occurs in Mitochondria and Is Coupled to the Respiratory Chain (2010). https://pmc.ncbi.nlm.nih.gov/articles/PMC2804207/ DOI: 10.1074/jbc.M109.054379

cross_nutrient

Provides the B5-derived CoA partner required by PDH, OGDH, BCKDH and OADH; simultaneous B1/B5 depletion was not tested.

evidence

[{"paper_key": "daugherty-2002-coa", "source_bundle": "artifacts/thiamine_metabolism_sources.json", "passage_ids": ["abstract"], "locator": "Primary publication abstract", "preservation": "Exact text retained in the source bundle; full source document retained when openly retrievable."}]

experimental_model

Reconstituted human enzyme pathway.

limitations

Cross-pathway connection is biochemical integration, not a tested clinical supplementation interaction.

nutrient

Thiamine (vitamin B1) · Thiamine (vitamin B1)

nutrient_topic

Thiamine research collection; topical membership is not evidence of a direct dietary effect. · Thiamine (vitamin B1)

organism

Homo sapiens

plain_language

Vitamin B5 supplies a separate carrier used after B1-dependent decarboxylation. The experiment starts with phosphorylated B5, so it does not test absorption or the first phosphorylation step.

primary_references

[daugherty-2002-coa] Complete reconstitution of the human coenzyme A biosynthetic pathway via comparative genomics (2002). https://pubmed.ncbi.nlm.nih.gov/11923312/ DOI: 10.1074/jbc.m201708200

tissue_or_cell_type

Purified recombinant enzymes

Thiamine: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 731–743

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Reconstituted human enzyme pathway. · source_derived_draft · unverified_draft

### b1-coa-b5-downstream-biosynthesis Purified human PPCS, PPCDC and bifunctional CoA synthase reconstituted CoA synthesis from phosphopantothenate in vitro. Condition category: normal nutrient_topic: Thiamine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin B5 supplies a separate carrier used after B1-dependent decarboxylation. The experiment starts with phosphorylated B5, so it does not test absorption or the first phosphorylation step. organism: Homo sapiens tissue_or_cell_type: Purified recombinant enzymes experimental_model: Reconstituted human enzyme pathway. limitations: Cross-pathway connection is biochemical integration, not a tested clinical supplementation interaction. evidence: [{"paper_key": "daugherty-2002-coa", "source_bundle": "artifacts/thiamine_metabolism_sources.json", "passage_ids": ["abstract"], "locator": "Primary publication abstract", "preservation": "Exact text retained in the source bundle; full source document retained when openly retrievable."}] cross_nutrient: Provides the B5-derived CoA partner required by PDH, OGDH, BCKDH and OADH; simultaneous B1/B5 depletion was not tested. nutrient: Thiamine (vitamin B1) [daugherty-2002-coa] Complete reconstitution of the human coenzyme A biosynthetic pathway via comparative genomics (2002). https://pubmed.ncbi.nlm.nih.gov/11923312/ DOI: 10.1074/jbc.m201708200

cross_nutrient

B2 activation and Mg-dependent FAD synthesis provide a biochemical partner to B1-dependent complexes; direct transfer of newly made FAD to DLD was not tested.

evidence

[{"paper_key": "brizio-2006-fad", "source_bundle": "artifacts/thiamine_metabolism_sources.json", "passage_ids": ["abstract"], "locator": "Primary publication abstract", "preservation": "Exact text retained in the source bundle; full source document retained when openly retrievable."}]

experimental_model

Recombinant human FLAD1 isoforms expressed in E. coli.

limitations

No tissue Mg threshold or combined B1/B2 deficiency experiment.

nutrient

Thiamine (vitamin B1) · Thiamine (vitamin B1)

nutrient_topic

Thiamine research collection; topical membership is not evidence of a direct dietary effect. · Thiamine (vitamin B1)

organism

Homo sapiens

plain_language

The flavin used by E3 must first be made from the riboflavin pathway. This distinct magnesium-dependent synthesis reaction should not be confused with magnesium binding to B1 enzymes.

primary_references

[brizio-2006-fad] Over-expression in Escherichia coli and characterization of two recombinant isoforms of human FAD synthetase (2006). https://pubmed.ncbi.nlm.nih.gov/16643857/ DOI: 10.1016/j.bbrc.2006.04.003

tissue_or_cell_type

Purified/expressed proteins

Thiamine: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 745–757

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human FLAD1 isoforms expressed in E. coli. · source_derived_draft · unverified_draft

### b1-fad-b2-cofactor-synthesis Recombinant human FLAD1 isoforms 1 and 2 exhibited FAD synthetase activity; isoform 2 was purified, and activity required MgCl2. Condition category: normal nutrient_topic: Thiamine research collection; topical membership is not evidence of a direct dietary effect. plain_language: The flavin used by E3 must first be made from the riboflavin pathway. This distinct magnesium-dependent synthesis reaction should not be confused with magnesium binding to B1 enzymes. organism: Homo sapiens tissue_or_cell_type: Purified/expressed proteins experimental_model: Recombinant human FLAD1 isoforms expressed in E. coli. limitations: No tissue Mg threshold or combined B1/B2 deficiency experiment. evidence: [{"paper_key": "brizio-2006-fad", "source_bundle": "artifacts/thiamine_metabolism_sources.json", "passage_ids": ["abstract"], "locator": "Primary publication abstract", "preservation": "Exact text retained in the source bundle; full source document retained when openly retrievable."}] cross_nutrient: B2 activation and Mg-dependent FAD synthesis provide a biochemical partner to B1-dependent complexes; direct transfer of newly made FAD to DLD was not tested. nutrient: Thiamine (vitamin B1) [brizio-2006-fad] Over-expression in Escherichia coli and characterization of two recombinant isoforms of human FAD synthetase (2006). https://pubmed.ncbi.nlm.nih.gov/16643857/ DOI: 10.1016/j.bbrc.2006.04.003

availability_state

machinery_impairment Imported condition classification; unverified.

evidence-scope

Recombinant enzyme

evidence_locator

Abstract

evidence_spans

[{"source_document": "artifacts/thiamine_transport_sources/onozuka-2003-tpk1-source-record.json", "source_field": "resultList.result[0].abstractText", "start_char": 0, "end_char": 1438}]

experimental_model

Purified His-tagged human TPK1; ATP/Mg kinetics and mutagenesis.

limitations

Engineered mutation; not an isolated clinical magnesium effect.

nutrient_topic

Thiamine research collection; topical membership is not evidence of a direct dietary effect. · Thiamine (vitamin B1)

organism

Homo sapiens

plain_language

Disrupting an active-site residue impairs B1 activation.

primary_references

[onozuka-2003-tpk1] Steady-state kinetics and mutational studies of recombinant human thiamin pyrophosphokinase (2003). https://pubmed.ncbi.nlm.nih.gov/12953792/ DOI: 10.3177/jnsv.49.156 [sambon-2022-tpk1] Product inhibition of mammalian thiamine pyrophosphokinase is an important mechanism for maintaining thiamine diphosphate homeostasis (2022). https://doi.org/10.1016/j.bbagen.2021.130071 DOI: 10.1016/j.bbagen.2021.130071

tissue_or_cell_type

Recombinant enzyme

trigger_kind

machinery_impairment Imported condition classification; unverified.

Thiamine: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 358–371

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified His-tagged human TPK1; ATP/Mg kinetics and mutagenesis. · source_derived_draft · unverified_draft

### b1-tpk1-d71n-catalysis D71N markedly decreased recombinant human TPK1 catalytic turnover. Condition category: machinery_impairment nutrient_topic: Thiamine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Disrupting an active-site residue impairs B1 activation. organism: Homo sapiens tissue_or_cell_type: Recombinant enzyme experimental_model: Purified His-tagged human TPK1; ATP/Mg kinetics and mutagenesis. limitations: Engineered mutation; not an isolated clinical magnesium effect. evidence_spans: [{"source_document": "artifacts/thiamine_transport_sources/onozuka-2003-tpk1-source-record.json", "source_field": "resultList.result[0].abstractText", "start_char": 0, "end_char": 1438}] evidence_locator: Abstract evidence-scope: Recombinant enzyme [onozuka-2003-tpk1] Steady-state kinetics and mutational studies of recombinant human thiamin pyrophosphokinase (2003). https://pubmed.ncbi.nlm.nih.gov/12953792/ DOI: 10.3177/jnsv.49.156 [sambon-2022-tpk1] Product inhibition of mammalian thiamine pyrophosphokinase is an important mechanism for maintaining thiamine diphosphate homeostasis (2022). https://doi.org/10.1016/j.bbagen.2021.130071 DOI: 10.1016/j.bbagen.2021.130071

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_location

Abstract

evidence_span

ATP level decreased after 8 days

experimental_model

Newborn-rat cardiac cells in culture; thiamine omitted from growth medium without an added thiamine antagonist; time course and readdition experiments.

exposure

Thiamine omitted from rat cardiac-cell growth medium

limitations

Total ATP content does not distinguish reduced synthesis from altered consumption or identify one limiting enzyme.

nutrient_topic

Thiamine research collection; topical membership is not evidence of a direct dietary effect. · Thiamine (vitamin B1)

organism

Rattus norvegicus

plain_language

Energy content fell before the reported onset of extensive degeneration.

primary_references

[zangen-1997-cardiac-culture] Thiamine deficiency in cardiac cells in culture (1997). https://pubmed.ncbi.nlm.nih.gov/9337073/ DOI: 10.1016/S0006-2952(97)00178-0

tissue_or_cell_type

Cultured cardiac cells

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Thiamine: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1353–1365

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Newborn-rat cardiac cells in culture; thiamine omitted from growth medium without an added thiamine antagonist; time course and readdition experiments. · source_derived_draft · unverified_draft

### thiamine-def-cardiac-atp-depletion ATP began falling after eight days without thiamine and reached about half of control by day ten. Condition category: nutrient_deficiency nutrient_topic: Thiamine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Energy content fell before the reported onset of extensive degeneration. organism: Rattus norvegicus tissue_or_cell_type: Cultured cardiac cells experimental_model: Newborn-rat cardiac cells in culture; thiamine omitted from growth medium without an added thiamine antagonist; time course and readdition experiments. limitations: Total ATP content does not distinguish reduced synthesis from altered consumption or identify one limiting enzyme. evidence_location: Abstract evidence_span: ATP level decreased after 8 days exposure: Thiamine omitted from rat cardiac-cell growth medium [zangen-1997-cardiac-culture] Thiamine deficiency in cardiac cells in culture (1997). https://pubmed.ncbi.nlm.nih.gov/9337073/ DOI: 10.1016/S0006-2952(97)00178-0

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_location

Abstract

evidence_span

before the onset of neurological signs

experimental_model

Adult male Wistar rats with pyrithiamine-induced acute thiamine-deficient encephalopathy; microwave fixation and regional ATP/phosphocreatine assays before and after neurological signs.

exposure

Pyrithiamine-induced severe thiamine deficiency in rats

limitations

Combined thiamine withdrawal and pyrithiamine exposure; not an estimate for mild dietary insufficiency or a human blood threshold.

nutrient_topic

Thiamine research collection; topical membership is not evidence of a direct dietary effect. · Thiamine (vitamin B1)

organism

Rattus norvegicus

plain_language

Energy reserves fell early in two vulnerable brain regions.

primary_references

[aikawa-1984-brain-energy] Low energy levels in thiamine-deficient encephalopathy. (1984). https://pubmed.ncbi.nlm.nih.gov/6726285/ DOI: 10.1097/00005072-198405000-00006

tissue_or_cell_type

Diencephalon and lower brainstem

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Thiamine: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1070–1082

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Adult male Wistar rats with pyrithiamine-induced acute thiamine-deficient encephalopathy; microwave fixation and regional ATP/phosphocreatine assays before and after neurological signs. · source_derived_draft · unverified_draft

### thiamine-def-regional-energy-loss Before neurological signs, total high-energy phosphates were 89% of control in diencephalon and 91% in lower brainstem; after signs, 76% and 79%. Condition category: nutrient_deficiency nutrient_topic: Thiamine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Energy reserves fell early in two vulnerable brain regions. organism: Rattus norvegicus tissue_or_cell_type: Diencephalon and lower brainstem experimental_model: Adult male Wistar rats with pyrithiamine-induced acute thiamine-deficient encephalopathy; microwave fixation and regional ATP/phosphocreatine assays before and after neurological signs. limitations: Combined thiamine withdrawal and pyrithiamine exposure; not an estimate for mild dietary insufficiency or a human blood threshold. evidence_location: Abstract evidence_span: before the onset of neurological signs exposure: Pyrithiamine-induced severe thiamine deficiency in rats [aikawa-1984-brain-energy] Low energy levels in thiamine-deficient encephalopathy. (1984). https://pubmed.ncbi.nlm.nih.gov/6726285/ DOI: 10.1097/00005072-198405000-00006

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_location

Abstract

evidence_span

high energy phosphates were not significantly reduced

experimental_model

Adult male Wistar rats with pyrithiamine-induced acute thiamine-deficient encephalopathy; microwave fixation and regional ATP/phosphocreatine assays before and after neurological signs.

exposure

Pyrithiamine-induced severe thiamine deficiency in rats

limitations

A nonsignificant result does not prove unchanged ATP in every cell or at later stages. Combined thiamine withdrawal and pyrithiamine exposure; not an estimate for mild dietary insufficiency or a human blood threshold.

nutrient_topic

Thiamine research collection; topical membership is not evidence of a direct dietary effect. · Thiamine (vitamin B1)

organism

Rattus norvegicus

plain_language

A severe thiamine-deficiency model did not cause uniform energy depletion across the brain.

primary_references

[aikawa-1984-brain-energy] Low energy levels in thiamine-deficient encephalopathy. (1984). https://pubmed.ncbi.nlm.nih.gov/6726285/ DOI: 10.1097/00005072-198405000-00006

tissue_or_cell_type

Cerebral cortex and cerebellum

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Thiamine: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1084–1096

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Adult male Wistar rats with pyrithiamine-induced acute thiamine-deficient encephalopathy; microwave fixation and regional ATP/phosphocreatine assays before and after neurological signs. · source_derived_draft · unverified_draft

### thiamine-def-regional-energy-preservation Cerebral cortex and cerebellum showed no significant high-energy phosphate reduction in the same encephalopathic rats. Condition category: nutrient_deficiency nutrient_topic: Thiamine research collection; topical membership is not evidence of a direct dietary effect. plain_language: A severe thiamine-deficiency model did not cause uniform energy depletion across the brain. organism: Rattus norvegicus tissue_or_cell_type: Cerebral cortex and cerebellum experimental_model: Adult male Wistar rats with pyrithiamine-induced acute thiamine-deficient encephalopathy; microwave fixation and regional ATP/phosphocreatine assays before and after neurological signs. limitations: A nonsignificant result does not prove unchanged ATP in every cell or at later stages. Combined thiamine withdrawal and pyrithiamine exposure; not an estimate for mild dietary insufficiency or a human blood threshold. evidence_location: Abstract evidence_span: high energy phosphates were not significantly reduced exposure: Pyrithiamine-induced severe thiamine deficiency in rats [aikawa-1984-brain-energy] Low energy levels in thiamine-deficient encephalopathy. (1984). https://pubmed.ncbi.nlm.nih.gov/6726285/ DOI: 10.1097/00005072-198405000-00006

evidence_span

{"source_cache": "artifacts/mangiferin-research/29563875.fulltext.txt", "locator": "Primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1a48a1f92d67cd91638969bb1ec3cb9f18cb3cb4e29c7e5f2bacf627dda76415", "start_char": 35775, "end_char": 36269, "text_sha256": "9c428b34591bbbb1e453a4e5e2829b160930ef301d3b39065822f132f5a7dcd9"}

experimental_model

KK-Ay mouse liver experiments and mechanistic HepG2 studies

exposure

Norathyriol in sodium-oleate lipid-loading model; micromolar range

limitations

Phosphorylation and expression are scoped to experiments; no established human fatty-liver therapy or direct SIRT1 ligand claim.

nutrient_topic

Mangiferin research collection; topical membership is not evidence of a direct dietary effect. · Mangiferin

organism

Homo sapiens for HepG2 experiments; mouse findings separately scoped

plain_language

The energy-sensing signal changed alongside AMPK activation.

primary_references

[mangiferin-p29563875] Mangiferin Improves Hepatic Lipid Metabolism Mainly Through Its Metabolite-Norathyriol by Modulating SIRT-1/AMPK/SREBP-1c Signaling. (2018). https://pubmed.ncbi.nlm.nih.gov/29563875/ DOI: 10.3389/fphar.2018.00201

tissue_or_cell_type

HepG2 cells

Mangiferin: metabolism, signaling and nutrient connections (2026-09-17) · lines 471–482

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · KK-Ay mouse liver experiments and mechanistic HepG2 studies · source_derived_draft · unverified_draft

### mangiferin-energy-ratio Norathyriol increased the cellular AMP-to-ATP ratio in the tested HepG2 model. Condition category: normal nutrient_topic: Mangiferin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The energy-sensing signal changed alongside AMPK activation. organism: Homo sapiens for HepG2 experiments; mouse findings separately scoped tissue_or_cell_type: HepG2 cells experimental_model: KK-Ay mouse liver experiments and mechanistic HepG2 studies limitations: Phosphorylation and expression are scoped to experiments; no established human fatty-liver therapy or direct SIRT1 ligand claim. exposure: Norathyriol in sodium-oleate lipid-loading model; micromolar range evidence_span: {"source_cache": "artifacts/mangiferin-research/29563875.fulltext.txt", "locator": "Primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1a48a1f92d67cd91638969bb1ec3cb9f18cb3cb4e29c7e5f2bacf627dda76415", "start_char": 35775, "end_char": 36269, "text_sha256": "9c428b34591bbbb1e453a4e5e2829b160930ef301d3b39065822f132f5a7dcd9"} [mangiferin-p29563875] Mangiferin Improves Hepatic Lipid Metabolism Mainly Through Its Metabolite-Norathyriol by Modulating SIRT-1/AMPK/SREBP-1c Signaling. (2018). https://pubmed.ncbi.nlm.nih.gov/29563875/ DOI: 10.3389/fphar.2018.00201

evidence_access

Primary abstract

experimental_model

125–500 micromolar citrinin; reported ATP declines 22–48% at selected 0.5–1.5 hour time points.

limitations

Not a measured amount ingested from red yeast rice; lower exposures and human relevance require separate data.

nutrient_topic

Red yeast rice collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Red yeast rice

plain_language

Energy loss was measured in the kidney-cell preparation.

primary_references

[1853344] The role of altered mitochondrial function in citrinin-induced toxicity to rat renal proximal tubule suspensions. · 1991 · https://pubmed.ncbi.nlm.nih.gov/1853344/ · DOI 10.1016/0041-008x(91)90008-3

Red yeast rice: constituents, mevalonate, CoQ and product-specific interactions (2026-09-20) · lines 316–322

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · 125–500 micromolar citrinin; reported ATP declines 22–48% at selected 0.5–1.5 hour time points. · source_derived_draft · unverified_draft

## red-yeast-rice-citrinin-atp Energy loss was measured in the kidney-cell preparation. Citrinin exposure reduced ATP in rat proximal-tubule suspensions before or during ensuing cell injury. Model: 125–500 micromolar citrinin; reported ATP declines 22–48% at selected 0.5–1.5 hour time points. Limitations: Not a measured amount ingested from red yeast rice; lower exposures and human relevance require separate data. Evidence access: Primary abstract [1853344] The role of altered mitochondrial function in citrinin-induced toxicity to rat renal proximal tubule suspensions. · 1991 · https://pubmed.ncbi.nlm.nih.gov/1853344/ · DOI 10.1016/0041-008x(91)90008-3

evidence_access

Primary abstract

experimental_model

Isolated rat mitochondria; the enzyme-panel experiments included 1 mM citrinin.

limitations

Multiple effects were reported; this is not a selective single-complex inhibitor or a human exposure threshold.

nutrient_topic

Red yeast rice collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Red yeast rice

plain_language

Mitochondrial oxygen use and ATP production became less efficiently coupled.

primary_references

[1556379] Mechanism of citrinin-induced dysfunction of mitochondria. I. Effects on respiration, enzyme activities and membrane potential of renal cortical mitochondria. · 1992 · https://pubmed.ncbi.nlm.nih.gov/1556379/ · DOI 10.1002/jat.2550120209

Red yeast rice: constituents, mevalonate, CoQ and product-specific interactions (2026-09-20) · lines 332–338

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Isolated rat mitochondria; the enzyme-panel experiments included 1 mM citrinin. · source_derived_draft · unverified_draft

## red-yeast-rice-citrinin-coupling Mitochondrial oxygen use and ATP production became less efficiently coupled. Citrinin lowered respiratory control, ADP/O ratio and membrane potential in rat renal cortical mitochondria. Model: Isolated rat mitochondria; the enzyme-panel experiments included 1 mM citrinin. Limitations: Multiple effects were reported; this is not a selective single-complex inhibitor or a human exposure threshold. Evidence access: Primary abstract [1556379] Mechanism of citrinin-induced dysfunction of mitochondria. I. Effects on respiration, enzyme activities and membrane potential of renal cortical mitochondria. · 1992 · https://pubmed.ncbi.nlm.nih.gov/1556379/ · DOI 10.1002/jat.2550120209

evidence_span

{"source_cache": "artifacts/chloride-research/1718606.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a66a28a6b6c5d2abfee4d416aeddca8f38a48e343d2715f599c8c05998943f67", "start_char": 0, "end_char": 925, "text_sha256": "a66a28a6b6c5d2abfee4d416aeddca8f38a48e343d2715f599c8c05998943f67"}

experimental_model

Phosphorylated CFTR channel nucleotide assays

exposure

Hydrolyzable nucleotides, analogues and Mg-free ATP

limitations

Records the measured Mg/nucleotide dependence, not the paper’s historical assignment of opening to NBD1 hydrolysis.

nutrient_topic

Chloride research collection; topical membership is not evidence of a direct dietary effect. · Chloride

organism

Human CFTR in expression preparations

plain_language

Magnesium and ATP are part of the working channel system; chloride alone is insufficient.

primary_references

[chloride-p1718606] Nucleoside triphosphates are required to open the CFTR chloride channel. (1991). https://pubmed.ncbi.nlm.nih.gov/1718606/ DOI: 10.1016/0092-8674(91)90072-7

tissue_or_cell_type

Cytosolic channel face

Chloride: transport, acid-base balance, nutrient interactions and loss states (2026-09-17) · lines 250–261

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Phosphorylated CFTR channel nucleotide assays · source_derived_draft · unverified_draft

### chloride-cftr-mgatp Phosphorylated CFTR channels opened with ATP but not Mg-free ATP in this preparation. Condition category: normal nutrient_topic: Chloride research collection; topical membership is not evidence of a direct dietary effect. plain_language: Magnesium and ATP are part of the working channel system; chloride alone is insufficient. organism: Human CFTR in expression preparations tissue_or_cell_type: Cytosolic channel face experimental_model: Phosphorylated CFTR channel nucleotide assays limitations: Records the measured Mg/nucleotide dependence, not the paper’s historical assignment of opening to NBD1 hydrolysis. exposure: Hydrolyzable nucleotides, analogues and Mg-free ATP evidence_span: {"source_cache": "artifacts/chloride-research/1718606.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a66a28a6b6c5d2abfee4d416aeddca8f38a48e343d2715f599c8c05998943f67", "start_char": 0, "end_char": 925, "text_sha256": "a66a28a6b6c5d2abfee4d416aeddca8f38a48e343d2715f599c8c05998943f67"} [chloride-p1718606] Nucleoside triphosphates are required to open the CFTR chloride channel. (1991). https://pubmed.ncbi.nlm.nih.gov/1718606/ DOI: 10.1016/0092-8674(91)90072-7

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/k2-research/22582012.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1f7c8600fd883b912c1fd697b1bffb6e442e2763230347e5c198d88c0c6bb4cc", "start_char": 0, "end_char": 926, "text_sha256": "1f7c8600fd883b912c1fd697b1bffb6e442e2763230347e5c198d88c0c6bb4cc"}

experimental_model

Genetic modifier and mitochondrial function experiments

exposure

Heix/Pink1 defects and vitamin K2 rescue

limitations

Fly electron-transfer rescue does not establish replacement of human CoQ10 or treatment of Parkinson disease.

nutrient_topic

Vitamin K2 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin K2 / menaquinone family

organism

Drosophila

plain_language

An energy role was found in flies and is recorded with that species boundary.

primary_references

[k2-p22582012] Vitamin K2 is a mitochondrial electron carrier that rescues pink1 deficiency. (2012). https://pubmed.ncbi.nlm.nih.gov/22582012/ DOI: 10.1126/science.1218632

tissue_or_cell_type

Mitochondria

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin K2: menaquinone forms, carboxylation, recycling and nutrient interactions (2026-09-17) · lines 864–875

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Genetic modifier and mitochondrial function experiments · source_derived_draft · unverified_draft

### k2-fly-mitochondria Vitamin K2 transferred electrons in Drosophila mitochondria and improved ATP production; Heix-mutant defects were rescued by K2. Condition category: machinery_impairment nutrient_topic: Vitamin K2 research collection; topical membership is not evidence of a direct dietary effect. plain_language: An energy role was found in flies and is recorded with that species boundary. organism: Drosophila tissue_or_cell_type: Mitochondria experimental_model: Genetic modifier and mitochondrial function experiments limitations: Fly electron-transfer rescue does not establish replacement of human CoQ10 or treatment of Parkinson disease. exposure: Heix/Pink1 defects and vitamin K2 rescue evidence_span: {"source_cache": "artifacts/k2-research/22582012.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1f7c8600fd883b912c1fd697b1bffb6e442e2763230347e5c198d88c0c6bb4cc", "start_char": 0, "end_char": 926, "text_sha256": "1f7c8600fd883b912c1fd697b1bffb6e442e2763230347e5c198d88c0c6bb4cc"} [k2-p22582012] Vitamin K2 is a mitochondrial electron carrier that rescues pink1 deficiency. (2012). https://pubmed.ncbi.nlm.nih.gov/22582012/ DOI: 10.1126/science.1218632

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/k2-research/31024065.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "23cca3c157b598de639355c855be4221ce916ee9a338e2b59923fc980614281e", "start_char": 0, "end_char": 943, "text_sha256": "23cca3c157b598de639355c855be4221ce916ee9a338e2b59923fc980614281e"}

experimental_model

Cellular uptake and respiratory rescue comparisons

exposure

MK-4 versus CoQ4

limitations

Different organism and deficiency model from the fly study; failure here is a boundary to extrapolation, not a clerical error in either experiment.

nutrient_topic

Vitamin K2 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin K2 / menaquinone family

organism

Human CoQ10-deficient cell lines and CoQ6-deficient yeast

plain_language

Getting into the organelle did not make MK-4 a functional substitute for CoQ.

primary_references

[k2-p31024065] Vitamin K2 cannot substitute Coenzyme Q10 as electron carrier in the mitochondrial respiratory chain of mammalian cells. (2019). https://pubmed.ncbi.nlm.nih.gov/31024065/ DOI: 10.1038/s41598-019-43014-y

tissue_or_cell_type

Mitochondrial respiratory chain

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin K2: menaquinone forms, carboxylation, recycling and nutrient interactions (2026-09-17) · lines 877–888

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cellular uptake and respiratory rescue comparisons · source_derived_draft · unverified_draft

### k2-mk4-not-coq Vitamin K2 entered mitochondria but restored neither respiratory electron flow nor ATP synthesis in CoQ-deficient human cells and yeast; CoQ4 did restore function. Condition category: machinery_impairment nutrient_topic: Vitamin K2 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Getting into the organelle did not make MK-4 a functional substitute for CoQ. organism: Human CoQ10-deficient cell lines and CoQ6-deficient yeast tissue_or_cell_type: Mitochondrial respiratory chain experimental_model: Cellular uptake and respiratory rescue comparisons limitations: Different organism and deficiency model from the fly study; failure here is a boundary to extrapolation, not a clerical error in either experiment. exposure: MK-4 versus CoQ4 evidence_span: {"source_cache": "artifacts/k2-research/31024065.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "23cca3c157b598de639355c855be4221ce916ee9a338e2b59923fc980614281e", "start_char": 0, "end_char": 943, "text_sha256": "23cca3c157b598de639355c855be4221ce916ee9a338e2b59923fc980614281e"} [k2-p31024065] Vitamin K2 cannot substitute Coenzyme Q10 as electron carrier in the mitochondrial respiratory chain of mammalian cells. (2019). https://pubmed.ncbi.nlm.nih.gov/31024065/ DOI: 10.1038/s41598-019-43014-y

evidence_access

Primary abstract

experimental_model

Established reaction described in a primary human GARS disease study.

limitations

Background enzyme chemistry is distinguished from the patient measurements; separate cytosolic/mitochondrial isoform kinetics were not measured here.

nutrient_topic

Glycine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Glycine

plain_language

A charging enzyme attaches glycine to the RNA adapter used to build protein.

primary_references

Compound heterozygous mutations in glycyl-tRNA synthetase (GARS) cause mitochondrial respiratory chain dysfunction. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28594869/ · DOI 10.1371/journal.pone.0178125

Glycine: supply, one-carbon allocation, receptors and cross-nutrient mechanisms (2026-09-19) · lines 386–392

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Established reaction described in a primary human GARS disease study. · source_derived_draft · unverified_draft

## glycine-trna-charging A charging enzyme attaches glycine to the RNA adapter used to build protein. GARS1 catalyzes glycyl-tRNA formation for glycine incorporation into cytosolic and mitochondrial proteins. Model: Established reaction described in a primary human GARS disease study. Limitations: Background enzyme chemistry is distinguished from the patient measurements; separate cytosolic/mitochondrial isoform kinetics were not measured here. Evidence access: Primary abstract Compound heterozygous mutations in glycyl-tRNA synthetase (GARS) cause mitochondrial respiratory chain dysfunction. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28594869/ · DOI 10.1371/journal.pone.0178125

cross_nutrient

Magnesium-nucleotide chemistry modifies potassium-channel gating; no dietary magnesium effect quantified.

experimental_model

Inside-out rat patches; Mg-free versus 2 mM Mg.

limitations

Assay concentrations are not clinical magnesium thresholds.

nutrient_topic

Potassium research collection; topical membership is not evidence of a direct dietary effect. · Potassium

organism

Rat

plain_language

Magnesium changed how the potassium channel responded to total ATP.

primary_references

[ashcroft-1989-magnesium] ATP-sensitive K+ channels in rat pancreatic beta-cells: modulation by ATP and Mg2+ ions (1989). https://pmc.ncbi.nlm.nih.gov/articles/PMC1189219/ DOI: 10.1113/jphysiol.1989.sp017765

tissue_or_cell_type

Pancreatic beta-cell membrane

Potassium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 798–808

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Inside-out rat patches; Mg-free versus 2 mM Mg. · source_derived_draft · unverified_draft

### k-beta-mg-atp-speciation Adding 2 mM Mg shifted apparent total-ATP inhibition from Ki 4 to 26 micromolar in excised beta-cell patches. Condition category: normal nutrient_topic: Potassium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Magnesium changed how the potassium channel responded to total ATP. organism: Rat tissue_or_cell_type: Pancreatic beta-cell membrane experimental_model: Inside-out rat patches; Mg-free versus 2 mM Mg. limitations: Assay concentrations are not clinical magnesium thresholds. cross_nutrient: Magnesium-nucleotide chemistry modifies potassium-channel gating; no dietary magnesium effect quantified. [ashcroft-1989-magnesium] ATP-sensitive K+ channels in rat pancreatic beta-cells: modulation by ATP and Mg2+ ions (1989). https://pmc.ncbi.nlm.nih.gov/articles/PMC1189219/ DOI: 10.1113/jphysiol.1989.sp017765

availability_state

nutrient_deficiency Imported condition classification; unverified.

endpoint

Potassium depletion increased collecting-tubule potassium-stimulated, ouabain-insensitive ATPase activity in rats.

experimental-exposure

Microdissected rabbit nephron segments and collecting tubules of potassium-depleted rats.

experimental_model

Microdissected rabbit nephron segments and collecting tubules of potassium-depleted rats.

limitations

ATP hydrolysis and inhibitor sensitivity establish activity class, not a specific protein isoform or whole-animal flux.

nutrient_topic

Potassium research collection; topical membership is not evidence of a direct dietary effect. · Potassium

organism

Rattus norvegicus

plain_language

The distal kidney increased an ATP-consuming activity compatible with potassium recovery.

primary_references

[doucet-1987-hka] Characterization of K-ATPase activity in distal nephron: stimulation by potassium depletion (1987). https://pubmed.ncbi.nlm.nih.gov/2957926/ DOI: 10.1152/ajprenal.1987.253.3.F418

tissue_or_cell_type

collecting tubule

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Potassium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 1124–1135

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Microdissected rabbit nephron segments and collecting tubules of potassium-depleted rats. · source_derived_draft · unverified_draft

### k-depletion-increases-hka-activity Potassium depletion increased collecting-tubule potassium-stimulated, ouabain-insensitive ATPase activity in rats. Condition category: nutrient_deficiency nutrient_topic: Potassium research collection; topical membership is not evidence of a direct dietary effect. plain_language: The distal kidney increased an ATP-consuming activity compatible with potassium recovery. organism: Rattus norvegicus tissue_or_cell_type: collecting tubule experimental_model: Microdissected rabbit nephron segments and collecting tubules of potassium-depleted rats. limitations: ATP hydrolysis and inhibitor sensitivity establish activity class, not a specific protein isoform or whole-animal flux. experimental-exposure: Microdissected rabbit nephron segments and collecting tubules of potassium-depleted rats. endpoint: Potassium depletion increased collecting-tubule potassium-stimulated, ouabain-insensitive ATPase activity in rats. [doucet-1987-hka] Characterization of K-ATPase activity in distal nephron: stimulation by potassium depletion (1987). https://pubmed.ncbi.nlm.nih.gov/2957926/ DOI: 10.1152/ajprenal.1987.253.3.F418

experimental_model

Primed mouse macrophages, extracellular-K titration.

exposure

Artificial extracellular potassium elevation; not dietary excess.

limitations

Stimulus-specific; does not justify elevating blood potassium.

nutrient_topic

Potassium research collection; topical membership is not evidence of a direct dietary effect. · Potassium

organism

Mouse

plain_language

Reducing the outward potassium gradient blocked these activation routes.

primary_references

[munoz-2013-nlrp3] K+ efflux is the Common Trigger of NLRP3 inflammasome Activation by Bacterial Toxins and Particulate Matter (2013). https://pmc.ncbi.nlm.nih.gov/articles/PMC3730833/ DOI: 10.1016/j.immuni.2013.05.016

tissue_or_cell_type

Bone-marrow macrophages

Potassium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 868–878

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Primed mouse macrophages, extracellular-K titration. · source_derived_draft · unverified_draft

### k-high-medium-nlrp3-block Raising extracellular K to 45 mM maximally inhibited NLRP3 responses to the tested toxins and particles. Condition category: normal nutrient_topic: Potassium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Reducing the outward potassium gradient blocked these activation routes. organism: Mouse tissue_or_cell_type: Bone-marrow macrophages experimental_model: Primed mouse macrophages, extracellular-K titration. limitations: Stimulus-specific; does not justify elevating blood potassium. exposure: Artificial extracellular potassium elevation; not dietary excess. [munoz-2013-nlrp3] K+ efflux is the Common Trigger of NLRP3 inflammasome Activation by Bacterial Toxins and Particulate Matter (2013). https://pmc.ncbi.nlm.nih.gov/articles/PMC3730833/ DOI: 10.1016/j.immuni.2013.05.016

cross_nutrient

MgADP supplies a magnesium-dependent regulatory input to potassium conductance.

experimental_model

Xenopus oocyte cloned-channel patches.

limitations

Heterologous channel biochemistry, not nutritional magnesium depletion.

nutrient_topic

Potassium research collection; topical membership is not evidence of a direct dietary effect. · Potassium

organism

Xenopus expression system

plain_language

Magnesium-bound ADP helps keep this potassium channel active.

primary_references

[gribble-1997-sur1] The essential role of the Walker A motifs of SUR1 in K-ATP channel activation by Mg-ADP and diazoxide (1997). https://pmc.ncbi.nlm.nih.gov/articles/PMC1169713/ DOI: 10.1093/emboj/16.6.1145

tissue_or_cell_type

Oocyte membrane

Potassium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 810–820

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Xenopus oocyte cloned-channel patches. · source_derived_draft · unverified_draft

### k-mgadp-sur1-activation MgADP potentiated cloned Kir6.2/SUR1 current through intact SUR1 nucleotide-binding machinery. Condition category: normal nutrient_topic: Potassium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Magnesium-bound ADP helps keep this potassium channel active. organism: Xenopus expression system tissue_or_cell_type: Oocyte membrane experimental_model: Xenopus oocyte cloned-channel patches. limitations: Heterologous channel biochemistry, not nutritional magnesium depletion. cross_nutrient: MgADP supplies a magnesium-dependent regulatory input to potassium conductance. [gribble-1997-sur1] The essential role of the Walker A motifs of SUR1 in K-ATP channel activation by Mg-ADP and diazoxide (1997). https://pmc.ncbi.nlm.nih.gov/articles/PMC1169713/ DOI: 10.1093/emboj/16.6.1145

cross_nutrient

Potassium transport depends jointly on sodium and magnesium-supported ATP chemistry.

experimental_model

Resealed human erythrocyte ghosts; sided ion substitutions.

limitations

Sided activation adds to existing catalog flux/phosphorylation records; MgATP-only binding is not asserted.

nutrient_topic

Potassium research collection; topical membership is not evidence of a direct dietary effect. · Potassium

organism

Human

plain_language

Potassium outside and sodium inside activate complementary sides of the pump.

primary_references

[garrahan-1967-pump] The stoicheiometry of the sodium pump (1967). https://pmc.ncbi.nlm.nih.gov/articles/PMC1365482/ DOI: 10.1113/jphysiol.1967.sp008297

tissue_or_cell_type

Erythrocyte membrane

Potassium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 575–585

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Resealed human erythrocyte ghosts; sided ion substitutions. · source_derived_draft · unverified_draft

### k-pump-extracellular-activation External potassium supported ouabain-sensitive ATP hydrolysis when erythrocyte ghosts contained sodium, ATP and magnesium. Condition category: normal nutrient_topic: Potassium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Potassium outside and sodium inside activate complementary sides of the pump. organism: Human tissue_or_cell_type: Erythrocyte membrane experimental_model: Resealed human erythrocyte ghosts; sided ion substitutions. limitations: Sided activation adds to existing catalog flux/phosphorylation records; MgATP-only binding is not asserted. cross_nutrient: Potassium transport depends jointly on sodium and magnesium-supported ATP chemistry. [garrahan-1967-pump] The stoicheiometry of the sodium pump (1967). https://pmc.ncbi.nlm.nih.gov/articles/PMC1365482/ DOI: 10.1113/jphysiol.1967.sp008297

cross_nutrient

Sodium export couples to potassium-supported pump cycling and magnesium-dependent energy use.

experimental_model

Radiotracer sodium and ATP-hydrolysis assay.

limitations

This measurement does not itself establish an exact two-potassium ratio.

nutrient_topic

Potassium research collection; topical membership is not evidence of a direct dietary effect. · Potassium

organism

Human

plain_language

ATP consumption pays for sodium extrusion while potassium is available externally.

primary_references

[garrahan-1967-pump] The stoicheiometry of the sodium pump (1967). https://pmc.ncbi.nlm.nih.gov/articles/PMC1365482/ DOI: 10.1113/jphysiol.1967.sp008297

tissue_or_cell_type

Erythrocyte membrane

Potassium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 587–597

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Radiotracer sodium and ATP-hydrolysis assay. · source_derived_draft · unverified_draft

### k-pump-sodium-atp-coupling Ouabain-sensitive extrusion was approximately three sodium ions per ATP hydrolyzed in resealed erythrocyte ghosts. Condition category: normal nutrient_topic: Potassium research collection; topical membership is not evidence of a direct dietary effect. plain_language: ATP consumption pays for sodium extrusion while potassium is available externally. organism: Human tissue_or_cell_type: Erythrocyte membrane experimental_model: Radiotracer sodium and ATP-hydrolysis assay. limitations: This measurement does not itself establish an exact two-potassium ratio. cross_nutrient: Sodium export couples to potassium-supported pump cycling and magnesium-dependent energy use. [garrahan-1967-pump] The stoicheiometry of the sodium pump (1967). https://pmc.ncbi.nlm.nih.gov/articles/PMC1365482/ DOI: 10.1113/jphysiol.1967.sp008297

cross_nutrient

Defines the sodium/chloride transporter step of the potassium switch.

evidence_location

Primary abstract; phosphosite mapping, docking and Thr60Ala assays.

experimental_model

Recombinant phosphosite mapping and cell mutants

limitations

The dietary K response was not tested in this experiment.

nutrient_topic

Potassium research collection; topical membership is not evidence of a direct dietary effect. · Potassium

organism

Human protein; HEK293/mpkDCT cells

plain_language

A kinase modifies the sodium-chloride transporter at regulatory sites.

primary_references

[richardson-2008-spak-osr1-ncc] Activation of the thiazide-sensitive Na+-Cl- cotransporter by the WNK-regulated kinases SPAK and OSR1 (2008). https://pubmed.ncbi.nlm.nih.gov/18270262/ DOI: 10.1242/jcs.025312

tissue_or_cell_type

Biochemical assay and cultured kidney-derived cells

Potassium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 177–188

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant phosphosite mapping and cell mutants · source_derived_draft · unverified_draft

### renal-oxsr1-phosphorylates-ncc OSR1 phosphorylated human NCC at Thr46, Thr55 and Thr60; Thr60 mutation impaired chloride-depletion-induced NCC activation. Condition category: normal nutrient_topic: Potassium research collection; topical membership is not evidence of a direct dietary effect. plain_language: A kinase modifies the sodium-chloride transporter at regulatory sites. organism: Human protein; HEK293/mpkDCT cells tissue_or_cell_type: Biochemical assay and cultured kidney-derived cells experimental_model: Recombinant phosphosite mapping and cell mutants limitations: The dietary K response was not tested in this experiment. cross_nutrient: Defines the sodium/chloride transporter step of the potassium switch. evidence_location: Primary abstract; phosphosite mapping, docking and Thr60Ala assays. [richardson-2008-spak-osr1-ncc] Activation of the thiazide-sensitive Na+-Cl- cotransporter by the WNK-regulated kinases SPAK and OSR1 (2008). https://pubmed.ncbi.nlm.nih.gov/18270262/ DOI: 10.1242/jcs.025312

cross_nutrient

This biochemical sodium-channel pathway contributes to the machinery for K handling.

evidence_location

Figure 2.

experimental_model

Expression, kinase-dead and site-mutant experiments

limitations

Residue numbers are construct/species-specific; nutritional K sensing was not tested.

nutrient_topic

Potassium research collection; topical membership is not evidence of a direct dietary effect. · Potassium

organism

Xenopus laevis

plain_language

SGK1 modifies the protein that normally restrains sodium channels.

primary_references

[debonneville-2001-sgk-nedd4] Phosphorylation of Nedd4-2 by Sgk1 regulates epithelial Na(+) channel cell surface expression (2001). https://pubmed.ncbi.nlm.nih.gov/11742982/ DOI: 10.1093/emboj/20.24.7052

tissue_or_cell_type

Oocytes

Potassium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 408–419

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Expression, kinase-dead and site-mutant experiments · source_derived_draft · unverified_draft

### renal-sgk1-phosphorylates-nedd4l Sgk1 phosphorylated Nedd4-2 at Ser444 and less strongly Ser338 in Xenopus constructs. Condition category: normal nutrient_topic: Potassium research collection; topical membership is not evidence of a direct dietary effect. plain_language: SGK1 modifies the protein that normally restrains sodium channels. organism: Xenopus laevis tissue_or_cell_type: Oocytes experimental_model: Expression, kinase-dead and site-mutant experiments limitations: Residue numbers are construct/species-specific; nutritional K sensing was not tested. cross_nutrient: This biochemical sodium-channel pathway contributes to the machinery for K handling. evidence_location: Figure 2. [debonneville-2001-sgk-nedd4] Phosphorylation of Nedd4-2 by Sgk1 regulates epithelial Na(+) channel cell surface expression (2001). https://pubmed.ncbi.nlm.nih.gov/11742982/ DOI: 10.1093/emboj/20.24.7052

cross_nutrient

Defines the sodium/chloride transporter step of the potassium switch.

evidence_location

Primary abstract; phosphosite mapping, docking and Thr60Ala assays.

experimental_model

Recombinant phosphosite mapping and cell mutants

limitations

The dietary K response was not tested in this experiment.

nutrient_topic

Potassium research collection; topical membership is not evidence of a direct dietary effect. · Potassium

organism

Human protein; HEK293/mpkDCT cells

plain_language

A kinase modifies the sodium-chloride transporter at regulatory sites.

primary_references

[richardson-2008-spak-osr1-ncc] Activation of the thiazide-sensitive Na+-Cl- cotransporter by the WNK-regulated kinases SPAK and OSR1 (2008). https://pubmed.ncbi.nlm.nih.gov/18270262/ DOI: 10.1242/jcs.025312

tissue_or_cell_type

Biochemical assay and cultured kidney-derived cells

Potassium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 164–175

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant phosphosite mapping and cell mutants · source_derived_draft · unverified_draft

### renal-stk39-phosphorylates-ncc SPAK phosphorylated human NCC at Thr46, Thr55 and Thr60; Thr60 mutation impaired chloride-depletion-induced NCC activation. Condition category: normal nutrient_topic: Potassium research collection; topical membership is not evidence of a direct dietary effect. plain_language: A kinase modifies the sodium-chloride transporter at regulatory sites. organism: Human protein; HEK293/mpkDCT cells tissue_or_cell_type: Biochemical assay and cultured kidney-derived cells experimental_model: Recombinant phosphosite mapping and cell mutants limitations: The dietary K response was not tested in this experiment. cross_nutrient: Defines the sodium/chloride transporter step of the potassium switch. evidence_location: Primary abstract; phosphosite mapping, docking and Thr60Ala assays. [richardson-2008-spak-osr1-ncc] Activation of the thiazide-sensitive Na+-Cl- cotransporter by the WNK-regulated kinases SPAK and OSR1 (2008). https://pubmed.ncbi.nlm.nih.gov/18270262/ DOI: 10.1242/jcs.025312

cross_nutrient

This kinase relay can regulate sodium/chloride transport downstream of K sensing.

evidence_location

Primary abstract; kinase-activity and substrate-phosphorylation experiments.

experimental_model

Recombinant kinase assay

limitations

Establishes biochemical capability; not dietary potassium regulation by itself.

nutrient_topic

Potassium research collection; topical membership is not evidence of a direct dietary effect. · Potassium

organism

Recombinant proteins

plain_language

WNK4 passes a phosphate signal to SPAK.

primary_references

[vitari-2005-wnk-spak-osr1] The WNK1 and WNK4 protein kinases that are mutated in Gordon's hypertension syndrome phosphorylate and activate SPAK and OSR1 protein kinases (2005). https://pubmed.ncbi.nlm.nih.gov/16083423/ DOI: 10.1042/BJ20051180

tissue_or_cell_type

Cell-free assay

Potassium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 151–162

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant kinase assay · source_derived_draft · unverified_draft

### renal-wnk4-activates-spak Catalytically active WNK4 phosphorylated and activated SPAK in biochemical assays. Condition category: normal nutrient_topic: Potassium research collection; topical membership is not evidence of a direct dietary effect. plain_language: WNK4 passes a phosphate signal to SPAK. organism: Recombinant proteins tissue_or_cell_type: Cell-free assay experimental_model: Recombinant kinase assay limitations: Establishes biochemical capability; not dietary potassium regulation by itself. cross_nutrient: This kinase relay can regulate sodium/chloride transport downstream of K sensing. evidence_location: Primary abstract; kinase-activity and substrate-phosphorylation experiments. [vitari-2005-wnk-spak-osr1] The WNK1 and WNK4 protein kinases that are mutated in Gordon's hypertension syndrome phosphorylate and activate SPAK and OSR1 protein kinases (2005). https://pubmed.ncbi.nlm.nih.gov/16083423/ DOI: 10.1042/BJ20051180

evidence_access

Primary abstract

experimental_model

Isolated bovine heart F1 structures and inhibition study.

limitations

The proposed block of rotation explains inhibition; the structure does not establish human tissue ATP loss after oral intake.

nutrient_topic

Resveratrol collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Resveratrol

plain_language

Binding can obstruct the rotary machinery for energy conversion.

primary_references

Mechanism of inhibition of bovine F1-ATPase by resveratrol and related polyphenols. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17698806/ · DOI 10.1073/pnas.0706290104

Resveratrol: metabolites, target selectivity and cross-nutrient mechanisms (2026-09-19) · lines 142–148

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Isolated bovine heart F1 structures and inhibition study. · source_derived_draft · unverified_draft

## resveratrol-f1-binding Binding can obstruct the rotary machinery for energy conversion. The bovine F1-ATPase crystal structure placed resveratrol in a pocket between the gamma tip and beta-TP subunit at the rotary bearing. Model: Isolated bovine heart F1 structures and inhibition study. Limitations: The proposed block of rotation explains inhibition; the structure does not establish human tissue ATP loss after oral intake. Evidence access: Primary abstract Mechanism of inhibition of bovine F1-ATPase by resveratrol and related polyphenols. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17698806/ · DOI 10.1073/pnas.0706290104

evidence_access

Primary full text

experimental_model

Gel-based biotin-acceptor assay and dose response.

limitations

Human biotin depletion or failure of biotin repletion was not demonstrated.

nutrient_topic

Resveratrol collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Resveratrol

plain_language

A direct laboratory connection to biotin activation is searchable.

primary_references

Resveratrol compounds inhibit human holocarboxylase synthetase and cause a lean phenotype in Drosophila melanogaster. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26303405/ · DOI 10.1016/j.jnutbio.2015.07.004

Resveratrol: metabolites, target selectivity and cross-nutrient mechanisms (2026-09-19) · lines 342–348

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Gel-based biotin-acceptor assay and dose response. · source_derived_draft · unverified_draft

## resveratrol-hlcs-inhibition A direct laboratory connection to biotin activation is searchable. Resveratrol inhibited recombinant human HLCS-dependent biotinylation in vitro, with reported IC50 approximately 3.70 micromolar. Model: Gel-based biotin-acceptor assay and dose response. Limitations: Human biotin depletion or failure of biotin repletion was not demonstrated. Evidence access: Primary full text Resveratrol compounds inhibit human holocarboxylase synthetase and cause a lean phenotype in Drosophila melanogaster. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26303405/ · DOI 10.1016/j.jnutbio.2015.07.004

evidence_access

Primary full text

experimental_model

Dose and time-course experiments.

limitations

Context difference is recorded directly, not labelled an unexplained contradiction.

nutrient_topic

Resveratrol collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Resveratrol

plain_language

AMPK activation can accompany energy stress rather than improved energy supply.

primary_references

SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22560220/ · DOI 10.1016/j.cmet.2012.04.003

Resveratrol: metabolites, target selectivity and cross-nutrient mechanisms (2026-09-19) · lines 190–196

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Dose and time-course experiments. · source_derived_draft · unverified_draft

## resveratrol-mouse-atp-dose AMPK activation can accompany energy stress rather than improved energy supply. In mouse C2C12 cells, 25 micromolar resveratrol increased ATP at later time points, while 50 micromolar reduced ATP and mitochondrial membrane potential. Model: Dose and time-course experiments. Limitations: Context difference is recorded directly, not labelled an unexplained contradiction. Evidence access: Primary full text SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22560220/ · DOI 10.1016/j.cmet.2012.04.003

cross_nutrient

Separates the B6 phosphorylation step from the B2-dependent oxidation step.

evidence_location

Abstract

experimental_model

Recombinant human PDXK expressed in E. coli; PL-to-PLP kinetics and unliganded/MgATP-bound structures.

exposure

Purified-enzyme assay

limitations

This biochemical route does not establish that dietary pyridoxal bypasses all consequences of PNPO disease.

nutrient_topic

Riboflavin research collection; topical membership is not evidence of a direct dietary effect. · Riboflavin (vitamin B2)

organism

Homo sapiens

plain_language

Not every route to active B6 passes through PNPO.

primary_references

[safo2007] Crystal Structure of human pyridoxal kinase: structural basis of M(+) and M(2+) activation. (2007). https://pubmed.ncbi.nlm.nih.gov/17766369/ DOI: 10.1110/ps.073022107

tissue_or_cell_type

Purified recombinant enzyme; no intact tissue

Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1192–1204

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human PDXK expressed in E. coli; PL-to-PLP kinetics and unliganded/MgATP-bound structures. · source_derived_draft · unverified_draft

### b2-pdxk-pyridoxal-route Human PDXK assays directly measured ATP-dependent conversion of pyridoxal to PLP, a reaction distinct from PNPO oxidation. Condition category: normal nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Not every route to active B6 passes through PNPO. organism: Homo sapiens tissue_or_cell_type: Purified recombinant enzyme; no intact tissue experimental_model: Recombinant human PDXK expressed in E. coli; PL-to-PLP kinetics and unliganded/MgATP-bound structures. limitations: This biochemical route does not establish that dietary pyridoxal bypasses all consequences of PNPO disease. exposure: Purified-enzyme assay cross_nutrient: Separates the B6 phosphorylation step from the B2-dependent oxidation step. evidence_location: Abstract [safo2007] Crystal Structure of human pyridoxal kinase: structural basis of M(+) and M(2+) activation. (2007). https://pubmed.ncbi.nlm.nih.gov/17766369/ DOI: 10.1110/ps.073022107

evidence_location

FAD synthesis and reverse pyrophosphorolysis assays

experimental_model

Purified recombinant human FADS2 catalytic assays

exposure

ATP and FMN in FAD-synthesis assays.

limitations

Adenylylation is distinct from RFK phosphorylation; reaction products should not be conflated.

nutrient_topic

Riboflavin research collection; topical membership is not evidence of a direct dietary effect. · Riboflavin (vitamin B2)

organism

Homo sapiens

plain_language

FLAD1 performs the second activation step, making FAD from FMN.

primary_references

[transport-fads2-2011] Human FAD synthase (isoform 2): a component of the machinery that delivers FAD to apo-flavoproteins. (2011). https://pubmed.ncbi.nlm.nih.gov/21951714/ DOI: 10.1111/j.1742-4658.2011.08368.x

tissue_or_cell_type

Purified protein

Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 320–331

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant human FADS2 catalytic assays · source_derived_draft · unverified_draft

### transport-flad1-adenylylation Human FAD synthase isoform 2 adenylylates FMN with ATP to form FAD and pyrophosphate. Condition category: normal nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: FLAD1 performs the second activation step, making FAD from FMN. organism: Homo sapiens tissue_or_cell_type: Purified protein experimental_model: Purified recombinant human FADS2 catalytic assays limitations: Adenylylation is distinct from RFK phosphorylation; reaction products should not be conflated. exposure: ATP and FMN in FAD-synthesis assays. evidence_location: FAD synthesis and reverse pyrophosphorolysis assays [transport-fads2-2011] Human FAD synthase (isoform 2): a component of the machinery that delivers FAD to apo-flavoproteins. (2011). https://pubmed.ncbi.nlm.nih.gov/21951714/ DOI: 10.1111/j.1742-4658.2011.08368.x

evidence_location

Abstract and product-bound structure

experimental_model

Human RFK structural and catalytic mechanism study

exposure

Purified RFK with flavin and adenine nucleotide ligands.

limitations

Reaction chemistry does not imply RFK controls every tissue flavin pool to the same extent.

nutrient_topic

Riboflavin research collection; topical membership is not evidence of a direct dietary effect. · Riboflavin (vitamin B2)

organism

Homo sapiens

plain_language

RFK performs the first activation step from riboflavin to FMN.

primary_references

[transport-rfk-2003] Ligand binding-induced conformational changes in riboflavin kinase: structural basis for the ordered mechanism. (2003). https://pubmed.ncbi.nlm.nih.gov/14580199/ DOI: 10.1021/bi035450t

tissue_or_cell_type

Purified protein

Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 293–304

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human RFK structural and catalytic mechanism study · source_derived_draft · unverified_draft

### transport-rfk-phosphorylation Human RFK phosphorylates riboflavin to FMN using ATP, yielding ADP; this precedes FLAD1-mediated FAD synthesis. Condition category: normal nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: RFK performs the first activation step from riboflavin to FMN. organism: Homo sapiens tissue_or_cell_type: Purified protein experimental_model: Human RFK structural and catalytic mechanism study limitations: Reaction chemistry does not imply RFK controls every tissue flavin pool to the same extent. exposure: Purified RFK with flavin and adenine nucleotide ligands. evidence_location: Abstract and product-bound structure [transport-rfk-2003] Ligand binding-induced conformational changes in riboflavin kinase: structural basis for the ordered mechanism. (2003). https://pubmed.ncbi.nlm.nih.gov/14580199/ DOI: 10.1021/bi035450t

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Mouse taste-bud knockout physiology.

limitations

The later CALHM3 work refines the channel composition; CALHM1 is not treated as the sole physiological subunit.

nutrient_topic

Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate

plain_language

A cell can detect a stimulus yet fail to transmit its message.

primary_references

CALHM1 ion channel mediates purinergic neurotransmission of sweet, bitter and umami tastes. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23467090/ · DOI 10.1038/nature11906

trigger_kind

machinery_impairment Imported condition classification; unverified.

Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 114–120

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse taste-bud knockout physiology. · source_derived_draft · unverified_draft

## monosodium-glutamate-calhm1-release A cell can detect a stimulus yet fail to transmit its message. Calhm1 knockout reduced taste-evoked ATP release without eliminating taste-cell excitability to the stimuli. Model: Mouse taste-bud knockout physiology. Limitations: The later CALHM3 work refines the channel composition; CALHM1 is not treated as the sole physiological subunit. Evidence access: Primary abstract CALHM1 ion channel mediates purinergic neurotransmission of sweet, bitter and umami tastes. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23467090/ · DOI 10.1038/nature11906

evidence_access

Primary abstract

experimental_model

Heterologous channel experiments and mouse taste-cell physiology.

limitations

Functional coassembly is recorded without treating the historical proposed stoichiometry as a universal structural assignment.

nutrient_topic

Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate

plain_language

Two separately stored subunits form the output channel.

primary_references

CALHM3 Is Essential for Rapid Ion Channel-Mediated Purinergic Neurotransmission of GPCR-Mediated Tastes. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29681531/ · DOI 10.1016/j.neuron.2018.03.043

Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 122–128

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Heterologous channel experiments and mouse taste-cell physiology. · source_derived_draft · unverified_draft

## monosodium-glutamate-calhm3-channel Two separately stored subunits form the output channel. CALHM3 coassembly with CALHM1 conferred rapid voltage-dependent ATP-release-channel gating; the study connected this complex to type II taste-cell physiology. Model: Heterologous channel experiments and mouse taste-cell physiology. Limitations: Functional coassembly is recorded without treating the historical proposed stoichiometry as a universal structural assignment. Evidence access: Primary abstract CALHM3 Is Essential for Rapid Ion Channel-Mediated Purinergic Neurotransmission of GPCR-Mediated Tastes. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29681531/ · DOI 10.1016/j.neuron.2018.03.043

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Mouse knockout experiments.

limitations

Shares investigators with the CALHM1 study; no human deficiency threshold follows.

nutrient_topic

Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate

plain_language

Intact upstream sensing cannot compensate for a missing release channel.

primary_references

CALHM3 Is Essential for Rapid Ion Channel-Mediated Purinergic Neurotransmission of GPCR-Mediated Tastes. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29681531/ · DOI 10.1016/j.neuron.2018.03.043

trigger_kind

machinery_impairment Imported condition classification; unverified.

Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 130–136

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse knockout experiments. · source_derived_draft · unverified_draft

## monosodium-glutamate-calhm3-loss Intact upstream sensing cannot compensate for a missing release channel. Calhm3 deletion abolished taste-evoked ATP release and disrupted GPCR-mediated taste perception in mice. Model: Mouse knockout experiments. Limitations: Shares investigators with the CALHM1 study; no human deficiency threshold follows. Evidence access: Primary abstract CALHM3 Is Essential for Rapid Ion Channel-Mediated Purinergic Neurotransmission of GPCR-Mediated Tastes. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29681531/ · DOI 10.1016/j.neuron.2018.03.043

evidence_access

Primary abstract

experimental_model

Human phenylalanyl-tRNA synthetase biochemical comparison.

limitations

This aminoacylation function is distinct from conversion of phenylalanine to tyrosine.

nutrient_topic

L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine

plain_language

Protein construction needs a molecular loading and proofreading system.

primary_references

Bacterial and eukaryotic phenylalanyl-tRNA synthetases catalyze misaminoacylation of tRNA(Phe) with 3,4-dihydroxy-L-phenylalanine. · 2011 · https://pubmed.ncbi.nlm.nih.gov/22035791/ · DOI 10.1016/j.chembiol.2011.08.008

L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 126–132

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human phenylalanyl-tRNA synthetase biochemical comparison. · source_derived_draft · unverified_draft

## l-phenylalanine-cytosolic-charging Protein construction needs a molecular loading and proofreading system. Human cytosolic phenylalanyl-tRNA synthetase activates phenylalanine and attaches it to tRNA(Phe), with editing that discriminates against mischarged aromatic amino acids. Model: Human phenylalanyl-tRNA synthetase biochemical comparison. Limitations: This aminoacylation function is distinct from conversion of phenylalanine to tyrosine. Evidence access: Primary abstract Bacterial and eukaryotic phenylalanyl-tRNA synthetases catalyze misaminoacylation of tRNA(Phe) with 3,4-dihydroxy-L-phenylalanine. · 2011 · https://pubmed.ncbi.nlm.nih.gov/22035791/ · DOI 10.1016/j.chembiol.2011.08.008

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Neonatal rat ventricular myocyte knockdown assays.

limitations

These are related cellular readouts, not proof of human niacin or phenylalanine deficiency.

nutrient_topic

L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine

plain_language

The downstream effects include both energy production and redox balance.

primary_references

FARS2 Deficiency Causes Cardiomyopathy by Disrupting Mitochondrial Homeostasis and the Mitochondrial Quality Control System. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38362779/ · DOI 10.1161/CIRCULATIONAHA.123.064489

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 158–164

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Neonatal rat ventricular myocyte knockdown assays. · source_derived_draft · unverified_draft

## l-phenylalanine-mitochondrial-energy The downstream effects include both energy production and redox balance. Fars2 knockdown in neonatal rat ventricular myocytes lowered ATP and mitochondrial membrane potential, increased ROS, and reduced the NAD+/NADH ratio. Model: Neonatal rat ventricular myocyte knockdown assays. Limitations: These are related cellular readouts, not proof of human niacin or phenylalanine deficiency. Evidence access: Primary full text FARS2 Deficiency Causes Cardiomyopathy by Disrupting Mitochondrial Homeostasis and the Mitochondrial Quality Control System. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38362779/ · DOI 10.1161/CIRCULATIONAHA.123.064489

evidence_access

Primary full text, aminoacylation mechanism and structural results

experimental_model

Human WARS1–tRNA structural analysis and biochemical aminoacylation.

limitations

Cytosolic WARS1 is distinct from mitochondrial WARS2.

nutrient_topic

Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan

plain_language

Tryptophan is a building block that must be attached to the correct transfer RNA.

primary_references

Structure of human tryptophanyl-tRNA synthetase in complex with tRNATrp reveals the molecular basis of tRNA recognition and specificity. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16798914/ · DOI 10.1093/nar/gkl441

Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 114–120

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human WARS1–tRNA structural analysis and biochemical aminoacylation. · source_derived_draft · unverified_draft

## tryptophan-wars1-charging Tryptophan is a building block that must be attached to the correct transfer RNA. Human WARS1 recognizes tryptophan and its cognate tRNA; ATP-dependent activation precedes transfer to tRNA in protein-synthesis aminoacylation. Model: Human WARS1–tRNA structural analysis and biochemical aminoacylation. Limitations: Cytosolic WARS1 is distinct from mitochondrial WARS2. Evidence access: Primary full text, aminoacylation mechanism and structural results Structure of human tryptophanyl-tRNA synthetase in complex with tRNATrp reveals the molecular basis of tRNA recognition and specificity. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16798914/ · DOI 10.1093/nar/gkl441

evidence_access

Primary abstract

experimental_model

Bacterial transporter genetics and structure.

limitations

Not evidence that oral ergothioneine worsens a human infection.

nutrient_topic

Ergothioneine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Ergothioneine

plain_language

Some bacteria acquire ergothioneine instead of making it.

primary_references

Discovery and structure of a widespread bacterial ABC transporter specific for ergothioneine. · 2022 · https://pubmed.ncbi.nlm.nih.gov/36481738/ · DOI 10.1038/s41467-022-35277-3

transport_effect

raises Encoded an ergothioneine-specific ABC uptake transporter.

transport_pool

the bacterial cytoplasm Encoded an ergothioneine-specific ABC uptake transporter.

Ergothioneine: transport, redox chemistry and cross-nutrient mechanisms (2026-09-19) · lines 232–238

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Bacterial transporter genetics and structure. · source_derived_draft · unverified_draft

## ergothioneine-bacterial-uptake Some bacteria acquire ergothioneine instead of making it. Streptococcus pneumoniae spd_1642-1643 encoded an ergothioneine-specific ABC uptake transporter. Model: Bacterial transporter genetics and structure. Limitations: Not evidence that oral ergothioneine worsens a human infection. Evidence access: Primary abstract Discovery and structure of a widespread bacterial ABC transporter specific for ergothioneine. · 2022 · https://pubmed.ncbi.nlm.nih.gov/36481738/ · DOI 10.1038/s41467-022-35277-3

evidence_access

Primary abstract

experimental_model

Human iPSC-derived neurons and neuroblastoma cells.

limitations

These correlated outcomes do not identify a single direct mitochondrial target.

nutrient_topic

Ergothioneine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Ergothioneine

plain_language

Protection involved energy and dopamine-related cell markers.

primary_references

Ergothioneine-Mediated Neuroprotection of Human iPSC-Derived Dopaminergic Neurons. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38929132/ · DOI 10.3390/antiox13060693

Ergothioneine: transport, redox chemistry and cross-nutrient mechanisms (2026-09-19) · lines 392–398

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human iPSC-derived neurons and neuroblastoma cells. · source_derived_draft · unverified_draft

## ergothioneine-dopaminergic-atp Protection involved energy and dopamine-related cell markers. Ergothioneine limited ATP loss, protein carbonylation and tyrosine hydroxylase loss in the human 6-OHDA cell experiments. Model: Human iPSC-derived neurons and neuroblastoma cells. Limitations: These correlated outcomes do not identify a single direct mitochondrial target. Evidence access: Primary abstract Ergothioneine-Mediated Neuroprotection of Human iPSC-Derived Dopaminergic Neurons. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38929132/ · DOI 10.3390/antiox13060693

evidence_access

Primary abstract

experimental_model

Human TH1 kinetics and surface plasmon resonance; PKA phosphorylation.

limitations

These kinetic values are not blood targets or instructions to supplement BH4.

nutrient_topic

L-Tyrosine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Tyrosine

plain_language

The cofactor response changes with enzyme regulation.

primary_references

Tyrosine hydroxylase binds tetrahydrobiopterin cofactor with negative cooperativity, as shown by kinetic analyses and surface plasmon resonance detection. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10411647/ · DOI 10.1046/j.1432-1327.1999.00445.x

L-Tyrosine: catecholamines, thyroid chemistry, pigment, metabolism and cross-nutrient mechanisms (2026-09-19) · lines 28–34

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human TH1 kinetics and surface plasmon resonance; PKA phosphorylation. · source_derived_draft · unverified_draft

## l-tyrosine-th-cofactor-regulation The cofactor response changes with enzyme regulation. Recombinant human TH1 bound natural BH4 with negative cooperativity; Ser40 phosphorylation increased apparent BH4 affinity. Model: Human TH1 kinetics and surface plasmon resonance; PKA phosphorylation. Limitations: These kinetic values are not blood targets or instructions to supplement BH4. Evidence access: Primary abstract Tyrosine hydroxylase binds tetrahydrobiopterin cofactor with negative cooperativity, as shown by kinetic analyses and surface plasmon resonance detection. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10411647/ · DOI 10.1046/j.1432-1327.1999.00445.x

evidence_access

Primary full text; Methods and structure

experimental_model

Chicken enzyme with bovine/porcine tubulin; 400 micromolar ATP, 2.4 millimolar MgCl2 and 5 micromolar labeled tyrosine in activity assays.

limitations

Mixed-species reconstitution is not a human supplementation experiment. This is retyrosination, not tyrosine phosphorylation.

nutrient_topic

L-Tyrosine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Tyrosine

plain_language

Tyrosine can be attached to an existing protein after translation.

primary_references

Structural basis of tubulin tyrosination by tubulin tyrosine ligase. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23358242/ · DOI 10.1083/jcb.201211017

L-Tyrosine: catecholamines, thyroid chemistry, pigment, metabolism and cross-nutrient mechanisms (2026-09-19) · lines 316–322

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Chicken enzyme with bovine/porcine tubulin; 400 micromolar ATP, 2.4 millimolar MgCl2 and 5 micromolar labeled tyrosine in activity assays. · source_derived_draft · unverified_draft

## l-tyrosine-tubulin-retyrosination Tyrosine can be attached to an existing protein after translation. Recombinant chicken TTL incorporated radiolabeled tyrosine into mammalian brain alpha-tubulin in ATP/Mg-containing assays. Model: Chicken enzyme with bovine/porcine tubulin; 400 micromolar ATP, 2.4 millimolar MgCl2 and 5 micromolar labeled tyrosine in activity assays. Limitations: Mixed-species reconstitution is not a human supplementation experiment. This is retyrosination, not tyrosine phosphorylation. Evidence access: Primary full text; Methods and structure Structural basis of tubulin tyrosination by tubulin tyrosine ligase. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23358242/ · DOI 10.1083/jcb.201211017

evidence_access

Primary full text; reaction description and experimental methods

experimental_model

Primary-paper description of YARS1 chemistry and human cellular/protein experiments.

limitations

The translation role is biochemical background in this paper; the main experiments concern extracellular signaling.

nutrient_topic

L-Tyrosine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Tyrosine

plain_language

Tyrosine must be loaded onto tRNA to enter a growing protein.

primary_references

Moonlighting matrix metalloproteinase substrates: Enhancement of proinflammatory functions of extracellular tyrosyl-tRNA synthetase upon cleavage. · 2020 · https://pubmed.ncbi.nlm.nih.gov/31771979/ · DOI 10.1074/jbc.RA119.010486

L-Tyrosine: catecholamines, thyroid chemistry, pigment, metabolism and cross-nutrient mechanisms (2026-09-19) · lines 68–74

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Primary-paper description of YARS1 chemistry and human cellular/protein experiments. · source_derived_draft · unverified_draft

## l-tyrosine-yars1-charging Tyrosine must be loaded onto tRNA to enter a growing protein. Human YARS1 ligates tyrosine to its cognate tRNA; the study separately examined the extracellular functions of this protein. Model: Primary-paper description of YARS1 chemistry and human cellular/protein experiments. Limitations: The translation role is biochemical background in this paper; the main experiments concern extracellular signaling. Evidence access: Primary full text; reaction description and experimental methods Moonlighting matrix metalloproteinase substrates: Enhancement of proinflammatory functions of extracellular tyrosyl-tRNA synthetase upon cleavage. · 2020 · https://pubmed.ncbi.nlm.nih.gov/31771979/ · DOI 10.1074/jbc.RA119.010486

evidence_access

Primary abstract

experimental_model

Wild-type and F52L human enzyme aminoacylation assays.

limitations

Retained activity does not mean normal function; this does not establish a tyrosine-rescue dose.

nutrient_topic

L-Tyrosine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Tyrosine

plain_language

Mitochondria use a separate tyrosine-loading enzyme.

primary_references

Mutation of the mitochondrial tyrosyl-tRNA synthetase gene, YARS2, causes myopathy, lactic acidosis, and sideroblastic anemia--MLASA syndrome. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20598274/ · DOI 10.1016/j.ajhg.2010.06.001

L-Tyrosine: catecholamines, thyroid chemistry, pigment, metabolism and cross-nutrient mechanisms (2026-09-19) · lines 76–82

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Wild-type and F52L human enzyme aminoacylation assays. · source_derived_draft · unverified_draft

## l-tyrosine-yars2-charging Mitochondria use a separate tyrosine-loading enzyme. Recombinant human YARS2 supported tyrosyl-tRNA aminoacylation; the F52L variant retained activity with abnormal kinetics. Model: Wild-type and F52L human enzyme aminoacylation assays. Limitations: Retained activity does not mean normal function; this does not establish a tyrosine-rescue dose. Evidence access: Primary abstract Mutation of the mitochondrial tyrosyl-tRNA synthetase gene, YARS2, causes myopathy, lactic acidosis, and sideroblastic anemia--MLASA syndrome. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20598274/ · DOI 10.1016/j.ajhg.2010.06.001

evidence_access

Primary abstract

experimental_model

Human cancer-cell metabolic tracing and nutrient manipulation.

limitations

This is not proof that adding serine increases methylation in every tissue.

nutrient_topic

L-Serine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Serine

plain_language

Methylation needs the ATP-making side of serine metabolism as well as one-carbon donation.

primary_references

Serine Metabolism Supports the Methionine Cycle and DNA/RNA Methylation through De Novo ATP Synthesis in Cancer Cells. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26774282/ · DOI 10.1016/j.molcel.2015.12.014

L-Serine: synthesis, one-carbon metabolism, lipids and cross-nutrient mechanisms (2026-09-19) · lines 182–188

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human cancer-cell metabolic tracing and nutrient manipulation. · source_derived_draft · unverified_draft

## l-serine-serine-atp-methylation Methylation needs the ATP-making side of serine metabolism as well as one-carbon donation. Serine metabolism supported the methionine cycle through de novo ATP synthesis both with and without extracellular methionine in the tested cancer cells. Model: Human cancer-cell metabolic tracing and nutrient manipulation. Limitations: This is not proof that adding serine increases methylation in every tissue. Evidence access: Primary abstract Serine Metabolism Supports the Methionine Cycle and DNA/RNA Methylation through De Novo ATP Synthesis in Cancer Cells. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26774282/ · DOI 10.1016/j.molcel.2015.12.014

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human cancer-cell starvation experiments.

limitations

No universal oncogene activation, whole-body methylation collapse or dietary threshold is established.

nutrient_topic

L-Serine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Serine

plain_language

A shortage can alter methylation without a simple energy-sensor response.

primary_references

Serine Metabolism Supports the Methionine Cycle and DNA/RNA Methylation through De Novo ATP Synthesis in Cancer Cells. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26774282/ · DOI 10.1016/j.molcel.2015.12.014

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Serine: synthesis, one-carbon metabolism, lipids and cross-nutrient mechanisms (2026-09-19) · lines 190–196

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human cancer-cell starvation experiments. · source_derived_draft · unverified_draft

## l-serine-serine-starvation-methylation A shortage can alter methylation without a simple energy-sensor response. Serine starvation increased the methionine/SAM ratio and reduced methyl-group transfer to DNA and RNA; ATP and AMP fell without AMPK activation. Model: Human cancer-cell starvation experiments. Limitations: No universal oncogene activation, whole-body methylation collapse or dietary threshold is established. Evidence access: Primary abstract Serine Metabolism Supports the Methionine Cycle and DNA/RNA Methylation through De Novo ATP Synthesis in Cancer Cells. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26774282/ · DOI 10.1016/j.molcel.2015.12.014

evidence_access

Primary full text

experimental_model

Purified human EPRS/ProRS biochemical assays.

limitations

tRNA charging and collagen hydroxylation are separate enzyme steps.

nutrient_topic

L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline

plain_language

A protein-building block must first be loaded onto the correct tRNA.

primary_references

Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22327401/ · DOI 10.1038/nchembio.790

L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 222–228

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Purified human EPRS/ProRS biochemical assays. · source_derived_draft · unverified_draft

## l-proline-eprs-charging A protein-building block must first be loaded onto the correct tRNA. The prolyl-tRNA synthetase domain of human EPRS attaches proline to its cognate tRNA in an ATP-dependent aminoacylation reaction. Model: Purified human EPRS/ProRS biochemical assays. Limitations: tRNA charging and collagen hydroxylation are separate enzyme steps. Evidence access: Primary full text Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22327401/ · DOI 10.1038/nchembio.790

evidence_access

Primary abstract

experimental_model

TGF-beta-stimulated fibroblast experiments; primary abstract, with mouse NIH3T3 model identified in the primary study.

limitations

No dietary dose or general antifibrotic benefit is inferred.

nutrient_topic

L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline

plain_language

Activated matrix-producing cells can use proline synthesis to handle metabolic demand.

primary_references

Proline biosynthesis is a vent for TGFβ-induced mitochondrial redox stress. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32134147/ · DOI 10.15252/embj.2019103334

L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 366–372

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · TGF-beta-stimulated fibroblast experiments; primary abstract, with mouse NIH3T3 model identified in the primary study. · source_derived_draft · unverified_draft

## l-proline-tgfb-proline Activated matrix-producing cells can use proline synthesis to handle metabolic demand. TGF-beta induced glutamine-derived proline synthesis in a Smad4-dependent fibroblast program; manipulations of mitochondrial redox potential or ATP production changed that synthesis. Model: TGF-beta-stimulated fibroblast experiments; primary abstract, with mouse NIH3T3 model identified in the primary study. Limitations: No dietary dose or general antifibrotic benefit is inferred. Evidence access: Primary abstract Proline biosynthesis is a vent for TGFβ-induced mitochondrial redox stress. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32134147/ · DOI 10.15252/embj.2019103334

evidence_access

Primary abstract

experimental_model

Hamster ex vivo intestine; mitochondrial enzyme activity and morphology assays.

limitations

This potentially disruptive millimolar exposure is not proof of safe, selective glucose blocking in humans.

nutrient_topic

Stevia collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Stevia

plain_language

High local exposure impaired the tissue machinery supporting absorption.

primary_references

Inhibitory effect of steviol, a metabolite of stevioside, on glucose absorption in everted hamster intestine in vitro. · 1995 · https://pubmed.ncbi.nlm.nih.gov/7482583/ · DOI 10.1016/0378-4274(95)03391-w

Stevia: glycoside metabolism, taste, ion channels and cross-nutrient mechanisms (2026-09-19) · lines 346–352

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Hamster ex vivo intestine; mitochondrial enzyme activity and morphology assays. · source_derived_draft · unverified_draft

## stevia-hamster-energy High local exposure impaired the tissue machinery supporting absorption. In everted hamster jejunum, 1 mM steviol reduced glucose absorption by 29%, accompanied by reduced mucosal ATP and altered absorptive morphology; stevioside at 1 or 5 mM did not inhibit absorption. Model: Hamster ex vivo intestine; mitochondrial enzyme activity and morphology assays. Limitations: This potentially disruptive millimolar exposure is not proof of safe, selective glucose blocking in humans. Evidence access: Primary abstract Inhibitory effect of steviol, a metabolite of stevioside, on glucose absorption in everted hamster intestine in vitro. · 1995 · https://pubmed.ncbi.nlm.nih.gov/7482583/ · DOI 10.1016/0378-4274(95)03391-w

evidence_access

Primary abstract

experimental_model

Mouse islet nucleotide assays; the same paper reports reduced KATP conductance.

limitations

The causal chain from nucleotide change to conductance was proposed rather than isolated by every possible intervention.

nutrient_topic

Stevia collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Stevia

plain_language

Energy state may connect a glycoside response to potassium-channel closure.

primary_references

Rebaudioside A directly stimulates insulin secretion from pancreatic beta cells: a glucose-dependent action via inhibition of ATP-sensitive K-channels. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18435771/ · DOI 10.1111/j.1463-1326.2008.00864.x

Stevia: glycoside metabolism, taste, ion channels and cross-nutrient mechanisms (2026-09-19) · lines 242–248

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse islet nucleotide assays; the same paper reports reduced KATP conductance. · source_derived_draft · unverified_draft

## stevia-reba-atp Energy state may connect a glycoside response to potassium-channel closure. Rebaudioside A at 1 nM increased the ATP/ADP ratio at 16.7 mM glucose while not changing measured cAMP. Model: Mouse islet nucleotide assays; the same paper reports reduced KATP conductance. Limitations: The causal chain from nucleotide change to conductance was proposed rather than isolated by every possible intervention. Evidence access: Primary abstract Rebaudioside A directly stimulates insulin secretion from pancreatic beta cells: a glucose-dependent action via inhibition of ATP-sensitive K-channels. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18435771/ · DOI 10.1111/j.1463-1326.2008.00864.x

evidence_access

Primary abstract

experimental_model

Alpha-ketoglutarate- or succinate-supported respiration.

limitations

Suggests effects on energy transduction; not direct structural proof of ATP-synthase binding.

nutrient_topic

Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin

plain_language

Energy conversion can be impaired at experimental exposures.

primary_references

Prooxidant activity of fisetin: effects on energy metabolism in the rat liver. · 2011 · https://pubmed.ncbi.nlm.nih.gov/20957679/ · DOI 10.1002/jbt.20367

Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 336–342

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Alpha-ketoglutarate- or succinate-supported respiration. · source_derived_draft · unverified_draft

## fisetin-rat-respiration Energy conversion can be impaired at experimental exposures. Fisetin reduced respiratory control and ADP/O ratios and inhibited ADP-stimulated respiration in isolated rat mitochondria. Model: Alpha-ketoglutarate- or succinate-supported respiration. Limitations: Suggests effects on energy transduction; not direct structural proof of ATP-synthase binding. Evidence access: Primary abstract Prooxidant activity of fisetin: effects on energy metabolism in the rat liver. · 2011 · https://pubmed.ncbi.nlm.nih.gov/20957679/ · DOI 10.1002/jbt.20367

evidence_access

Primary abstract

experimental_model

In-vitro mitochondrial exposure, 40-360 mg/L; lower-molecular-weight fractions had larger effects.

limitations

No oral pharmacokinetics or human ATP benefit is demonstrated. The abstract groups humic substances when describing phosphorylation efficiency, so a fulvic-specific efficiency claim is not inferred.

nutrient_topic

Fulvic acid collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Fulvic acid (heterogeneous humic fraction)

plain_language

A soil-derived fraction changed respiration in isolated organelles.

primary_references

Effect of humic substances on mitochondrial respiration and oxidative phosphorylation. · 1987 · https://pubmed.ncbi.nlm.nih.gov/2953069/ · DOI 10.1016/0048-9697(87)90521-3

Fulvic acid: mixture identity, mineral chemistry, signaling and cross-nutrient mechanisms (2026-09-19) · lines 188–194

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · In-vitro mitochondrial exposure, 40-360 mg/L; lower-molecular-weight fractions had larger effects. · source_derived_draft · unverified_draft

## fulvic-acid-mitochondrial-respiration A soil-derived fraction changed respiration in isolated organelles. Podzol-derived fulvic material increased respiration in isolated rat liver mitochondria. Model: In-vitro mitochondrial exposure, 40-360 mg/L; lower-molecular-weight fractions had larger effects. Limitations: No oral pharmacokinetics or human ATP benefit is demonstrated. The abstract groups humic substances when describing phosphorylation efficiency, so a fulvic-specific efficiency claim is not inferred. Evidence access: Primary abstract Effect of humic substances on mitochondrial respiration and oxidative phosphorylation. · 1987 · https://pubmed.ncbi.nlm.nih.gov/2953069/ · DOI 10.1016/0048-9697(87)90521-3

cross_nutrient

false

evidence_location

Results: Figures 3, 4, 5; Experimental procedures: liposomes and transport assays

experimental_model

Purified human ABCD4/LMBD1 in synthetic liposomes after yeast expression

exposure

100 micromolar lumenal cobalamin, external ATP, 37 C

limitations

Artificial membrane orientation models lysosomal export; exact cobalamin upper ligand was not specified in retrieved methods.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

ABCD4 used ATP-dependent machinery to move B12 across a membrane.

primary_references

[kitai-2021-abcd4-transport] The lysosomal protein ABCD4 can transport vitamin B12 across liposomal membranes in vitro (2021). https://pubmed.ncbi.nlm.nih.gov/33845046/ DOI: 10.1016/j.jbc.2021.100654

tissue_or_cell_type

Cell-free membrane system

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 613–625

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human ABCD4/LMBD1 in synthetic liposomes after yeast expression · source_derived_draft · unverified_draft

### b12-abcd4-atp-export Reconstituted human ABCD4 moved cobalamin from liposome interior to exterior with external ATP; the ATPase-defective K427A control lacked this activity. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: ABCD4 used ATP-dependent machinery to move B12 across a membrane. organism: Homo sapiens tissue_or_cell_type: Cell-free membrane system experimental_model: Purified human ABCD4/LMBD1 in synthetic liposomes after yeast expression limitations: Artificial membrane orientation models lysosomal export; exact cobalamin upper ligand was not specified in retrieved methods. exposure: 100 micromolar lumenal cobalamin, external ATP, 37 C cross_nutrient: false evidence_location: Results: Figures 3, 4, 5; Experimental procedures: liposomes and transport assays [kitai-2021-abcd4-transport] The lysosomal protein ABCD4 can transport vitamin B12 across liposomal membranes in vitro (2021). https://pubmed.ncbi.nlm.nih.gov/33845046/ DOI: 10.1016/j.jbc.2021.100654

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

evidence_location

Results: Figures 3, 4, 5; Experimental procedures: liposomes and transport assays

experimental_model

Purified human ABCD4/LMBD1 in synthetic liposomes after yeast expression

exposure

Variant versus wild-type ABCD4 proteoliposomes

limitations

Disease-related variant tested outside cells; ATP hydrolysis and transport are distinct measured endpoints.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

The variant disrupted B12 movement across the membrane.

primary_references

[kitai-2021-abcd4-transport] The lysosomal protein ABCD4 can transport vitamin B12 across liposomal membranes in vitro (2021). https://pubmed.ncbi.nlm.nih.gov/33845046/ DOI: 10.1016/j.jbc.2021.100654

tissue_or_cell_type

Cell-free membrane system

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 641–653

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human ABCD4/LMBD1 in synthetic liposomes after yeast expression · source_derived_draft · unverified_draft

### b12-abcd4-n141k-transport Purified human ABCD4 N141K lost detectable cobalamin transport in liposomes, despite ATPase activity comparable with wild type. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The variant disrupted B12 movement across the membrane. organism: Homo sapiens tissue_or_cell_type: Cell-free membrane system experimental_model: Purified human ABCD4/LMBD1 in synthetic liposomes after yeast expression limitations: Disease-related variant tested outside cells; ATP hydrolysis and transport are distinct measured endpoints. exposure: Variant versus wild-type ABCD4 proteoliposomes cross_nutrient: false evidence_location: Results: Figures 3, 4, 5; Experimental procedures: liposomes and transport assays [kitai-2021-abcd4-transport] The lysosomal protein ABCD4 can transport vitamin B12 across liposomal membranes in vitro (2021). https://pubmed.ncbi.nlm.nih.gov/33845046/ DOI: 10.1016/j.jbc.2021.100654

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

evidence_location

Results: Figures 3, 4, 5; Experimental procedures: liposomes and transport assays

experimental_model

Purified human ABCD4/LMBD1 in synthetic liposomes after yeast expression

exposure

Variant versus wild-type ABCD4 proteoliposomes

limitations

Disease-related variant tested outside cells; ATP hydrolysis and transport are distinct measured endpoints.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

The variant disrupted B12 movement across the membrane.

primary_references

[kitai-2021-abcd4-transport] The lysosomal protein ABCD4 can transport vitamin B12 across liposomal membranes in vitro (2021). https://pubmed.ncbi.nlm.nih.gov/33845046/ DOI: 10.1016/j.jbc.2021.100654

tissue_or_cell_type

Cell-free membrane system

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 655–667

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human ABCD4/LMBD1 in synthetic liposomes after yeast expression · source_derived_draft · unverified_draft

### b12-abcd4-y319c-transport Purified human ABCD4 Y319C lost detectable cobalamin transport in liposomes, together with loss of ATPase activity. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The variant disrupted B12 movement across the membrane. organism: Homo sapiens tissue_or_cell_type: Cell-free membrane system experimental_model: Purified human ABCD4/LMBD1 in synthetic liposomes after yeast expression limitations: Disease-related variant tested outside cells; ATP hydrolysis and transport are distinct measured endpoints. exposure: Variant versus wild-type ABCD4 proteoliposomes cross_nutrient: false evidence_location: Results: Figures 3, 4, 5; Experimental procedures: liposomes and transport assays [kitai-2021-abcd4-transport] The lysosomal protein ABCD4 can transport vitamin B12 across liposomal membranes in vitro (2021). https://pubmed.ncbi.nlm.nih.gov/33845046/ DOI: 10.1016/j.jbc.2021.100654

cross_nutrient

true

evidence_location

Abstract and indexed primary Results, Figure 3

experimental_model

Purified human proteins

exposure

FDX1, FDXR and NADPH with MMAB, cob(II)alamin and ATP

limitations

Biochemically competent donor; exclusivity or necessity in living humans was not tested.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

In the purified human system, an iron-sulfur electron carrier supported B12 activation.

primary_references

[gouda-2023-mmab-redox] Coordination Chemistry Controls Coenzyme B12 Synthesis by Human Adenosine Triphosphate:Cob(I)alamin Adenosyltransferase. (2023). https://pubmed.ncbi.nlm.nih.gov/37526260/ DOI: 10.1021/acs.inorgchem.3c02163

tissue_or_cell_type

Purified protein assay

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1005–1017

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human proteins · source_derived_draft · unverified_draft

### fdx1-supports-mmab Human [2Fe-2S] ferredoxin FDX1 supplied electrons for MMAB-dependent adenosylcobalamin synthesis in the FDXR/NADPH reconstitution. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: In the purified human system, an iron-sulfur electron carrier supported B12 activation. organism: Homo sapiens tissue_or_cell_type: Purified protein assay experimental_model: Purified human proteins limitations: Biochemically competent donor; exclusivity or necessity in living humans was not tested. exposure: FDX1, FDXR and NADPH with MMAB, cob(II)alamin and ATP cross_nutrient: true evidence_location: Abstract and indexed primary Results, Figure 3 [gouda-2023-mmab-redox] Coordination Chemistry Controls Coenzyme B12 Synthesis by Human Adenosine Triphosphate:Cob(I)alamin Adenosyltransferase. (2023). https://pubmed.ncbi.nlm.nih.gov/37526260/ DOI: 10.1021/acs.inorgchem.3c02163

cross_nutrient

false

evidence_location

Full text Results; Figures 2-4; cofactor off-loading and MMUT activity Methods

experimental_model

Purified human proteins

exposure

Anaerobic assay; MMAB, MMAA, GTP and ATP

limitations

Reconstituted transfer; spectroscopy reports cofactor environment, not cellular turnover.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

In the purified repair assay, inactive B12 moved from MMUT back to MMAB.

primary_references

[mascarenhas-2023-nanoassembly] Architecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B12 delivery and repair. (2023). https://pubmed.ncbi.nlm.nih.gov/37468522/ DOI: 10.1038/s41467-023-40077-4

tissue_or_cell_type

Purified protein assay

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1131–1143

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human proteins · source_derived_draft · unverified_draft

### mmaa-mmab-offload-cob-ii A human MMAA/MMAB repair mixture with GTP and ATP transferred cob(II)alamin from MMUT to MMAB in anaerobic spectroscopy. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: In the purified repair assay, inactive B12 moved from MMUT back to MMAB. organism: Homo sapiens tissue_or_cell_type: Purified protein assay experimental_model: Purified human proteins limitations: Reconstituted transfer; spectroscopy reports cofactor environment, not cellular turnover. exposure: Anaerobic assay; MMAB, MMAA, GTP and ATP cross_nutrient: false evidence_location: Full text Results; Figures 2-4; cofactor off-loading and MMUT activity Methods [mascarenhas-2023-nanoassembly] Architecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B12 delivery and repair. (2023). https://pubmed.ncbi.nlm.nih.gov/37468522/ DOI: 10.1038/s41467-023-40077-4

cross_nutrient

false

evidence_location

Indexed primary abstract

experimental_model

Purified human proteins

exposure

Cob(I)alamin and ATP

limitations

Biochemical reconstitution; does not determine cellular rate or dietary requirement.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

In a purified human-protein assay, MMAB made the B12 cofactor used by MMUT.

primary_references

[leal-2004-human-mmab] Human ATP:Cob(I)alamin adenosyltransferase and its interaction with methionine synthase reductase. (2004). https://pubmed.ncbi.nlm.nih.gov/15347655/ DOI: 10.1074/jbc.m405449200

tissue_or_cell_type

Purified protein assay

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 977–989

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human proteins · source_derived_draft · unverified_draft

### mmab-adenosylates-cob-i Purified human MMAB uses ATP to adenosylate cob(I)alamin to adenosylcobalamin. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: In a purified human-protein assay, MMAB made the B12 cofactor used by MMUT. organism: Homo sapiens tissue_or_cell_type: Purified protein assay experimental_model: Purified human proteins limitations: Biochemical reconstitution; does not determine cellular rate or dietary requirement. exposure: Cob(I)alamin and ATP cross_nutrient: false evidence_location: Indexed primary abstract [leal-2004-human-mmab] Human ATP:Cob(I)alamin adenosyltransferase and its interaction with methionine synthase reductase. (2004). https://pubmed.ncbi.nlm.nih.gov/15347655/ DOI: 10.1074/jbc.m405449200

cross_nutrient

true

evidence_location

Indexed primary abstract; Full text Methods 2.6 and Results 3.6; Figure 5

experimental_model

Human fibroblast PCC and coupled-pathway assays

exposure

Propionyl-CoA, ATP and bicarbonate in enzyme pathway

limitations

Pathway assignment combines human PCC characterization with coupled assays; it is not a simultaneous dietary biotin/B12 intervention.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Biotin-dependent PCC makes the precursor that must be rearranged before human MMUT can use B12 on it.

primary_references

[hsia-1979-pcc] Human propionyl CoA carboxylase: some properties of the partially purified enzyme in fibroblasts from controls and patients with propionic acidemia. (1979). https://pubmed.ncbi.nlm.nih.gov/481943/ DOI: 10.1203/00006450-197906000-00005 [heuberger-2019-mcee] Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency. (2019). https://pubmed.ncbi.nlm.nih.gov/30682498/ DOI: 10.1016/j.bbadis.2019.01.021

tissue_or_cell_type

Fibroblasts

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1159–1172

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human fibroblast PCC and coupled-pathway assays · source_derived_draft · unverified_draft

### pcc-carboxylation-upstream-b12 Human PCC supplies (S)-methylmalonyl-CoA by propionyl-CoA carboxylation upstream of the MCEE-MMUT sequence examined in fibroblast assays. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Biotin-dependent PCC makes the precursor that must be rearranged before human MMUT can use B12 on it. organism: Homo sapiens tissue_or_cell_type: Fibroblasts experimental_model: Human fibroblast PCC and coupled-pathway assays limitations: Pathway assignment combines human PCC characterization with coupled assays; it is not a simultaneous dietary biotin/B12 intervention. exposure: Propionyl-CoA, ATP and bicarbonate in enzyme pathway cross_nutrient: true evidence_location: Indexed primary abstract; Full text Methods 2.6 and Results 3.6; Figure 5 [hsia-1979-pcc] Human propionyl CoA carboxylase: some properties of the partially purified enzyme in fibroblasts from controls and patients with propionic acidemia. (1979). https://pubmed.ncbi.nlm.nih.gov/481943/ DOI: 10.1203/00006450-197906000-00005 [heuberger-2019-mcee] Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency. (2019). https://pubmed.ncbi.nlm.nih.gov/30682498/ DOI: 10.1016/j.bbadis.2019.01.021

evidence_access

Primary abstract

experimental_model

Biochemical and cellular transformation experiments.

limitations

Do not relabel the unresolved construct as human AKT1; docking is supporting modeling, not an independent experiment.

nutrient_topic

Myricetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Myricetin

plain_language

Direct binding evidence is recorded without guessing the isoform.

primary_references

Akt is a direct target for myricetin to inhibit cell transformation. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19504174/ · DOI 10.1007/s11010-009-0171-9

Myricetin: metabolism, immune signaling, redox chemistry and cross-nutrient mechanisms (2026-09-19) · lines 476–482

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Biochemical and cellular transformation experiments. · source_derived_draft · unverified_draft

## myricetin-akt-binding Direct binding evidence is recorded without guessing the isoform. Myricetin bound Akt in an ATP-competitive binding assay and reduced Akt kinase activity. Model: Biochemical and cellular transformation experiments. Limitations: Do not relabel the unresolved construct as human AKT1; docking is supporting modeling, not an independent experiment. Evidence access: Primary abstract Akt is a direct target for myricetin to inhibit cell transformation. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19504174/ · DOI 10.1007/s11010-009-0171-9

evidence_access

Primary abstract

experimental_model

Recombinant human subunits; radiolabeled ATP incorporation.

limitations

Not a measured therapeutic human exposure.

nutrient_topic

Myricetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Myricetin

plain_language

The same canonical kinase can connect multiple flavonoid chapters.

primary_references

Structure-activity relationship of 7 flavonoids on recombinant human protein kinase CK2 holoenzyme. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19197122/

Myricetin: metabolism, immune signaling, redox chemistry and cross-nutrient mechanisms (2026-09-19) · lines 484–490

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Recombinant human subunits; radiolabeled ATP incorporation. · source_derived_draft · unverified_draft

## myricetin-ck2 The same canonical kinase can connect multiple flavonoid chapters. Myricetin inhibited reconstituted human CK2 alpha-prime/beta holoenzyme, IC50 1.18 micromolar. Model: Recombinant human subunits; radiolabeled ATP incorporation. Limitations: Not a measured therapeutic human exposure. Evidence access: Primary abstract Structure-activity relationship of 7 flavonoids on recombinant human protein kinase CK2 holoenzyme. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19197122/

evidence_access

Primary full text

experimental_model

Purified bacterial DnaK/DnaJ/GrpE system.

limitations

Not demonstrated infection treatment or host chaperone inhibition.

nutrient_topic

Myricetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Myricetin

plain_language

The same enzyme responds differently to its partner.

primary_references

Chemical screens against a reconstituted multiprotein complex: myricetin blocks DnaJ regulation of DnaK through an allosteric mechanism. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21338918/ · DOI 10.1016/j.chembiol.2010.12.010

Myricetin: metabolism, immune signaling, redox chemistry and cross-nutrient mechanisms (2026-09-19) · lines 588–594

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Purified bacterial DnaK/DnaJ/GrpE system. · source_derived_draft · unverified_draft

## myricetin-dnaj-atpase The same enzyme responds differently to its partner. Myricetin blocked DnaJ-stimulated DnaK ATPase activity with little effect on intrinsic or GrpE-stimulated turnover. Model: Purified bacterial DnaK/DnaJ/GrpE system. Limitations: Not demonstrated infection treatment or host chaperone inhibition. Evidence access: Primary full text Chemical screens against a reconstituted multiprotein complex: myricetin blocks DnaJ regulation of DnaK through an allosteric mechanism. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21338918/ · DOI 10.1016/j.chembiol.2010.12.010

evidence_access

Primary abstract

experimental_model

Mouse JB6 P+ cells and UVB-exposed mouse skin.

limitations

No human skin-cancer prevention trial; related papers share investigators.

nutrient_topic

Myricetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Myricetin

plain_language

A separate kinase connects UVB signaling to downstream responses.

primary_references

Myricetin suppresses UVB-induced skin cancer by targeting Fyn. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18632659/ · DOI 10.1158/0008-5472.CAN-08-0899

Myricetin: metabolism, immune signaling, redox chemistry and cross-nutrient mechanisms (2026-09-19) · lines 468–474

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse JB6 P+ cells and UVB-exposed mouse skin. · source_derived_draft · unverified_draft

## myricetin-fyn A separate kinase connects UVB signaling to downstream responses. Myricetin inhibited Fyn kinase activity in mouse epidermal cells and skin; pull-down supported ATP-competitive binding. Model: Mouse JB6 P+ cells and UVB-exposed mouse skin. Limitations: No human skin-cancer prevention trial; related papers share investigators. Evidence access: Primary abstract Myricetin suppresses UVB-induced skin cancer by targeting Fyn. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18632659/ · DOI 10.1158/0008-5472.CAN-08-0899

evidence_access

Primary abstract

experimental_model

Purified human transporter and cellular transport experiments.

limitations

Polyamine-class result; strongest affinity was for spermine, not necessarily spermidine.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

A molecule can enter a cell yet remain trapped in a compartment.

primary_references

ATP13A2 deficiency disrupts lysosomal polyamine export. · 2020 · https://pubmed.ncbi.nlm.nih.gov/31996848/ · DOI 10.1038/s41586-020-1968-7

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 118–124

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Purified human transporter and cellular transport experiments. · source_derived_draft · unverified_draft

## spermidine-atp13a2-export A molecule can enter a cell yet remain trapped in a compartment. ATP13A2 supports lysosomal polyamine export to cytosol after endocytic uptake; spermine had the highest tested affinity. Model: Purified human transporter and cellular transport experiments. Limitations: Polyamine-class result; strongest affinity was for spermine, not necessarily spermidine. Evidence access: Primary abstract ATP13A2 deficiency disrupts lysosomal polyamine export. · 2020 · https://pubmed.ncbi.nlm.nih.gov/31996848/ · DOI 10.1038/s41586-020-1968-7

evidence_span

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experimental_model

Liver-specific AMPK-deficient and LKB1-deficient mouse hepatocytes with PGC-1alpha overexpression

exposure

Metformin dose-response in hepatocytes lacking AMPK or LKB1

limitations

A direct challenge to the AMPK requirement. The measured correlate is intracellular ATP, so this is an energy-state mechanism rather than a signalling one.

nutrient_topic

Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin

organism

Mouse

plain_language

The drug lowered the cell’s energy currency, and that alone tracked the effect.

primary_references

[metformin-p20577053] Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. (2010). https://pubmed.ncbi.nlm.nih.gov/20577053/ DOI: 10.1172/jci40671

tissue_or_cell_type

Liver

Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 606–617

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Liver-specific AMPK-deficient and LKB1-deficient mouse hepatocytes with PGC-1alpha overexpression · source_derived_draft · unverified_draft

### metformin-energy-state-mechanism Inhibition of glucose production correlated in a dose-dependent manner with a reduction in intracellular ATP content, and was preserved when gluconeogenic genes were force-expressed through PGC-1alpha. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The drug lowered the cell’s energy currency, and that alone tracked the effect. organism: Mouse tissue_or_cell_type: Liver experimental_model: Liver-specific AMPK-deficient and LKB1-deficient mouse hepatocytes with PGC-1alpha overexpression limitations: A direct challenge to the AMPK requirement. The measured correlate is intracellular ATP, so this is an energy-state mechanism rather than a signalling one. exposure: Metformin dose-response in hepatocytes lacking AMPK or LKB1 evidence_span: {"source_cache": "artifacts/metformin-research/20577053.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f6019de6b5a35f860f55b39d91656e5fd1077d34e301d244a1ea498b96faac14", "start_char": 0, "end_char": 1707, "text_sha256": "f6019de6b5a35f860f55b39d91656e5fd1077d34e301d244a1ea498b96faac14"} [metformin-p20577053] Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. (2010). https://pubmed.ncbi.nlm.nih.gov/20577053/ DOI: 10.1172/jci40671

evidence_span

{"source_cache": "artifacts/metformin-research/12086935.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a7807ae8af1c0f438eeff1dd4106d0198681e72f0333f0556786b9151b0df680", "start_char": 0, "end_char": 1474, "text_sha256": "a7807ae8af1c0f438eeff1dd4106d0198681e72f0333f0556786b9151b0df680"}

experimental_model

Ten weeks of metformin in people with type 2 diabetes with muscle biopsies

exposure

Therapeutic metformin doses for 10 weeks

limitations

A human tissue measurement at therapeutic dose. It is an association within a treatment study, not a demonstration that AMPK causes the glucose disposal change.

nutrient_topic

Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin

organism

Human

plain_language

Human muscle showed the fall in energy stores that the sensor responds to.

primary_references

[metformin-p12086935] Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. (2002). https://pubmed.ncbi.nlm.nih.gov/12086935/ DOI: 10.2337/diabetes.51.7.2074

tissue_or_cell_type

Skeletal muscle

Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 749–760

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Ten weeks of metformin in people with type 2 diabetes with muscle biopsies · source_derived_draft · unverified_draft

### metformin-human-muscle-energy The increase in AMPK alpha2 activity was accompanied by lower muscle ATP and phosphocreatine concentrations after treatment. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Human muscle showed the fall in energy stores that the sensor responds to. organism: Human tissue_or_cell_type: Skeletal muscle experimental_model: Ten weeks of metformin in people with type 2 diabetes with muscle biopsies limitations: A human tissue measurement at therapeutic dose. It is an association within a treatment study, not a demonstration that AMPK causes the glucose disposal change. exposure: Therapeutic metformin doses for 10 weeks evidence_span: {"source_cache": "artifacts/metformin-research/12086935.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a7807ae8af1c0f438eeff1dd4106d0198681e72f0333f0556786b9151b0df680", "start_char": 0, "end_char": 1474, "text_sha256": "a7807ae8af1c0f438eeff1dd4106d0198681e72f0333f0556786b9151b0df680"} [metformin-p12086935] Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. (2002). https://pubmed.ncbi.nlm.nih.gov/12086935/ DOI: 10.2337/diabetes.51.7.2074

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Mouse shRNA and enzyme re-expression experiments.

limitations

PARP activity is not a direct measurement of all nuclear NAD-dependent reactions.

nutrient_topic

NAD+ collection; molecular form, preparation, species, exposure and manipulation remain explicit. · NAD+

plain_language

DNA-associated enzymes can depend on local NAD production.

primary_references

Metabolic regulation of transcription through compartmentalized NAD+ biosynthesis. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29748257/ · DOI 10.1126/science.aan5780

trigger_kind

machinery_impairment Imported condition classification; unverified.

NAD+: compartmental supply, consumption and cross-nutrient mechanisms (2026-09-19) · lines 60–66

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse shRNA and enzyme re-expression experiments. · source_derived_draft · unverified_draft

## nad-plus-nmnat1-loss DNA-associated enzymes can depend on local NAD production. Nmnat1 knockdown reduced PARP1-mediated PARylation in mouse 3T3-L1 preadipocytes; catalytically active but not inactive NMNAT1 rescued the activity. Model: Mouse shRNA and enzyme re-expression experiments. Limitations: PARP activity is not a direct measurement of all nuclear NAD-dependent reactions. Evidence access: Primary full text Metabolic regulation of transcription through compartmentalized NAD+ biosynthesis. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29748257/ · DOI 10.1126/science.aan5780

evidence_access

Primary full text

experimental_model

Established enzymatic role in a primary HARS variant study.

limitations

Background chemistry rather than a new dietary intervention.

nutrient_topic

L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine

plain_language

A charging enzyme connects free histidine to the protein-building machinery.

primary_references

A loss-of-function variant in the human histidyl-tRNA synthetase (HARS) gene is neurotoxic in vivo. · 2013 · https://pubmed.ncbi.nlm.nih.gov/22930593/ · DOI 10.1002/humu.22210

L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 458–464

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Established enzymatic role in a primary HARS variant study. · source_derived_draft · unverified_draft

## histidine-hars-charging A charging enzyme connects free histidine to the protein-building machinery. HARS1 ligates histidine to its cognate tRNA for protein synthesis. Model: Established enzymatic role in a primary HARS variant study. Limitations: Background chemistry rather than a new dietary intervention. Evidence access: Primary full text A loss-of-function variant in the human histidyl-tRNA synthetase (HARS) gene is neurotoxic in vivo. · 2013 · https://pubmed.ncbi.nlm.nih.gov/22930593/ · DOI 10.1002/humu.22210

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human family study with recombinant activity, transcript analysis and yeast/worm experiments.

limitations

Background role and measured variant impairment are distinguished; direct respiratory-chain failure in every affected tissue is not established here.

nutrient_topic

L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine

plain_language

Mitochondria have a separate histidine-charging requirement.

primary_references

Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21464306/ · DOI 10.1073/pnas.1103471108

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 474–480

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human family study with recombinant activity, transcript analysis and yeast/worm experiments. · source_derived_draft · unverified_draft

## histidine-hars2-charging Mitochondria have a separate histidine-charging requirement. HARS2 provides histidyl-tRNA for mitochondrial translation; L200V and V368L variants reduced aminoacylation in the study assays. Model: Human family study with recombinant activity, transcript analysis and yeast/worm experiments. Limitations: Background role and measured variant impairment are distinguished; direct respiratory-chain failure in every affected tissue is not established here. Evidence access: Primary abstract Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21464306/ · DOI 10.1073/pnas.1103471108

evidence_access

Primary abstract

experimental_model

Reconstituted enzyme kinetics and bicarbonate-deprived human cell culture.

limitations

The culture manipulation is not a bicarbonate supplementation trial or a clinical intracellular threshold.

nutrient_topic

L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine

plain_language

An additional substrate can limit the threonine-dependent reaction.

primary_references

CO2-sensitive tRNA modification associated with human mitochondrial disease. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29760464/ · DOI 10.1038/s41467-018-04250-4

L-Threonine: translation, intestinal barrier, metabolism and cross-nutrient mechanisms (2026-09-19) · lines 138–144

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Reconstituted enzyme kinetics and bicarbonate-deprived human cell culture. · source_derived_draft · unverified_draft

## l-threonine-bicarbonate-limitation An additional substrate can limit the threonine-dependent reaction. The measured bicarbonate/CO2 Km for t6A37 formation was 31 millimolar; human cells cultured without bicarbonate had less t6A37 in mitochondrial tRNAs. Model: Reconstituted enzyme kinetics and bicarbonate-deprived human cell culture. Limitations: The culture manipulation is not a bicarbonate supplementation trial or a clinical intracellular threshold. Evidence access: Primary abstract CO2-sensitive tRNA modification associated with human mitochondrial disease. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29760464/ · DOI 10.1038/s41467-018-04250-4

evidence_access

Primary abstract

experimental_model

Mutant pathway analysis and enzyme characterization.

limitations

Whether this pathway changes human host exposure depends on community, substrate supply and environmental conditions.

nutrient_topic

L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine

plain_language

A microbial fermentation step releases energy as well as a short-chain fatty acid.

primary_references

Novel keto acid formate-lyase and propionate kinase enzymes are components of an anaerobic pathway in Escherichia coli that degrades L-threonine to propionate. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9484901/ · DOI 10.1046/j.1365-2958.1998.00696.x

L-Threonine: translation, intestinal barrier, metabolism and cross-nutrient mechanisms (2026-09-19) · lines 434–440

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mutant pathway analysis and enzyme characterization. · source_derived_draft · unverified_draft

## l-threonine-microbial-atp A microbial fermentation step releases energy as well as a short-chain fatty acid. E. coli TdcD or AckA converted propionyl phosphate to propionate with ATP generation in the anaerobic threonine-degradation pathway. Model: Mutant pathway analysis and enzyme characterization. Limitations: Whether this pathway changes human host exposure depends on community, substrate supply and environmental conditions. Evidence access: Primary abstract Novel keto acid formate-lyase and propionate kinase enzymes are components of an anaerobic pathway in Escherichia coli that degrades L-threonine to propionate. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9484901/ · DOI 10.1046/j.1365-2958.1998.00696.x

evidence_access

Primary abstract

experimental_model

Human enzyme biochemistry alongside inhibitor structures and cellular studies.

limitations

The charging reaction and extracellular signaling by the enzyme are separate functions.

nutrient_topic

L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine

plain_language

The amino acid must be attached to its matching tRNA before translation.

primary_references

Aminoacyl-tRNA synthetase dependent angiogenesis revealed by a bioengineered macrolide inhibitor. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26271225/ · DOI 10.1038/srep13160

L-Threonine: translation, intestinal barrier, metabolism and cross-nutrient mechanisms (2026-09-19) · lines 58–64

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human enzyme biochemistry alongside inhibitor structures and cellular studies. · source_derived_draft · unverified_draft

## l-threonine-tars1-charging The amino acid must be attached to its matching tRNA before translation. Human cytosolic TARS aminoacylation assays measured threonine loading onto tRNA and competitive inhibition by borrelidin-class compounds. Model: Human enzyme biochemistry alongside inhibitor structures and cellular studies. Limitations: The charging reaction and extracellular signaling by the enzyme are separate functions. Evidence access: Primary abstract Aminoacyl-tRNA synthetase dependent angiogenesis revealed by a bioengineered macrolide inhibitor. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26271225/ · DOI 10.1038/srep13160

evidence_access

Primary abstract

experimental_model

Human TARS2 functional characterization and disease-variant assays.

limitations

Cytosolic TARS1 does not replace this mitochondrial record.

nutrient_topic

L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine

plain_language

Mitochondria have their own threonine-loading enzyme.

primary_references

Elucidating the molecular mechanisms associated with TARS2-related mitochondrial disease. · 2022 · https://pubmed.ncbi.nlm.nih.gov/34508595/ · DOI 10.1093/hmg/ddab257

L-Threonine: translation, intestinal barrier, metabolism and cross-nutrient mechanisms (2026-09-19) · lines 66–72

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human TARS2 functional characterization and disease-variant assays. · source_derived_draft · unverified_draft

## l-threonine-tars2-charging Mitochondria have their own threonine-loading enzyme. Human TARS2 generates mitochondrial Thr-tRNA Thr for mitochondrial translation. Model: Human TARS2 functional characterization and disease-variant assays. Limitations: Cytosolic TARS1 does not replace this mitochondrial record. Evidence access: Primary abstract Elucidating the molecular mechanisms associated with TARS2-related mitochondrial disease. · 2022 · https://pubmed.ncbi.nlm.nih.gov/34508595/ · DOI 10.1093/hmg/ddab257

evidence_access

Primary abstract and accessible primary-paper pathway description

experimental_model

Primary paper pathway description supporting human mitochondrial experiments.

limitations

The reaction sequence is described in the primary paper introduction; the 2024 study primarily tests loss of the downstream enzyme.

nutrient_topic

L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine

plain_language

An activated intermediate links nutrient supply to an RNA modification.

primary_references

Multifaceted roles of t6A biogenesis in efficiency and fidelity of mitochondrial gene expression. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38227555/ · DOI 10.1093/nar/gkae013

L-Threonine: translation, intestinal barrier, metabolism and cross-nutrient mechanisms (2026-09-19) · lines 130–136

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Primary paper pathway description supporting human mitochondrial experiments. · source_derived_draft · unverified_draft

## l-threonine-trna-intermediate An activated intermediate links nutrient supply to an RNA modification. The t6A pathway first forms threonylcarbamoyladenylate from threonine, bicarbonate and ATP; OSGEPL1 then transfers the threonylcarbamoyl group to mitochondrial tRNA A37. Model: Primary paper pathway description supporting human mitochondrial experiments. Limitations: The reaction sequence is described in the primary paper introduction; the 2024 study primarily tests loss of the downstream enzyme. Evidence access: Primary abstract and accessible primary-paper pathway description Multifaceted roles of t6A biogenesis in efficiency and fidelity of mitochondrial gene expression. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38227555/ · DOI 10.1093/nar/gkae013

evidence_access

Primary abstract

experimental_model

Human mitochondrial tRNA-modification reconstitution and cellular experiments.

limitations

The mark occurs on multiple tRNAs; it is not restricted to the tRNA that carries threonine.

nutrient_topic

L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine

plain_language

Threonine helps make a decoding mark on tRNA, separate from being loaded for protein synthesis.

primary_references

CO2-sensitive tRNA modification associated with human mitochondrial disease. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29760464/ · DOI 10.1038/s41467-018-04250-4

L-Threonine: translation, intestinal barrier, metabolism and cross-nutrient mechanisms (2026-09-19) · lines 122–128

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human mitochondrial tRNA-modification reconstitution and cellular experiments. · source_derived_draft · unverified_draft

## l-threonine-trna-mark-substrates Threonine helps make a decoding mark on tRNA, separate from being loaded for protein synthesis. Human YRDC and OSGEPL1 supported mitochondrial t6A37 formation using L-threonine, ATP and CO2/bicarbonate as substrates. Model: Human mitochondrial tRNA-modification reconstitution and cellular experiments. Limitations: The mark occurs on multiple tRNAs; it is not restricted to the tRNA that carries threonine. Evidence access: Primary abstract CO2-sensitive tRNA modification associated with human mitochondrial disease. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29760464/ · DOI 10.1038/s41467-018-04250-4

evidence_access

Primary abstract

experimental_model

Recombinant enzyme and cell-extract experiments; construct species not resolved in accessed abstract.

limitations

This is a shared-machinery connection, not a demonstrated magnesium effect on D-aspartate flux.

nutrient_topic

D-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · D-Aspartate

plain_language

Mineral and energy cofactors affect this enzyme, but the measured substrate was serine.

primary_references

Cofactors of serine racemase that physiologically stimulate the synthesis of the N-methyl-D-aspartate (NMDA) receptor coagonist D-serine. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12393813/ · DOI 10.1073/pnas.222421299

D-Aspartate: synthesis, clearance, neural and endocrine mechanisms (2026-09-19) · lines 64–70

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Recombinant enzyme and cell-extract experiments; construct species not resolved in accessed abstract. · source_derived_draft · unverified_draft

## d-aspartate-srr-mg-atp Mineral and energy cofactors affect this enzyme, but the measured substrate was serine. Mg2+ and ATP increased recombinant serine-racemase serine racemization and pyruvate production by approximately five- to ten-fold in the study assay. Model: Recombinant enzyme and cell-extract experiments; construct species not resolved in accessed abstract. Limitations: This is a shared-machinery connection, not a demonstrated magnesium effect on D-aspartate flux. Evidence access: Primary abstract Cofactors of serine racemase that physiologically stimulate the synthesis of the N-methyl-D-aspartate (NMDA) receptor coagonist D-serine. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12393813/ · DOI 10.1073/pnas.222421299

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human HEK293T CARS2-deficient cells and C78/257D versus lysine-motif mutant complementation.

limitations

MTCO1 expression is a translation-related readout, not a direct measurement of dietary cysteine incorporation.

nutrient_topic

L-Cysteine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Cysteine

plain_language

Mitochondria need their own enzyme to place cysteine into proteins.

primary_references

Cysteinyl-tRNA synthetase governs cysteine polysulfidation and mitochondrial bioenergetics. · 2017 · https://pubmed.ncbi.nlm.nih.gov/29079736/ · DOI 10.1038/s41467-017-01311-y

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Cysteine: sulfur allocation, redox supply and cross-nutrient mechanisms (2026-09-19) · lines 156–162

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human HEK293T CARS2-deficient cells and C78/257D versus lysine-motif mutant complementation. · source_derived_draft · unverified_draft

## l-cysteine-cars2-translation Mitochondria need their own enzyme to place cysteine into proteins. CARS2 disruption reduced mitochondrial cysteinyl-tRNA synthetase function, assessed in part through mitochondrial MTCO1 expression; mutant rescue distinguished this from persulfide synthesis. Model: Human HEK293T CARS2-deficient cells and C78/257D versus lysine-motif mutant complementation. Limitations: MTCO1 expression is a translation-related readout, not a direct measurement of dietary cysteine incorporation. Evidence access: Primary full text Cysteinyl-tRNA synthetase governs cysteine polysulfidation and mitochondrial bioenergetics. · 2017 · https://pubmed.ncbi.nlm.nih.gov/29079736/ · DOI 10.1038/s41467-017-01311-y

evidence_access

Primary abstract

experimental_model

Mouse-cell isolated mitochondrial experiments.

limitations

The proposed GTPase/reductase mediators were not individually established by this study; do not assign a universal ATP requirement to each substep.

nutrient_topic

L-Cysteine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Cysteine

plain_language

The pathway has several gates, with different requirements at different steps.

primary_references

Fe-S cluster biogenesis in isolated mammalian mitochondria: coordinated use of persulfide sulfur and iron and requirements for GTP, NADH, and ATP. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25398879/ · DOI 10.1074/jbc.M114.610402

L-Cysteine: sulfur allocation, redox supply and cross-nutrient mechanisms (2026-09-19) · lines 276–282

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse-cell isolated mitochondrial experiments. · source_derived_draft · unverified_draft

## l-cysteine-nfs1-persulfide-gate The pathway has several gates, with different requirements at different steps. Labeled NFS1-bound persulfide was an intermediate; its sulfur release required iron, GTP and NADH, whereas ATP was required for the overall assembly pathway but not this release step. Model: Mouse-cell isolated mitochondrial experiments. Limitations: The proposed GTPase/reductase mediators were not individually established by this study; do not assign a universal ATP requirement to each substep. Evidence access: Primary abstract Fe-S cluster biogenesis in isolated mammalian mitochondria: coordinated use of persulfide sulfur and iron and requirements for GTP, NADH, and ATP. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25398879/ · DOI 10.1074/jbc.M114.610402

evidence_span

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experimental_model

Crystal structure and biochemical reaction characterization

exposure

Citrulline and aspartate bound to recombinant enzyme

limitations

Structure and established reaction; no clinical magnesium, aspartate or ATP deficiency threshold is established.

nutrient_topic

Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline

organism

Human ASS1

plain_language

Aspartate supplies part of the molecule built at this step.

primary_references

[citrulline-p18323623] Structure of human argininosuccinate synthetase. (2008). https://pubmed.ncbi.nlm.nih.gov/18323623/ DOI: 10.1107/s0907444907067455

tissue_or_cell_type

Cytosolic arginine-regeneration reaction

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 138–149

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Crystal structure and biochemical reaction characterization · source_derived_draft · unverified_draft

### citrulline-ass1-aspartate Aspartate is a substrate of human ASS1 and was resolved with citrulline in the enzyme structure. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Aspartate supplies part of the molecule built at this step. organism: Human ASS1 tissue_or_cell_type: Cytosolic arginine-regeneration reaction experimental_model: Crystal structure and biochemical reaction characterization limitations: Structure and established reaction; no clinical magnesium, aspartate or ATP deficiency threshold is established. exposure: Citrulline and aspartate bound to recombinant enzyme evidence_span: {"source_cache": "artifacts/citrulline-research/18323623.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "079be80a0ea1a47308efb069d3c9522c96c0aa5923ad1d7ce79ac620b2d9502f", "start_char": 0, "end_char": 840, "text_sha256": "079be80a0ea1a47308efb069d3c9522c96c0aa5923ad1d7ce79ac620b2d9502f"} [citrulline-p18323623] Structure of human argininosuccinate synthetase. (2008). https://pubmed.ncbi.nlm.nih.gov/18323623/ DOI: 10.1107/s0907444907067455

evidence_span

{"source_cache": "artifacts/citrulline-research/2788888.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "29b1553359d37a53c529b8a2b53ba646cca6b4b401ba7a9722e0e1f15510e676", "start_char": 0, "end_char": 1043, "text_sha256": "29b1553359d37a53c529b8a2b53ba646cca6b4b401ba7a9722e0e1f15510e676"}

experimental_model

Chemical modification and substrate protection of enzyme

exposure

Alpha-dicarbonyl modification with Mg-ATP protection

limitations

Protection assay identifies binding requirements; it is not a magnesium supplementation or depletion study.

nutrient_topic

Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline

organism

Human ASS1

plain_language

The active energy substrate is linked to magnesium, but more magnesium is not automatically rate-limiting.

primary_references

[citrulline-p2788888] Identification of essential arginine residue(s) for Mg-ATP binding of human argininosuccinate synthetase. (1989). https://pubmed.ncbi.nlm.nih.gov/2788888/

tissue_or_cell_type

ATP-binding region

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 164–175

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Chemical modification and substrate protection of enzyme · source_derived_draft · unverified_draft

### citrulline-ass1-mg-atp Mg-ATP almost completely protected human ASS1 against alpha-dicarbonyl inactivation, implicating arginine residues in its binding site. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: The active energy substrate is linked to magnesium, but more magnesium is not automatically rate-limiting. organism: Human ASS1 tissue_or_cell_type: ATP-binding region experimental_model: Chemical modification and substrate protection of enzyme limitations: Protection assay identifies binding requirements; it is not a magnesium supplementation or depletion study. exposure: Alpha-dicarbonyl modification with Mg-ATP protection evidence_span: {"source_cache": "artifacts/citrulline-research/2788888.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "29b1553359d37a53c529b8a2b53ba646cca6b4b401ba7a9722e0e1f15510e676", "start_char": 0, "end_char": 1043, "text_sha256": "29b1553359d37a53c529b8a2b53ba646cca6b4b401ba7a9722e0e1f15510e676"} [citrulline-p2788888] Identification of essential arginine residue(s) for Mg-ATP binding of human argininosuccinate synthetase. (1989). https://pubmed.ncbi.nlm.nih.gov/2788888/

evidence_span

{"source_cache": "artifacts/citrulline-research/18323623.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "079be80a0ea1a47308efb069d3c9522c96c0aa5923ad1d7ce79ac620b2d9502f", "start_char": 0, "end_char": 840, "text_sha256": "079be80a0ea1a47308efb069d3c9522c96c0aa5923ad1d7ce79ac620b2d9502f"}

experimental_model

Crystal structure and biochemical reaction characterization

exposure

Citrulline and aspartate bound to recombinant enzyme

limitations

Structure and established reaction; no clinical magnesium, aspartate or ATP deficiency threshold is established.

nutrient_topic

Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline

organism

Human ASS1

plain_language

Citrulline needs a second amino acid and an enzyme-controlled step before it becomes arginine.

primary_references

[citrulline-p18323623] Structure of human argininosuccinate synthetase. (2008). https://pubmed.ncbi.nlm.nih.gov/18323623/ DOI: 10.1107/s0907444907067455

tissue_or_cell_type

Cytosolic arginine-regeneration reaction

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 125–136

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Crystal structure and biochemical reaction characterization · source_derived_draft · unverified_draft

### citrulline-ass1-reaction Human ASS1 combines citrulline and aspartate to form argininosuccinate in an ATP-dependent reaction. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Citrulline needs a second amino acid and an enzyme-controlled step before it becomes arginine. organism: Human ASS1 tissue_or_cell_type: Cytosolic arginine-regeneration reaction experimental_model: Crystal structure and biochemical reaction characterization limitations: Structure and established reaction; no clinical magnesium, aspartate or ATP deficiency threshold is established. exposure: Citrulline and aspartate bound to recombinant enzyme evidence_span: {"source_cache": "artifacts/citrulline-research/18323623.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "079be80a0ea1a47308efb069d3c9522c96c0aa5923ad1d7ce79ac620b2d9502f", "start_char": 0, "end_char": 840, "text_sha256": "079be80a0ea1a47308efb069d3c9522c96c0aa5923ad1d7ce79ac620b2d9502f"} [citrulline-p18323623] Structure of human argininosuccinate synthetase. (2008). https://pubmed.ncbi.nlm.nih.gov/18323623/ DOI: 10.1107/s0907444907067455

evidence_span

{"source_cache": "artifacts/citrulline-research/26592762.fulltext.txt", "locator": "Primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9807338d87ba1b5602512aa3765c7cc48d391595cc1f35e6a43bcbe1250d3c7d", "start_char": 1169, "end_char": 1477, "text_sha256": "c5e2a8e1d3e3a09064b7b233635f7d573f8761b3f6ae18a68bc9b102a2d5874c"}

experimental_model

Human recombinant enzyme crystallography and mutation analysis

exposure

Structures without NAG and with NAG plus nucleotides

limitations

Mechanism of enzyme activation; clinical effects of adding nutritional cofactors were not tested.

nutrient_topic

Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline

organism

Human CPS1

plain_language

The upstream part of citrulline synthesis consumes energy to handle ammonia.

primary_references

[citrulline-p26592762] Structure of human carbamoyl phosphate synthetase: deciphering the on/off switch of human ureagenesis. (2015). https://pubmed.ncbi.nlm.nih.gov/26592762/ DOI: 10.1038/srep16950

tissue_or_cell_type

Mitochondrial carbamoyl-phosphate synthesis

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 242–253

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human recombinant enzyme crystallography and mutation analysis · source_derived_draft · unverified_draft

### citrulline-cps1-product CPS1 uses two ATP-dependent phosphorylation steps to convert bicarbonate and ammonia into carbamoyl phosphate. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: The upstream part of citrulline synthesis consumes energy to handle ammonia. organism: Human CPS1 tissue_or_cell_type: Mitochondrial carbamoyl-phosphate synthesis experimental_model: Human recombinant enzyme crystallography and mutation analysis limitations: Mechanism of enzyme activation; clinical effects of adding nutritional cofactors were not tested. exposure: Structures without NAG and with NAG plus nucleotides evidence_span: {"source_cache": "artifacts/citrulline-research/26592762.fulltext.txt", "locator": "Primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9807338d87ba1b5602512aa3765c7cc48d391595cc1f35e6a43bcbe1250d3c7d", "start_char": 1169, "end_char": 1477, "text_sha256": "c5e2a8e1d3e3a09064b7b233635f7d573f8761b3f6ae18a68bc9b102a2d5874c"} [citrulline-p26592762] Structure of human carbamoyl phosphate synthetase: deciphering the on/off switch of human ureagenesis. (2015). https://pubmed.ncbi.nlm.nih.gov/26592762/ DOI: 10.1038/srep16950

evidence_span

{"source_cache": "artifacts/citrulline-research/11092761.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "09706fd9ec135c472473decaa612e06b3e5aa021c9b1493d77daf4fe98b8d5d2", "start_char": 0, "end_char": 1688, "text_sha256": "09706fd9ec135c472473decaa612e06b3e5aa021c9b1493d77daf4fe98b8d5d2"}

experimental_model

Patient genetics and recombinant variant expression

exposure

ALDH18A1 R84Q compared with wild-type isoforms

limitations

Rare inherited enzyme disorder; does not imply low dietary citrulline caused the clinical phenotype.

nutrient_topic

Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline

organism

Human, two siblings and mammalian expression systems

plain_language

A niacin-derived electron donor participates upstream of citrulline.

primary_references

[citrulline-p11092761] Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase. (2000). https://pubmed.ncbi.nlm.nih.gov/11092761/ DOI: 10.1093/hmg/9.19.2853

tissue_or_cell_type

Mitochondrial P5CS and circulating amino acids

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 307–318

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Patient genetics and recombinant variant expression · source_derived_draft · unverified_draft

### citrulline-p5cs-nadph P5CS requires NADPH for its reductive step in glutamate-to-P5C synthesis. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: A niacin-derived electron donor participates upstream of citrulline. organism: Human, two siblings and mammalian expression systems tissue_or_cell_type: Mitochondrial P5CS and circulating amino acids experimental_model: Patient genetics and recombinant variant expression limitations: Rare inherited enzyme disorder; does not imply low dietary citrulline caused the clinical phenotype. exposure: ALDH18A1 R84Q compared with wild-type isoforms evidence_span: {"source_cache": "artifacts/citrulline-research/11092761.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "09706fd9ec135c472473decaa612e06b3e5aa021c9b1493d77daf4fe98b8d5d2", "start_char": 0, "end_char": 1688, "text_sha256": "09706fd9ec135c472473decaa612e06b3e5aa021c9b1493d77daf4fe98b8d5d2"} [citrulline-p11092761] Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase. (2000). https://pubmed.ncbi.nlm.nih.gov/11092761/ DOI: 10.1093/hmg/9.19.2853

evidence_span

{"source_cache": "artifacts/citrulline-research/11092761.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "09706fd9ec135c472473decaa612e06b3e5aa021c9b1493d77daf4fe98b8d5d2", "start_char": 0, "end_char": 1688, "text_sha256": "09706fd9ec135c472473decaa612e06b3e5aa021c9b1493d77daf4fe98b8d5d2"}

experimental_model

Patient genetics and recombinant variant expression

exposure

ALDH18A1 R84Q compared with wild-type isoforms

limitations

Rare inherited enzyme disorder; does not imply low dietary citrulline caused the clinical phenotype.

nutrient_topic

Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline

organism

Human, two siblings and mammalian expression systems

plain_language

This supplies a precursor route connected to ornithine and arginine production.

primary_references

[citrulline-p11092761] Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase. (2000). https://pubmed.ncbi.nlm.nih.gov/11092761/ DOI: 10.1093/hmg/9.19.2853

tissue_or_cell_type

Mitochondrial P5CS and circulating amino acids

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 294–305

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Patient genetics and recombinant variant expression · source_derived_draft · unverified_draft

### citrulline-p5cs-reaction Human P5CS links glutamate to P5C synthesis through ATP- and NADPH-dependent chemistry. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: This supplies a precursor route connected to ornithine and arginine production. organism: Human, two siblings and mammalian expression systems tissue_or_cell_type: Mitochondrial P5CS and circulating amino acids experimental_model: Patient genetics and recombinant variant expression limitations: Rare inherited enzyme disorder; does not imply low dietary citrulline caused the clinical phenotype. exposure: ALDH18A1 R84Q compared with wild-type isoforms evidence_span: {"source_cache": "artifacts/citrulline-research/11092761.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "09706fd9ec135c472473decaa612e06b3e5aa021c9b1493d77daf4fe98b8d5d2", "start_char": 0, "end_char": 1688, "text_sha256": "09706fd9ec135c472473decaa612e06b3e5aa021c9b1493d77daf4fe98b8d5d2"} [citrulline-p11092761] Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase. (2000). https://pubmed.ncbi.nlm.nih.gov/11092761/ DOI: 10.1093/hmg/9.19.2853

cross_nutrient

Glutamine supplies nitrogen for the final amidation of the nicotinic-acid/de novo NAD pathway.

evidence_span

{"source_cache": "artifacts/niacin-precursors-sources/nadsyn2019.paragraphs.txt", "locator": "Normalized full-text paragraphs 8–8 (0-based)", "start_char": 7090, "end_char": 8684, "file_sha256": "36ad82ce734c8e0c44d01c7dc813b1641708738319b53a926e429155b1a602f4", "text_sha256": "90cb4d2ce3001f2ecf18f1d751db36047726b71a75be94b073474f6f518c96cd"}

experimental_model

Recombinant human NADSYN1 steady-state kinetic assays and crystallography; bacterial comparison kept separate

exposure

Biochemical or structural assay; no dietary intervention

limitations

Purified-enzyme evidence does not establish dietary intake requirements or clinical outcomes.

nutrient_topic

Niacin research collection; topical membership is not evidence of a direct dietary effect. · Niacin (vitamin B3)

organism

Homo sapiens

plain_language

The deamidated route finishes by making NAD+ through NADSYN1.

primary_references

[b3-pre-nadsyn2019] Different ways to transport ammonia in human and Mycobacterium tuberculosis NAD+ synthetases. (2020). https://pubmed.ncbi.nlm.nih.gov/31911602/ DOI: 10.1038/s41467-019-13845-4

tissue_or_cell_type

Purified recombinant protein; no intact tissue

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 328–340

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human NADSYN1 steady-state kinetic assays and crystallography; bacterial comparison kept separate · source_derived_draft · unverified_draft

### b3-pre-nadsyn-amidation Purified human NADSYN1 catalyzed ATP-dependent NAD+ production from nicotinic acid adenine dinucleotide in glutamine-supported assays. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The deamidated route finishes by making NAD+ through NADSYN1. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Recombinant human NADSYN1 steady-state kinetic assays and crystallography; bacterial comparison kept separate limitations: Purified-enzyme evidence does not establish dietary intake requirements or clinical outcomes. exposure: Biochemical or structural assay; no dietary intervention cross_nutrient: Glutamine supplies nitrogen for the final amidation of the nicotinic-acid/de novo NAD pathway. evidence_span: {"source_cache": "artifacts/niacin-precursors-sources/nadsyn2019.paragraphs.txt", "locator": "Normalized full-text paragraphs 8–8 (0-based)", "start_char": 7090, "end_char": 8684, "file_sha256": "36ad82ce734c8e0c44d01c7dc813b1641708738319b53a926e429155b1a602f4", "text_sha256": "90cb4d2ce3001f2ecf18f1d751db36047726b71a75be94b073474f6f518c96cd"} [b3-pre-nadsyn2019] Different ways to transport ammonia in human and Mycobacterium tuberculosis NAD+ synthetases. (2020). https://pubmed.ncbi.nlm.nih.gov/31911602/ DOI: 10.1038/s41467-019-13845-4

cross_nutrient

Glutamine nitrogen handling and magnesium-containing ATP chemistry couple in a niacin precursor enzyme.

evidence_span

{"source_cache": "artifacts/niacin-precursors-sources/nadsyn2019.paragraphs.txt", "locator": "Normalized full-text paragraphs 10–10 (0-based)", "start_char": 8754, "end_char": 10450, "file_sha256": "36ad82ce734c8e0c44d01c7dc813b1641708738319b53a926e429155b1a602f4", "text_sha256": "32dd95b3bef542cb15f227e9dd3de1ed68b6b9c8f6cda41d34daf7b6fe387ce7"}

experimental_model

Recombinant human NADSYN1 steady-state kinetic assays and crystallography; bacterial comparison kept separate

exposure

Biochemical or structural assay; no dietary intervention

limitations

Purified-enzyme evidence does not establish dietary intake requirements or clinical outcomes.

nutrient_topic

Niacin research collection; topical membership is not evidence of a direct dietary effect. · Niacin (vitamin B3)

organism

Homo sapiens

plain_language

The two enzyme activities communicate while NAD is assembled.

primary_references

[b3-pre-nadsyn2019] Different ways to transport ammonia in human and Mycobacterium tuberculosis NAD+ synthetases. (2020). https://pubmed.ncbi.nlm.nih.gov/31911602/ DOI: 10.1038/s41467-019-13845-4

tissue_or_cell_type

Purified recombinant protein; no intact tissue

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 342–354

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human NADSYN1 steady-state kinetic assays and crystallography; bacterial comparison kept separate · source_derived_draft · unverified_draft

### b3-pre-nadsyn-glutaminase Human NADSYN1 glutaminase activity was measured as glutamate production; NaAD plus ATP/Mg2+ increased that activity 31-fold over glutamine alone in the reported assay. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The two enzyme activities communicate while NAD is assembled. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Recombinant human NADSYN1 steady-state kinetic assays and crystallography; bacterial comparison kept separate limitations: Purified-enzyme evidence does not establish dietary intake requirements or clinical outcomes. exposure: Biochemical or structural assay; no dietary intervention cross_nutrient: Glutamine nitrogen handling and magnesium-containing ATP chemistry couple in a niacin precursor enzyme. evidence_span: {"source_cache": "artifacts/niacin-precursors-sources/nadsyn2019.paragraphs.txt", "locator": "Normalized full-text paragraphs 10–10 (0-based)", "start_char": 8754, "end_char": 10450, "file_sha256": "36ad82ce734c8e0c44d01c7dc813b1641708738319b53a926e429155b1a602f4", "text_sha256": "32dd95b3bef542cb15f227e9dd3de1ed68b6b9c8f6cda41d34daf7b6fe387ce7"} [b3-pre-nadsyn2019] Different ways to transport ammonia in human and Mycobacterium tuberculosis NAD+ synthetases. (2020). https://pubmed.ncbi.nlm.nih.gov/31911602/ DOI: 10.1038/s41467-019-13845-4

evidence_span

{"source_cache": "artifacts/niacin-precursors-sources/nmnat2002.abstract.txt", "locator": "Indexed primary abstract", "start_char": 0, "end_char": 826, "file_sha256": "5064cc6a7b31875eeaea8def5544c3cce75a971f73aa74f332d89e06c3c54477", "text_sha256": "5064cc6a7b31875eeaea8def5544c3cce75a971f73aa74f332d89e06c3c54477"}

experimental_model

Cloned, expressed and purified recombinant human NMNAT2

exposure

Biochemical or structural assay; no dietary intervention

limitations

Purified-enzyme evidence does not establish dietary intake requirements or clinical outcomes.

nutrient_topic

Niacin research collection; topical membership is not evidence of a direct dietary effect. · Niacin (vitamin B3)

organism

Homo sapiens

plain_language

The same human isozyme processes either the amidated or deamidated mononucleotide.

primary_references

[b3-pre-nmnat2002] Identification of a novel human nicotinamide mononucleotide adenylyltransferase. (2002). https://pubmed.ncbi.nlm.nih.gov/12359228/ DOI: 10.1016/s0006-291x(02)02285-4

tissue_or_cell_type

Purified recombinant protein; no intact tissue

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 315–326

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cloned, expressed and purified recombinant human NMNAT2 · source_derived_draft · unverified_draft

### b3-pre-nmnat2-namn Purified recombinant human NMNAT2 has adenylyltransferase activity toward nicotinic acid mononucleotide, supporting NaAD formation. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The same human isozyme processes either the amidated or deamidated mononucleotide. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Cloned, expressed and purified recombinant human NMNAT2 limitations: Purified-enzyme evidence does not establish dietary intake requirements or clinical outcomes. exposure: Biochemical or structural assay; no dietary intervention evidence_span: {"source_cache": "artifacts/niacin-precursors-sources/nmnat2002.abstract.txt", "locator": "Indexed primary abstract", "start_char": 0, "end_char": 826, "file_sha256": "5064cc6a7b31875eeaea8def5544c3cce75a971f73aa74f332d89e06c3c54477", "text_sha256": "5064cc6a7b31875eeaea8def5544c3cce75a971f73aa74f332d89e06c3c54477"} [b3-pre-nmnat2002] Identification of a novel human nicotinamide mononucleotide adenylyltransferase. (2002). https://pubmed.ncbi.nlm.nih.gov/12359228/ DOI: 10.1016/s0006-291x(02)02285-4

evidence_span

{"source_cache": "artifacts/niacin-precursors-sources/nmnat2002.abstract.txt", "locator": "Indexed primary abstract", "start_char": 0, "end_char": 826, "file_sha256": "5064cc6a7b31875eeaea8def5544c3cce75a971f73aa74f332d89e06c3c54477", "text_sha256": "5064cc6a7b31875eeaea8def5544c3cce75a971f73aa74f332d89e06c3c54477"}

experimental_model

Cloned, expressed and purified recombinant human NMNAT2

exposure

Biochemical or structural assay; no dietary intervention

limitations

Purified-enzyme evidence does not establish dietary intake requirements or clinical outcomes.

nutrient_topic

Niacin research collection; topical membership is not evidence of a direct dietary effect. · Niacin (vitamin B3)

organism

Homo sapiens

plain_language

The same human isozyme processes either the amidated or deamidated mononucleotide.

primary_references

[b3-pre-nmnat2002] Identification of a novel human nicotinamide mononucleotide adenylyltransferase. (2002). https://pubmed.ncbi.nlm.nih.gov/12359228/ DOI: 10.1016/s0006-291x(02)02285-4

tissue_or_cell_type

Purified recombinant protein; no intact tissue

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 302–313

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cloned, expressed and purified recombinant human NMNAT2 · source_derived_draft · unverified_draft

### b3-pre-nmnat2-nmn Purified recombinant human NMNAT2 has adenylyltransferase activity toward NMN, supporting NAD+ formation. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The same human isozyme processes either the amidated or deamidated mononucleotide. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Cloned, expressed and purified recombinant human NMNAT2 limitations: Purified-enzyme evidence does not establish dietary intake requirements or clinical outcomes. exposure: Biochemical or structural assay; no dietary intervention evidence_span: {"source_cache": "artifacts/niacin-precursors-sources/nmnat2002.abstract.txt", "locator": "Indexed primary abstract", "start_char": 0, "end_char": 826, "file_sha256": "5064cc6a7b31875eeaea8def5544c3cce75a971f73aa74f332d89e06c3c54477", "text_sha256": "5064cc6a7b31875eeaea8def5544c3cce75a971f73aa74f332d89e06c3c54477"} [b3-pre-nmnat2002] Identification of a novel human nicotinamide mononucleotide adenylyltransferase. (2002). https://pubmed.ncbi.nlm.nih.gov/12359228/ DOI: 10.1016/s0006-291x(02)02285-4

cross_nutrient

Mg-ATP supplies the phosphate donor for generating niacin-derived NADP+. NADP+ production is distinct from its later reduction to NADPH.

evidence_span

{"source_cache": "artifacts/niacin-redox-sources/nadk-human-2025.fulltext.txt", "locator": "Results", "start_char": 53525, "end_char": 54577, "file_sha256": "72c7b9625e1bf4137d6833adac6ae49fc108f2cd75bb4945c5b04d72a0355f9b", "text_sha256": "db49fc47ad605562e1c1cf93e1b39596505906831ae509e7ec0031485f84ba4f"}

experimental_model

Full-length recombinant human NADK; G6PD-coupled assay

exposure

5 mM MgATP; 0.1–2 mM NAD+; 1 mM additional MgCl2; 30°C

limitations

Scoped experimental observation; no dietary niacin or magnesium deficiency threshold or treatment benefit was tested.

nutrient_topic

Niacin research collection; topical membership is not evidence of a direct dietary effect. · Niacin (vitamin B3)

organism

Homo sapiens

plain_language

The cytosolic kinase makes the phosphorylated cofactor using magnesium-associated ATP.

primary_references

[nadk-human-2025] Cryo-EM structure and regulation of human NAD kinase. (2025). https://pubmed.ncbi.nlm.nih.gov/39854463/ DOI: 10.1126/sciadv.ads2664

tissue_or_cell_type

Purified enzyme

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 831–843

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Full-length recombinant human NADK; G6PD-coupled assay · source_derived_draft · unverified_draft

### b3-redox-nadk-mgatp Purified full-length human NADK catalyzed NADP+ production from NAD+ in a coupled assay supplied with 5 mM MgATP. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The cytosolic kinase makes the phosphorylated cofactor using magnesium-associated ATP. organism: Homo sapiens tissue_or_cell_type: Purified enzyme experimental_model: Full-length recombinant human NADK; G6PD-coupled assay limitations: Scoped experimental observation; no dietary niacin or magnesium deficiency threshold or treatment benefit was tested. exposure: 5 mM MgATP; 0.1–2 mM NAD+; 1 mM additional MgCl2; 30°C cross_nutrient: Mg-ATP supplies the phosphate donor for generating niacin-derived NADP+. NADP+ production is distinct from its later reduction to NADPH. evidence_span: {"source_cache": "artifacts/niacin-redox-sources/nadk-human-2025.fulltext.txt", "locator": "Results", "start_char": 53525, "end_char": 54577, "file_sha256": "72c7b9625e1bf4137d6833adac6ae49fc108f2cd75bb4945c5b04d72a0355f9b", "text_sha256": "db49fc47ad605562e1c1cf93e1b39596505906831ae509e7ec0031485f84ba4f"} [nadk-human-2025] Cryo-EM structure and regulation of human NAD kinase. (2025). https://pubmed.ncbi.nlm.nih.gov/39854463/ DOI: 10.1126/sciadv.ads2664

evidence_span

{"source_cache": "artifacts/niacin-redox-sources/nadk2-2012.fulltext.txt", "locator": "Results", "start_char": 9582, "end_char": 11594, "file_sha256": "65209c0b4ea7220bc95afdd182e40910f2445345172956e85552d5c6db649648", "text_sha256": "ffd25dd072f6f8f486b11ca632f28acf37e3ef2b0dbd2b20eecf32fce649eaf1"}

experimental_model

Purified NADK2 Δ62

exposure

ATP-dependent NADH versus NAD+ assays

limitations

Relative activity under the reported substrate conditions; not a universal cellular flux ratio.

nutrient_topic

Niacin research collection; topical membership is not evidence of a direct dietary effect. · Niacin (vitamin B3)

organism

Homo sapiens

plain_language

NADK2 could phosphorylate NADH in this assay, but favored NAD+.

primary_references

[nadk2-2012] Identification and characterization of a human mitochondrial NAD kinase. (2012). https://pubmed.ncbi.nlm.nih.gov/23212377/ DOI: 10.1038/ncomms2262

tissue_or_cell_type

Purified enzyme

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 899–910

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified NADK2 Δ62 · source_derived_draft · unverified_draft

### b3-redox-nadk2-nadh-preference The tested NADH kinase activity of purified human NADK2 Δ62 was about 10% of its NAD+ kinase activity. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: NADK2 could phosphorylate NADH in this assay, but favored NAD+. organism: Homo sapiens tissue_or_cell_type: Purified enzyme experimental_model: Purified NADK2 Δ62 limitations: Relative activity under the reported substrate conditions; not a universal cellular flux ratio. exposure: ATP-dependent NADH versus NAD+ assays evidence_span: {"source_cache": "artifacts/niacin-redox-sources/nadk2-2012.fulltext.txt", "locator": "Results", "start_char": 9582, "end_char": 11594, "file_sha256": "65209c0b4ea7220bc95afdd182e40910f2445345172956e85552d5c6db649648", "text_sha256": "ffd25dd072f6f8f486b11ca632f28acf37e3ef2b0dbd2b20eecf32fce649eaf1"} [nadk2-2012] Identification and characterization of a human mitochondrial NAD kinase. (2012). https://pubmed.ncbi.nlm.nih.gov/23212377/ DOI: 10.1038/ncomms2262

cross_nutrient

Magnesium is present with ATP during phosphorylation of the niacin-derived dinucleotide; this assay does not quantify effects of dietary magnesium shortage.

evidence_span

[{"source_cache": "artifacts/niacin-redox-sources/nadk2-2012.fulltext.txt", "locator": "Results", "start_char": 8475, "end_char": 9580, "file_sha256": "65209c0b4ea7220bc95afdd182e40910f2445345172956e85552d5c6db649648", "text_sha256": "c86810a1a5342cd4e7ea126e070f28ed3182d81f17ea76c0fbb3833612c0f529"}, {"source_cache": "artifacts/niacin-redox-sources/nadk2-2012.fulltext.txt", "locator": "Methods, NADK activity assay", "start_char": 26694, "end_char": 28732, "file_sha256": "65209c0b4ea7220bc95afdd182e40910f2445345172956e85552d5c6db649648", "text_sha256": "907b651f0c0aae7a31306bdc42264cdfd22fb0e236e7ab8f37900467b0b0ab72"}]

experimental_model

Purified His-tagged Δ62C5orf33/NADK2

exposure

TLC: 5 mM NAD+, 5 mM ATP, 5 mM MgCl2; 37°C

limitations

Scoped experimental observation; no dietary niacin or magnesium deficiency threshold or treatment benefit was tested.

nutrient_topic

Niacin research collection; topical membership is not evidence of a direct dietary effect. · Niacin (vitamin B3)

organism

Homo sapiens

plain_language

The mitochondrial kinase uses a phosphate-transfer reaction to create NADP+.

primary_references

[nadk2-2012] Identification and characterization of a human mitochondrial NAD kinase. (2012). https://pubmed.ncbi.nlm.nih.gov/23212377/ DOI: 10.1038/ncomms2262

tissue_or_cell_type

Purified protein

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 871–883

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified His-tagged Δ62C5orf33/NADK2 · source_derived_draft · unverified_draft

### b3-redox-nadk2-phosphorylation Purified human NADK2 Δ62 converted NAD+ to NADP+ with ATP in MgCl2-containing reactions; TLC also detected ADP formation. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The mitochondrial kinase uses a phosphate-transfer reaction to create NADP+. organism: Homo sapiens tissue_or_cell_type: Purified protein experimental_model: Purified His-tagged Δ62C5orf33/NADK2 limitations: Scoped experimental observation; no dietary niacin or magnesium deficiency threshold or treatment benefit was tested. exposure: TLC: 5 mM NAD+, 5 mM ATP, 5 mM MgCl2; 37°C cross_nutrient: Magnesium is present with ATP during phosphorylation of the niacin-derived dinucleotide; this assay does not quantify effects of dietary magnesium shortage. evidence_span: [{"source_cache": "artifacts/niacin-redox-sources/nadk2-2012.fulltext.txt", "locator": "Results", "start_char": 8475, "end_char": 9580, "file_sha256": "65209c0b4ea7220bc95afdd182e40910f2445345172956e85552d5c6db649648", "text_sha256": "c86810a1a5342cd4e7ea126e070f28ed3182d81f17ea76c0fbb3833612c0f529"}, {"source_cache": "artifacts/niacin-redox-sources/nadk2-2012.fulltext.txt", "locator": "Methods, NADK activity assay", "start_char": 26694, "end_char": 28732, "file_sha256": "65209c0b4ea7220bc95afdd182e40910f2445345172956e85552d5c6db649648", "text_sha256": "907b651f0c0aae7a31306bdc42264cdfd22fb0e236e7ab8f37900467b0b0ab72"}] [nadk2-2012] Identification and characterization of a human mitochondrial NAD kinase. (2012). https://pubmed.ncbi.nlm.nih.gov/23212377/ DOI: 10.1038/ncomms2262

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/niacin-redox-sources/nnt-reverse-2015.abstract.txt", "locator": "Indexed abstract, pathological workload results", "start_char": 373, "end_char": 1028, "file_sha256": "88e6510d357946cd087e5af7ca3c9fdfd2ac22f2fb1851dd1164f176c5e39ce4", "text_sha256": "a8e2d67ccb1f5f041786aecfb33760602a804017dccfe41c54b34213ea0c6223"}

experimental_model

Mouse cardiac pressure-overload / pathological-demand experiments

exposure

Pathological cardiac metabolic demand

limitations

Context-dependent reversal, not genetic kinase failure or dietary niacin deficiency. Abstract-only extraction; do not generalize to all hearts or propose NNT inhibition clinically.

nutrient_topic

Niacin research collection; topical membership is not evidence of a direct dietary effect. · Niacin (vitamin B3)

organism

Mus musculus

plain_language

Under this high-workload condition Nnt used up NADPH instead of supplying it.

primary_references

[nnt-reverse-2015] Reversal of Mitochondrial Transhydrogenase Causes Oxidative Stress in Heart Failure. (2015). https://pubmed.ncbi.nlm.nih.gov/26256392/ DOI: 10.1016/j.cmet.2015.07.008

tissue_or_cell_type

Heart

trigger_kind

machinery_impairment Imported condition classification; unverified.

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 1016–1027

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse cardiac pressure-overload / pathological-demand experiments · source_derived_draft · unverified_draft

### b3-redox-nnt-reversal In the cardiac pathological-workload study, reverse-mode Nnt consumed NADPH while supporting NADH and ATP production. Condition category: machinery_impairment nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Under this high-workload condition Nnt used up NADPH instead of supplying it. organism: Mus musculus tissue_or_cell_type: Heart experimental_model: Mouse cardiac pressure-overload / pathological-demand experiments limitations: Context-dependent reversal, not genetic kinase failure or dietary niacin deficiency. Abstract-only extraction; do not generalize to all hearts or propose NNT inhibition clinically. exposure: Pathological cardiac metabolic demand evidence_span: {"source_cache": "artifacts/niacin-redox-sources/nnt-reverse-2015.abstract.txt", "locator": "Indexed abstract, pathological workload results", "start_char": 373, "end_char": 1028, "file_sha256": "88e6510d357946cd087e5af7ca3c9fdfd2ac22f2fb1851dd1164f176c5e39ce4", "text_sha256": "a8e2d67ccb1f5f041786aecfb33760602a804017dccfe41c54b34213ea0c6223"} [nnt-reverse-2015] Reversal of Mitochondrial Transhydrogenase Causes Oxidative Stress in Heart Failure. (2015). https://pubmed.ncbi.nlm.nih.gov/26256392/ DOI: 10.1016/j.cmet.2015.07.008

evidence_access

Primary abstract

experimental_model

Recombinant human enzyme substrate comparison.

limitations

Shared synthesis does not mean the two peptides have identical functions.

nutrient_topic

Carnosine collection; isomer, preparation, species, exposure and manipulation remain explicit. · L-Carnosine / beta-alanyl-L-histidine

plain_language

The same enzyme can assemble a related GABA-containing peptide.

primary_references

Molecular identification of carnosine synthase as ATP-grasp domain-containing protein 1 (ATPGD1). · 2010 · https://pubmed.ncbi.nlm.nih.gov/20097752/ · DOI 10.1074/jbc.M109.095505

Carnosine: synthesis, transport, carbonyl chemistry and nutrient interactions (2026-09-19) · lines 36–42

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Recombinant human enzyme substrate comparison. · source_derived_draft · unverified_draft

## carnosine-homocarnosine The same enzyme can assemble a related GABA-containing peptide. Purified human CARNS1 also synthesized homocarnosine using GABA, with lower catalytic efficiency than the beta-alanine reaction. Model: Recombinant human enzyme substrate comparison. Limitations: Shared synthesis does not mean the two peptides have identical functions. Evidence access: Primary abstract Molecular identification of carnosine synthase as ATP-grasp domain-containing protein 1 (ATPGD1). · 2010 · https://pubmed.ncbi.nlm.nih.gov/20097752/ · DOI 10.1074/jbc.M109.095505

evidence_access

Primary abstract and full-text enzyme methods

experimental_model

Human enzyme expressed in HEK293T cells.

limitations

An enzyme assay does not define dietary requirements.

nutrient_topic

Carnosine collection; isomer, preparation, species, exposure and manipulation remain explicit. · L-Carnosine / beta-alanyl-L-histidine

plain_language

Two building blocks are assembled by a specific enzyme.

primary_references

Molecular identification of carnosine synthase as ATP-grasp domain-containing protein 1 (ATPGD1). · 2010 · https://pubmed.ncbi.nlm.nih.gov/20097752/ · DOI 10.1074/jbc.M109.095505

Carnosine: synthesis, transport, carbonyl chemistry and nutrient interactions (2026-09-19) · lines 20–26

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human enzyme expressed in HEK293T cells. · source_derived_draft · unverified_draft

## carnosine-synthesis Two building blocks are assembled by a specific enzyme. Purified recombinant human CARNS1 joined beta-alanine and L-histidine to form carnosine in an ATP-containing assay. Model: Human enzyme expressed in HEK293T cells. Limitations: An enzyme assay does not define dietary requirements. Evidence access: Primary abstract and full-text enzyme methods Molecular identification of carnosine synthase as ATP-grasp domain-containing protein 1 (ATPGD1). · 2010 · https://pubmed.ncbi.nlm.nih.gov/20097752/ · DOI 10.1074/jbc.M109.095505

evidence_access

Primary abstract

experimental_model

Human-cell GLS2 expression/perturbation study.

limitations

The effect depends on cell context; it is not a clinical energy claim.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

The generated carbon skeleton can support mitochondrial metabolism.

primary_references

Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20378837/ · DOI 10.1073/pnas.1001006107

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 218–224

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human-cell GLS2 expression/perturbation study. · source_derived_draft · unverified_draft

## glutamate-gls2-energy The generated carbon skeleton can support mitochondrial metabolism. GLS2 manipulation linked increased glutamate and 2-oxoglutarate production with increased respiration and ATP generation in the tested human cells. Model: Human-cell GLS2 expression/perturbation study. Limitations: The effect depends on cell context; it is not a clinical energy claim. Evidence access: Primary abstract Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20378837/ · DOI 10.1073/pnas.1001006107

evidence_access

Primary abstract

experimental_model

Purified GSK3 kinetic experiments; mammalian and Dictyostelium isoforms.

limitations

The abstract does not resolve every mammalian isoform; no systemic magnesium depletion was measured.

nutrient_topic

Lithium collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Lithium

plain_language

Magnesium availability changes inhibition of a signaling enzyme.

primary_references

Lithium inhibits glycogen synthase kinase-3 by competition for magnesium. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11162580/ · DOI 10.1006/bbrc.2000.4169

Lithium: metal-sensitive enzymes, transport and cross-nutrient mechanisms (2026-09-19) · lines 16–22

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Purified GSK3 kinetic experiments; mammalian and Dictyostelium isoforms. · source_derived_draft · unverified_draft

## lithium-gsk3-magnesium Magnesium availability changes inhibition of a signaling enzyme. Lithium competitively inhibited mammalian GSK3 with respect to magnesium, but not ATP or substrate. Model: Purified GSK3 kinetic experiments; mammalian and Dictyostelium isoforms. Limitations: The abstract does not resolve every mammalian isoform; no systemic magnesium depletion was measured. Evidence access: Primary abstract Lithium inhibits glycogen synthase kinase-3 by competition for magnesium. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11162580/ · DOI 10.1006/bbrc.2000.4169

experimental_model

Human GLUL ligand-complex crystal structures; canine apoenzyme comparison

exposure

ADP/phosphate/Mn and ADP/phosphorylated-inhibitor/Mn complexes

limitations

Reaction identity does not determine the predominant metal in living human brain.

nutrient_topic

Manganese research collection; topical membership is not evidence of a direct dietary effect. · Manganese

organism

Homo sapiens protein

plain_language

GLUL combines glutamate and ammonia using ATP.

primary_references

[mn-enz-18005987] Crystal structures of mammalian glutamine synthetases illustrate substrate-induced conformational changes and provide opportunities for drug and herbicide design. (2008). https://pubmed.ncbi.nlm.nih.gov/18005987/ DOI: 10.1016/j.jmb.2007.10.029

tissue_or_cell_type

Purified GLUL

Manganese: enzyme cofactors, glycosylation, transport and nutrient interactions (2026-09-17) · lines 596–606

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human GLUL ligand-complex crystal structures; canine apoenzyme comparison · source_derived_draft · unverified_draft

### mn-enz-glul-reaction Human glutamine synthetase catalyzes ATP-coupled ligation of glutamate and ammonia to make glutamine. Condition category: normal nutrient_topic: Manganese research collection; topical membership is not evidence of a direct dietary effect. plain_language: GLUL combines glutamate and ammonia using ATP. organism: Homo sapiens protein tissue_or_cell_type: Purified GLUL experimental_model: Human GLUL ligand-complex crystal structures; canine apoenzyme comparison limitations: Reaction identity does not determine the predominant metal in living human brain. exposure: ADP/phosphate/Mn and ADP/phosphorylated-inhibitor/Mn complexes [mn-enz-18005987] Crystal structures of mammalian glutamine synthetases illustrate substrate-induced conformational changes and provide opportunities for drug and herbicide design. (2008). https://pubmed.ncbi.nlm.nih.gov/18005987/ DOI: 10.1016/j.jmb.2007.10.029

cross_nutrient

Mn and Mg can support activity in vitro, with distinct metal:ATP ratios and pH conditions.

experimental_model

Ovine brain glutamine synthetase steady-state kinetics and metal-binding measurements

exposure

Mn(II) and Mg(II) titrations; binding and tissue metal measurements

limitations

Different assay optima are not evidence that Mn is the preferred cofactor at physiological brain pH.

nutrient_topic

Manganese research collection; topical membership is not evidence of a direct dietary effect. · Manganese

organism

Ovis aries

plain_language

Magnesium and manganese supported GLUL under different assay conditions.

primary_references

[mn-enz-6129892] Glutamine synthetase from ovine brain is a manganese(II) enzyme. (1982). https://pubmed.ncbi.nlm.nih.gov/6129892/ DOI: 10.1021/bi00268a011

tissue_or_cell_type

Brain-derived purified enzyme

Manganese: enzyme cofactors, glycosylation, transport and nutrient interactions (2026-09-17) · lines 620–631

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Ovine brain glutamine synthetase steady-state kinetics and metal-binding measurements · source_derived_draft · unverified_draft

### mn-enz-ovine-glul-metal-kinetics Ovine brain GLUL assays showed optimal Mg:ATP at 2:1 and Mn:ATP at 1:1, with different reported pH optima of 7.5 and 5.0, respectively. Condition category: normal nutrient_topic: Manganese research collection; topical membership is not evidence of a direct dietary effect. plain_language: Magnesium and manganese supported GLUL under different assay conditions. organism: Ovis aries tissue_or_cell_type: Brain-derived purified enzyme experimental_model: Ovine brain glutamine synthetase steady-state kinetics and metal-binding measurements limitations: Different assay optima are not evidence that Mn is the preferred cofactor at physiological brain pH. exposure: Mn(II) and Mg(II) titrations; binding and tissue metal measurements cross_nutrient: Mn and Mg can support activity in vitro, with distinct metal:ATP ratios and pH conditions. [mn-enz-6129892] Glutamine synthetase from ovine brain is a manganese(II) enzyme. (1982). https://pubmed.ncbi.nlm.nih.gov/6129892/ DOI: 10.1021/bi00268a011

cross_nutrient

calcium ion (transported_ion); Manganese(II) ion (alternative_ion); Adenosine triphosphate (energy_substrate); Golgi apparatus (destination)

evidence_span

{"source_cache": "artifacts/manganese-glycosylation-sources/spca2023.abstract.txt", "locator": "Indexed primary abstract", "file_sha256": "06a3eac4cc4e989b9195bdb14847c868ddaa68935a12f2d5c5f50a1a47259fb8", "start_char": 0, "end_char": 1276, "text_sha256": "06a3eac4cc4e989b9195bdb14847c868ddaa68935a12f2d5c5f50a1a47259fb8", "text_characters": 1276}

experimental_model

Cryo-EM of purified human SPCA1a with ATP and divalent ions

exposure

ATP/Ca2+, ATP/Mn2+ and phosphorylated metal-free structural states.

limitations

Structural states explain the transport cycle but do not supply a dietary requirement or prove that calcium supplementation impairs manganese delivery.

nutrient_topic

Manganese research collection; topical membership is not evidence of a direct dietary effect. · Manganese

organism

Homo sapiens

plain_language

The same pump handles calcium and manganese through a shared site.

primary_references

[mn-gly-spca2023] Cryo-EM structures of human SPCA1a reveal the mechanism of Ca²⁺/Mn²⁺ transport into the Golgi apparatus. (2023). https://pubmed.ncbi.nlm.nih.gov/36867705/ DOI: 10.1126/sciadv.add9742

tissue_or_cell_type

Golgi membrane transport protein

transport_effect

raises The object already names import into the Golgi lumen.

transport_pool

the Golgi lumen The object already names import into the Golgi lumen.

Manganese: enzyme cofactors, glycosylation, transport and nutrient interactions (2026-09-17) · lines 712–724

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cryo-EM of purified human SPCA1a with ATP and divalent ions · source_derived_draft · unverified_draft

### mn-gly-spca-calcium Human SPCA1a also transports calcium; calcium and manganese occupy the same transmembrane pocket in the respective structures. Condition category: normal nutrient_topic: Manganese research collection; topical membership is not evidence of a direct dietary effect. plain_language: The same pump handles calcium and manganese through a shared site. organism: Homo sapiens tissue_or_cell_type: Golgi membrane transport protein experimental_model: Cryo-EM of purified human SPCA1a with ATP and divalent ions limitations: Structural states explain the transport cycle but do not supply a dietary requirement or prove that calcium supplementation impairs manganese delivery. exposure: ATP/Ca2+, ATP/Mn2+ and phosphorylated metal-free structural states. cross_nutrient: calcium ion (transported_ion); Manganese(II) ion (alternative_ion); Adenosine triphosphate (energy_substrate); Golgi apparatus (destination) evidence_span: {"source_cache": "artifacts/manganese-glycosylation-sources/spca2023.abstract.txt", "locator": "Indexed primary abstract", "file_sha256": "06a3eac4cc4e989b9195bdb14847c868ddaa68935a12f2d5c5f50a1a47259fb8", "start_char": 0, "end_char": 1276, "text_sha256": "06a3eac4cc4e989b9195bdb14847c868ddaa68935a12f2d5c5f50a1a47259fb8", "text_characters": 1276} [mn-gly-spca2023] Cryo-EM structures of human SPCA1a reveal the mechanism of Ca²⁺/Mn²⁺ transport into the Golgi apparatus. (2023). https://pubmed.ncbi.nlm.nih.gov/36867705/ DOI: 10.1126/sciadv.add9742

cross_nutrient

Secretory pathway calcium/manganese ATPase 1 (parent_protein); Manganese(II) ion (transported_ion); Adenosine triphosphate (energy_substrate); Golgi apparatus (destination)

evidence_span

{"source_cache": "artifacts/manganese-glycosylation-sources/spca2023.abstract.txt", "locator": "Indexed primary abstract", "file_sha256": "06a3eac4cc4e989b9195bdb14847c868ddaa68935a12f2d5c5f50a1a47259fb8", "start_char": 0, "end_char": 1276, "text_sha256": "06a3eac4cc4e989b9195bdb14847c868ddaa68935a12f2d5c5f50a1a47259fb8", "text_characters": 1276}

experimental_model

Cryo-EM of purified human SPCA1a with ATP and divalent ions

exposure

ATP/Ca2+, ATP/Mn2+ and phosphorylated metal-free structural states.

limitations

Structural states explain the transport cycle but do not supply a dietary requirement or prove that calcium supplementation impairs manganese delivery.

nutrient_topic

Manganese research collection; topical membership is not evidence of a direct dietary effect. · Manganese

organism

Homo sapiens

plain_language

An ATP-powered pump delivers manganese to the Golgi.

primary_references

[mn-gly-spca2023] Cryo-EM structures of human SPCA1a reveal the mechanism of Ca²⁺/Mn²⁺ transport into the Golgi apparatus. (2023). https://pubmed.ncbi.nlm.nih.gov/36867705/ DOI: 10.1126/sciadv.add9742

tissue_or_cell_type

Golgi membrane transport protein

transport_effect

raises Recorded as manganese movement from cytosol into the Golgi lumen.

transport_pool

the Golgi lumen Recorded as manganese movement from cytosol into the Golgi lumen.

Manganese: enzyme cofactors, glycosylation, transport and nutrient interactions (2026-09-17) · lines 698–710

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cryo-EM of purified human SPCA1a with ATP and divalent ions · source_derived_draft · unverified_draft

### mn-gly-spca-manganese Human SPCA1a couples its ATPase cycle to manganese movement from cytosol into the Golgi lumen. Condition category: normal nutrient_topic: Manganese research collection; topical membership is not evidence of a direct dietary effect. plain_language: An ATP-powered pump delivers manganese to the Golgi. organism: Homo sapiens tissue_or_cell_type: Golgi membrane transport protein experimental_model: Cryo-EM of purified human SPCA1a with ATP and divalent ions limitations: Structural states explain the transport cycle but do not supply a dietary requirement or prove that calcium supplementation impairs manganese delivery. exposure: ATP/Ca2+, ATP/Mn2+ and phosphorylated metal-free structural states. cross_nutrient: Secretory pathway calcium/manganese ATPase 1 (parent_protein); Manganese(II) ion (transported_ion); Adenosine triphosphate (energy_substrate); Golgi apparatus (destination) evidence_span: {"source_cache": "artifacts/manganese-glycosylation-sources/spca2023.abstract.txt", "locator": "Indexed primary abstract", "file_sha256": "06a3eac4cc4e989b9195bdb14847c868ddaa68935a12f2d5c5f50a1a47259fb8", "start_char": 0, "end_char": 1276, "text_sha256": "06a3eac4cc4e989b9195bdb14847c868ddaa68935a12f2d5c5f50a1a47259fb8", "text_characters": 1276} [mn-gly-spca2023] Cryo-EM structures of human SPCA1a reveal the mechanism of Ca²⁺/Mn²⁺ transport into the Golgi apparatus. (2023). https://pubmed.ncbi.nlm.nih.gov/36867705/ DOI: 10.1126/sciadv.add9742

experimental_model

Human LysRS cryo-EM and aminoacylation assays

limitations

The structural experiment used tRNA-Lys3; KARS1 is not the leucyl-tRNA synthetase LARS1.

organism

Homo sapiens

plain_language

ATP activates lysine before it is attached to its carrier RNA.

primary_references

[devarkar2025] Structural basis for aminoacylation of cellular modified tRNALys3 by human lysyl-tRNA synthetase (2025). https://pubmed.ncbi.nlm.nih.gov/40036503/ DOI: 10.1093/nar/gkaf114

tissue_or_cell_type

Cytosolic tRNA charging

L-Lysine: mechanism-first literature curation (2026-09-17) · lines 54–62

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human LysRS cryo-EM and aminoacylation assays · source_derived_draft · unverified_draft

### lysine-adenylation KARS1 activates lysine with ATP, forming enzyme-bound lysyl-adenylate and releasing pyrophosphate. Plain language: ATP activates lysine before it is attached to its carrier RNA. Condition category: normal organism: Homo sapiens tissue_or_cell_type: Cytosolic tRNA charging experimental_model: Human LysRS cryo-EM and aminoacylation assays limitations: The structural experiment used tRNA-Lys3; KARS1 is not the leucyl-tRNA synthetase LARS1. [devarkar2025] Structural basis for aminoacylation of cellular modified tRNALys3 by human lysyl-tRNA synthetase (2025). https://pubmed.ncbi.nlm.nih.gov/40036503/ DOI: 10.1093/nar/gkaf114

dose

Fructose 250 mg/kg bolus

duration

Early 5 min changes; sugar-phosphate recovery within about 20 min

evidence_access

Primary abstract/metadata; unrecovered methods explicitly retained.

evidence_scope

literature_reviewed; source-specific curation

experimental_model

Seven healthy human volunteers

exposure_scope

Isolated fructose, intravenous

limitations

Injection bypasses the intestine. Magnitude cannot be assigned to a normal oral HFCS serving or to dietary phosphate deficiency.

nutrient_topic

HFCS chapter: actual formulation studies, component biochemistry and interventions are explicitly distinguished. · High-Fructose Corn Syrup / HFCS

organism

Seven healthy human volunteers

plain_language

Intravenous fructose acutely lowered hepatic ATP in seven healthy volunteers.

primary_references

Assessment of human liver metabolism by phosphorus-31 magnetic resonance spectroscopy. (1986). https://pubmed.ncbi.nlm.nih.gov/3730768/ DOI: 10.1259/0007-1285-59-703-695

route

Intravenous injection

tissue

Liver phosphorus-31 MRS

High-Fructose Corn Syrup: mechanism of action and metabolic impact (2026-09-20) · lines 233–243

Original AI-assisted curation of twenty primary studies and official FDA composition information, with one reused canonical glucose-transport claim. Study-specific citations, negative findings and limitations retained. Not publisher full text. · supports · Seven healthy human volunteers · source_derived_draft · unverified_draft

## hfcs-iv-atp Intravenous fructose acutely lowered hepatic ATP in seven healthy volunteers. Model/species: Seven healthy human volunteers Tissue: Liver phosphorus-31 MRS Exposure: Fructose 250 mg/kg bolus Route: Intravenous injection Duration: Early 5 min changes; sugar-phosphate recovery within about 20 min Exposure scope: Isolated fructose, intravenous Limits: Injection bypasses the intestine. Magnitude cannot be assigned to a normal oral HFCS serving or to dietary phosphate deficiency. Reference: Assessment of human liver metabolism by phosphorus-31 magnetic resonance spectroscopy. (1986). https://pubmed.ncbi.nlm.nih.gov/3730768/ DOI: 10.1259/0007-1285-59-703-695 Access: Primary abstract/metadata; unrecovered methods explicitly retained.

dose

Fructose substrate and ATP-dependent enzyme characterization; exact concentrations not in abstract

duration

Assay duration not recovered

evidence_access

Primary abstract/metadata; unrecovered methods explicitly retained.

evidence_scope

literature_reviewed; source-specific curation

experimental_model

Ketohexokinase purified from human liver

exposure_scope

Human component biochemistry

limitations

Isoform unresolved; enzyme chemistry does not quantify whole-body flux after ordinary HFCS intake. Only abstract/metadata recovered for this scanned article.

nutrient_topic

HFCS chapter: actual formulation studies, component biochemistry and interventions are explicitly distinguished. · High-Fructose Corn Syrup / HFCS

organism

Ketohexokinase purified from human liver

plain_language

Purified human liver ketohexokinase catalyzed the ATP-dependent phosphorylation of fructose.

primary_references

The purification and properties of human liver ketohexokinase. A role for ketohexokinase and fructose-bisphosphate aldolase in the metabolic production of oxalate from xylitol. (1985). https://pubmed.ncbi.nlm.nih.gov/2996495/ DOI: 10.1042/bj2300053

route

In vitro enzyme/substrate incubation

tissue

Cell-free enzyme kinetics

High-Fructose Corn Syrup: mechanism of action and metabolic impact (2026-09-20) · lines 101–111

Original AI-assisted curation of twenty primary studies and official FDA composition information, with one reused canonical glucose-transport claim. Study-specific citations, negative findings and limitations retained. Not publisher full text. · supports · Ketohexokinase purified from human liver · source_derived_draft · unverified_draft

## hfcs-khk-phosphorylation Purified human liver ketohexokinase catalyzed the ATP-dependent phosphorylation of fructose. Model/species: Ketohexokinase purified from human liver Tissue: Cell-free enzyme kinetics Exposure: Fructose substrate and ATP-dependent enzyme characterization; exact concentrations not in abstract Route: In vitro enzyme/substrate incubation Duration: Assay duration not recovered Exposure scope: Human component biochemistry Limits: Isoform unresolved; enzyme chemistry does not quantify whole-body flux after ordinary HFCS intake. Only abstract/metadata recovered for this scanned article. Reference: The purification and properties of human liver ketohexokinase. A role for ketohexokinase and fructose-bisphosphate aldolase in the metabolic production of oxalate from xylitol. (1985). https://pubmed.ncbi.nlm.nih.gov/2996495/ DOI: 10.1042/bj2300053 Access: Primary abstract/metadata; unrecovered methods explicitly retained.

dose

75 g fructose challenge

duration

60 min

evidence_access

Primary abstract/metadata; unrecovered methods explicitly retained.

evidence_scope

literature_reviewed; source-specific curation

experimental_model

37 overweight/obese adults without diabetes, stratified by MASLD

exposure_scope

Isolated fructose, oral

limitations

Small acute component study; the ATP response was blunted in MASLD, not uniformly greater. Metabolite signals are not chronic clinical outcomes.

nutrient_topic

HFCS chapter: actual formulation studies, component biochemistry and interventions are explicitly distinguished. · High-Fructose Corn Syrup / HFCS

organism

37 overweight/obese adults without diabetes, stratified by MASLD

plain_language

After 75 g oral fructose, hepatic ATP decreased within 15 minutes and remained lower at 60 minutes in participants without MASLD.

primary_references

Patients with MASLD exhibit in vivo changes in hepatic response to oral fructose consumption. (2026). https://pubmed.ncbi.nlm.nih.gov/41866318/ DOI: 10.1210/clinem/dgag125

route

Oral solution

tissue

Liver phosphorus-31 MRS

High-Fructose Corn Syrup: mechanism of action and metabolic impact (2026-09-20) · lines 257–267

Original AI-assisted curation of twenty primary studies and official FDA composition information, with one reused canonical glucose-transport claim. Study-specific citations, negative findings and limitations retained. Not publisher full text. · supports · 37 overweight/obese adults without diabetes, stratified by MASLD · source_derived_draft · unverified_draft

## hfcs-oral-atp After 75 g oral fructose, hepatic ATP decreased within 15 minutes and remained lower at 60 minutes in participants without MASLD. Model/species: 37 overweight/obese adults without diabetes, stratified by MASLD Tissue: Liver phosphorus-31 MRS Exposure: 75 g fructose challenge Route: Oral solution Duration: 60 min Exposure scope: Isolated fructose, oral Limits: Small acute component study; the ATP response was blunted in MASLD, not uniformly greater. Metabolite signals are not chronic clinical outcomes. Reference: Patients with MASLD exhibit in vivo changes in hepatic response to oral fructose consumption. (2026). https://pubmed.ncbi.nlm.nih.gov/41866318/ DOI: 10.1210/clinem/dgag125 Access: Primary abstract/metadata; unrecovered methods explicitly retained.

dose

75 g fructose challenge

duration

60 min

evidence_access

Primary abstract/metadata; unrecovered methods explicitly retained.

evidence_scope

literature_reviewed; source-specific curation

experimental_model

37 overweight/obese adults without diabetes, stratified by MASLD

exposure_scope

Isolated fructose, oral

limitations

Small acute component study; the ATP response was blunted in MASLD, not uniformly greater. Metabolite signals are not chronic clinical outcomes.

nutrient_topic

HFCS chapter: actual formulation studies, component biochemistry and interventions are explicitly distinguished. · High-Fructose Corn Syrup / HFCS

organism

37 overweight/obese adults without diabetes, stratified by MASLD

plain_language

Participants with MASLD showed a blunted ATP response to oral fructose, with only a nonsignificant early drop and recovery by 30 minutes.

primary_references

Patients with MASLD exhibit in vivo changes in hepatic response to oral fructose consumption. (2026). https://pubmed.ncbi.nlm.nih.gov/41866318/ DOI: 10.1210/clinem/dgag125

route

Oral solution

tissue

Liver phosphorus-31 MRS

High-Fructose Corn Syrup: mechanism of action and metabolic impact (2026-09-20) · lines 269–279

Original AI-assisted curation of twenty primary studies and official FDA composition information, with one reused canonical glucose-transport claim. Study-specific citations, negative findings and limitations retained. Not publisher full text. · supports · 37 overweight/obese adults without diabetes, stratified by MASLD · source_derived_draft · unverified_draft

## hfcs-oral-atp-masld Participants with MASLD showed a blunted ATP response to oral fructose, with only a nonsignificant early drop and recovery by 30 minutes. Model/species: 37 overweight/obese adults without diabetes, stratified by MASLD Tissue: Liver phosphorus-31 MRS Exposure: 75 g fructose challenge Route: Oral solution Duration: 60 min Exposure scope: Isolated fructose, oral Limits: Small acute component study; the ATP response was blunted in MASLD, not uniformly greater. Metabolite signals are not chronic clinical outcomes. Reference: Patients with MASLD exhibit in vivo changes in hepatic response to oral fructose consumption. (2026). https://pubmed.ncbi.nlm.nih.gov/41866318/ DOI: 10.1210/clinem/dgag125 Access: Primary abstract/metadata; unrecovered methods explicitly retained.

dose

400 microliters of 25% HFCS solution daily, approximately 3% of mouse daily calories

duration

8 weeks; acute bolus for ATP analysis

evidence_access

Primary full-text methods/results and metadata inspected.

evidence_scope

literature_reviewed; source-specific curation

experimental_model

Genetically Apc-deficient mice predisposed to intestinal adenomas

exposure_scope

Direct HFCS in predisposed mice

limitations

Growth of predisposed mouse tumors, not initiation of cancer in healthy humans. Total tumor number was similar in the main comparison; human-equivalent risk is unresolved.

nutrient_topic

HFCS chapter: actual formulation studies, component biochemistry and interventions are explicitly distinguished. · High-Fructose Corn Syrup / HFCS

organism

Genetically Apc-deficient mice predisposed to intestinal adenomas

plain_language

An acute HFCS bolus lowered ATP in Apc-deficient intestinal tumors; the change was absent with Khk deletion.

primary_references

High-fructose corn syrup enhances intestinal tumor growth in mice. (2019). https://pubmed.ncbi.nlm.nih.gov/30898933/ DOI: 10.1126/science.aat8515

route

Oral gavage; Khk or Fasn deletion where specified

tissue

Tumor size/grade and metabolic perturbations

High-Fructose Corn Syrup: mechanism of action and metabolic impact (2026-09-20) · lines 653–663

Original AI-assisted curation of twenty primary studies and official FDA composition information, with one reused canonical glucose-transport claim. Study-specific citations, negative findings and limitations retained. Not publisher full text. · supports · Genetically Apc-deficient mice predisposed to intestinal adenomas · source_derived_draft · unverified_draft

## hfcs-tumor-atp An acute HFCS bolus lowered ATP in Apc-deficient intestinal tumors; the change was absent with Khk deletion. Model/species: Genetically Apc-deficient mice predisposed to intestinal adenomas Tissue: Tumor size/grade and metabolic perturbations Exposure: 400 microliters of 25% HFCS solution daily, approximately 3% of mouse daily calories Route: Oral gavage; Khk or Fasn deletion where specified Duration: 8 weeks; acute bolus for ATP analysis Exposure scope: Direct HFCS in predisposed mice Limits: Growth of predisposed mouse tumors, not initiation of cancer in healthy humans. Total tumor number was similar in the main comparison; human-equivalent risk is unresolved. Reference: High-fructose corn syrup enhances intestinal tumor growth in mice. (2019). https://pubmed.ncbi.nlm.nih.gov/30898933/ DOI: 10.1126/science.aat8515 Access: Primary full-text methods/results and metadata inspected.

evidence_span

{"source_cache": "artifacts/dihydrocapsaicin-research/30090648.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e688b4cd16fdd3847d8fe10113d243edf17839f32bef46fe85790a18ad6b920c", "start_char": 0, "end_char": 2110, "text_sha256": "e688b4cd16fdd3847d8fe10113d243edf17839f32bef46fe85790a18ad6b920c"}

experimental_model

Randomised seven-group study in 144 male Sprague Dawley rats after middle cerebral artery occlusion

exposure

Low-dose dihydrocapsaicin at 0.5 mg/kg or high-dose at 1.5 mg/kg, an ice pad at 31 degrees, and the combination, with an external-temperature-control arm

limitations

A large randomised design with a dose-response surprise: the high dose alone did nothing while the low dose worked. That non-monotonicity is recorded because it contradicts the simple dose-response in the other records.

nutrient_topic

Dihydrocapsaicin research collection; topical membership is not evidence of a direct clinical effect, and dihydrocapsaicin is recorded separately from capsaicin. · Dihydrocapsaicin

organism

Rat

plain_language

Drug plus ice pack cooled faster and protected better than either on its own.

primary_references

[dhc-p30090648] Synergistically Induced Hypothermia and Enhanced Neuroprotection by Pharmacological and Physical Approaches in Stroke. (2018). https://pubmed.ncbi.nlm.nih.gov/30090648/ DOI: 10.14336/ad.2017.0817

tissue_or_cell_type

Brain

Dihydrocapsaicin: the second capsaicinoid, the hypothermia it is used to induce, what the gut and liver do to it, and what it does without TRPV1 (2026-09-21) · lines 335–346

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomised seven-group study in 144 male Sprague Dawley rats after middle cerebral artery occlusion · source_derived_draft · unverified_draft

### dhc-combination-beats-either Combination therapy of low-dose dihydrocapsaicin and an ice pad significantly improved every measured outcome compared with monotherapies, achieving hypothermia faster by 28.6% than the ice pad, 350% than low-dose dihydrocapsaicin and 200% than high-dose dihydrocapsaicin alone, reducing neurological deficits by 63% against 26% with low-dose alone, reducing reactive oxygen species at 6 and 24 hours, increasing ATP by 42.9% against 25%, and decreasing apoptotic cell death by 48.5% against 24.9%. Condition category: normal nutrient_topic: Dihydrocapsaicin research collection; topical membership is not evidence of a direct clinical effect, and dihydrocapsaicin is recorded separately from capsaicin. plain_language: Drug plus ice pack cooled faster and protected better than either on its own. organism: Rat tissue_or_cell_type: Brain experimental_model: Randomised seven-group study in 144 male Sprague Dawley rats after middle cerebral artery occlusion limitations: A large randomised design with a dose-response surprise: the high dose alone did nothing while the low dose worked. That non-monotonicity is recorded because it contradicts the simple dose-response in the other records. exposure: Low-dose dihydrocapsaicin at 0.5 mg/kg or high-dose at 1.5 mg/kg, an ice pad at 31 degrees, and the combination, with an external-temperature-control arm evidence_span: {"source_cache": "artifacts/dihydrocapsaicin-research/30090648.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e688b4cd16fdd3847d8fe10113d243edf17839f32bef46fe85790a18ad6b920c", "start_char": 0, "end_char": 2110, "text_sha256": "e688b4cd16fdd3847d8fe10113d243edf17839f32bef46fe85790a18ad6b920c"} [dhc-p30090648] Synergistically Induced Hypothermia and Enhanced Neuroprotection by Pharmacological and Physical Approaches in Stroke. (2018). https://pubmed.ncbi.nlm.nih.gov/30090648/ DOI: 10.14336/ad.2017.0817

dose

Indicaxanthin 1-5 micromolar; aqueous cigarette smoke extract

duration

3 h

evidence_access

Primary PubMed abstract; detailed exposure for PMID 23931157 additionally checked in publisher results. No uninspected full text is claimed.

evidence_scope

literature_reviewed; source-derived curation, not universally established human effects

experimental_model

Human isolated red blood cells challenged with cigarette smoke extract

limitations

An isolated-cell smoke-extract experiment does not establish protection against smoking-related disease; no direct Fas-binding assay was reported in the abstract.

nutrient_topic

Betalains collection; each molecular form, species, exposure and preparation remains explicit. · Betalains

organism

Human isolated red blood cells challenged with cigarette smoke extract

plain_language

Indicaxanthin reduced ATP depletion during smoke-extract exposure of isolated red cells.

primary_references

Indicaxanthin prevents eryptosis induced by cigarette smoke extract by interfering with active Fas-mediated signaling. (2024). https://pubmed.ncbi.nlm.nih.gov/38520710/ DOI: 10.1002/biof.2051

route

Ex vivo co-incubation

tissue

Erythrocyte membrane and cytosol

Betalains: mechanisms, molecular forms and cross-actor connections (2026-09-20) · lines 477–485

Original AI-assisted curation of twelve primary research papers; study-specific PubMed/DOI links and limitations retained. Not publisher full text. · supports · Human isolated red blood cells challenged with cigarette smoke extract · source_derived_draft · unverified_draft

## betalains-redcell-atp Indicaxanthin reduced ATP depletion during smoke-extract exposure of isolated red cells. Model/species: Human isolated red blood cells challenged with cigarette smoke extract Tissue: Erythrocyte membrane and cytosol Exposure: Indicaxanthin 1-5 micromolar; aqueous cigarette smoke extract Route: Ex vivo co-incubation Duration: 3 h Limits: An isolated-cell smoke-extract experiment does not establish protection against smoking-related disease; no direct Fas-binding assay was reported in the abstract. Primary reference: Indicaxanthin prevents eryptosis induced by cigarette smoke extract by interfering with active Fas-mediated signaling. (2024). https://pubmed.ncbi.nlm.nih.gov/38520710/ DOI: 10.1002/biof.2051

dose

Annonacin concentration series

duration

48 hours

evidence_access

Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

evidence_scope

literature_reviewed; model-specific source-derived curation

experimental_model

Primary rat striatal neurons

limitations

Purified-cell exposure establishes a hazard mechanism, not the dose delivered to human neurons by a particular graviola food.

nutrient_topic

Graviola (Annona muricata) chapter; interacting nutrients, drugs, peptides and proteins retain their experimental settings. · Graviola / Annona muricata

organism

Primary rat striatal neurons

plain_language

Annonacin inhibited mitochondrial complex-I-linked energy production, producing a concentration-dependent ATP fall, tau redistribution and death in cultured rat striatal neurons.

primary_references

Annonacin, a natural mitochondrial complex I inhibitor, causes tau pathology in cultured neurons. (2007). https://pubmed.ncbi.nlm.nih.gov/17634376/ DOI: 10.1523/JNEUROSCI.1644-07.2007

route

In vitro

tissue

ATP, mitochondrial transport, tau localization and cell death

Graviola (Annona muricata): mechanism of action and interactions (2026-09-20) · lines 44–53

Original AI-assisted source-specific curation with primary-study citations, model, exposure, route, duration, negative findings and limitations preserved. Not publisher full text. · supports · Primary rat striatal neurons · source_derived_draft · unverified_draft

## graviola-complex1-atp Annonacin inhibited mitochondrial complex-I-linked energy production, producing a concentration-dependent ATP fall, tau redistribution and death in cultured rat striatal neurons. Model/species: Primary rat striatal neurons Tissue/system: ATP, mitochondrial transport, tau localization and cell death Exposure: Annonacin concentration series Route: In vitro Duration: 48 hours Limits: Purified-cell exposure establishes a hazard mechanism, not the dose delivered to human neurons by a particular graviola food. Primary reference: Annonacin, a natural mitochondrial complex I inhibitor, causes tau pathology in cultured neurons. (2007). https://pubmed.ncbi.nlm.nih.gov/17634376/ DOI: 10.1523/JNEUROSCI.1644-07.2007 Access: Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

availability_state

machinery_impairment Imported condition classification; unverified.

dose

Annonacin with NDI1 expression, glycolysis stimulation or antioxidants

duration

48 hours

evidence_access

Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

evidence_scope

literature_reviewed; model-specific source-derived curation

experimental_model

Primary rat striatal neurons

limitations

NDI1 is an experimental bypass, and lack of antioxidant rescue does not exclude every redox contribution in vivo.

nutrient_topic

Graviola (Annona muricata) chapter; interacting nutrients, drugs, peptides and proteins retain their experimental settings. · Graviola / Annona muricata

organism

Primary rat striatal neurons

plain_language

Forced yeast NDI1 expression or stimulation of anaerobic glycolysis prevented annonacin-associated tau redistribution and neuronal death, whereas antioxidants did not.

primary_references

Annonacin, a natural mitochondrial complex I inhibitor, causes tau pathology in cultured neurons. (2007). https://pubmed.ncbi.nlm.nih.gov/17634376/ DOI: 10.1523/JNEUROSCI.1644-07.2007

route

In vitro perturbation

tissue

Energy-pathway rescue and antioxidant controls

trigger_kind

machinery_impairment Imported condition classification; unverified.

Graviola (Annona muricata): mechanism of action and interactions (2026-09-20) · lines 55–64

Original AI-assisted source-specific curation with primary-study citations, model, exposure, route, duration, negative findings and limitations preserved. Not publisher full text. · supports · Primary rat striatal neurons · source_derived_draft · unverified_draft

## graviola-ndi1-rescue Forced yeast NDI1 expression or stimulation of anaerobic glycolysis prevented annonacin-associated tau redistribution and neuronal death, whereas antioxidants did not. Model/species: Primary rat striatal neurons Tissue/system: Energy-pathway rescue and antioxidant controls Exposure: Annonacin with NDI1 expression, glycolysis stimulation or antioxidants Route: In vitro perturbation Duration: 48 hours Limits: NDI1 is an experimental bypass, and lack of antioxidant rescue does not exclude every redox contribution in vivo. Primary reference: Annonacin, a natural mitochondrial complex I inhibitor, causes tau pathology in cultured neurons. (2007). https://pubmed.ncbi.nlm.nih.gov/17634376/ DOI: 10.1523/JNEUROSCI.1644-07.2007 Access: Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

evidence_span

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experimental_model

X-ray structures and human homology model

exposure

Glutamate/MgCl2 with or without ADP

limitations

Direct metal-site observation is yeast; the human model is an inference, not a human deficiency experiment.

nutrient_topic

Glutathione research collection; topical membership is not evidence of a direct dietary effect. · GSH

organism

Saccharomyces cerevisiae enzyme; separate human model

plain_language

Magnesium has a role beyond merely being present in the assay buffer.

primary_references

[glutathione-p19726687] Mechanistic details of glutathione biosynthesis revealed by crystal structures of Saccharomyces cerevisiae glutamate cysteine ligase. (2009). https://pubmed.ncbi.nlm.nih.gov/19726687/ DOI: 10.1074/jbc.m109.025114

tissue_or_cell_type

Purified Gsh1

Glutathione: metabolism, signaling and nutrient connections (2026-09-17) · lines 346–357

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · X-ray structures and human homology model · source_derived_draft · unverified_draft

### glutathione-gcl-magnesium The yeast GCL structures identified an ATP-independent magnesium coordination site associated with the enzyme’s Mg dependence. Condition category: normal nutrient_topic: Glutathione research collection; topical membership is not evidence of a direct dietary effect. plain_language: Magnesium has a role beyond merely being present in the assay buffer. organism: Saccharomyces cerevisiae enzyme; separate human model tissue_or_cell_type: Purified Gsh1 experimental_model: X-ray structures and human homology model limitations: Direct metal-site observation is yeast; the human model is an inference, not a human deficiency experiment. exposure: Glutamate/MgCl2 with or without ADP evidence_span: {"source_cache": "artifacts/glutathione-research/19726687.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "fd125689fc03eaf0ec433fd6b967eecc6c52c234e99e3717f10218c2c4b97625", "start_char": 0, "end_char": 1461, "text_sha256": "fd125689fc03eaf0ec433fd6b967eecc6c52c234e99e3717f10218c2c4b97625"} [glutathione-p19726687] Mechanistic details of glutathione biosynthesis revealed by crystal structures of Saccharomyces cerevisiae glutamate cysteine ligase. (2009). https://pubmed.ncbi.nlm.nih.gov/19726687/ DOI: 10.1074/jbc.m109.025114

evidence_span

{"source_cache": "artifacts/glutathione-research/10369661.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ccdd02e451ba6a6d432012c382911ff7fac556e99f9e8d60ce9f3dc94baf9941", "start_char": 0, "end_char": 1327, "text_sha256": "ccdd02e451ba6a6d432012c382911ff7fac556e99f9e8d60ce9f3dc94baf9941"}

experimental_model

Crystal structure and disease-variant mapping

exposure

ADP/GSH/sulfate-bound structure

limitations

Two Mg ions observed; structure is not a dietary-magnesium depletion experiment. The main synthesis reaction is reused from its existing claim.

nutrient_topic

Glutathione research collection; topical membership is not evidence of a direct dietary effect. · GSH

organism

Human enzyme

plain_language

The synthesis enzyme has a metal-containing nucleotide-binding environment.

primary_references

[glutathione-p10369661] Molecular basis of glutathione synthetase deficiency and a rare gene permutation event. (1999). https://pubmed.ncbi.nlm.nih.gov/10369661/ DOI: 10.1093/emboj/18.12.3204

tissue_or_cell_type

Purified GSS

Glutathione: metabolism, signaling and nutrient connections (2026-09-17) · lines 333–344

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Crystal structure and disease-variant mapping · source_derived_draft · unverified_draft

### glutathione-gss-magnesium Human GSS crystallized with two magnesium ions, ADP, glutathione and sulfate. Condition category: normal nutrient_topic: Glutathione research collection; topical membership is not evidence of a direct dietary effect. plain_language: The synthesis enzyme has a metal-containing nucleotide-binding environment. organism: Human enzyme tissue_or_cell_type: Purified GSS experimental_model: Crystal structure and disease-variant mapping limitations: Two Mg ions observed; structure is not a dietary-magnesium depletion experiment. The main synthesis reaction is reused from its existing claim. exposure: ADP/GSH/sulfate-bound structure evidence_span: {"source_cache": "artifacts/glutathione-research/10369661.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ccdd02e451ba6a6d432012c382911ff7fac556e99f9e8d60ce9f3dc94baf9941", "start_char": 0, "end_char": 1327, "text_sha256": "ccdd02e451ba6a6d432012c382911ff7fac556e99f9e8d60ce9f3dc94baf9941"} [glutathione-p10369661] Molecular basis of glutathione synthetase deficiency and a rare gene permutation event. (1999). https://pubmed.ncbi.nlm.nih.gov/10369661/ DOI: 10.1093/emboj/18.12.3204

evidence_span

{"source_cache": "artifacts/glutathione-research/8670053.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9178e466ea8bd18f0957cc65594934ec1681ad7483e6ac64d79c4b8d8ca2afc3", "start_char": 0, "end_char": 1433, "text_sha256": "9178e466ea8bd18f0957cc65594934ec1681ad7483e6ac64d79c4b8d8ca2afc3"}

experimental_model

Membrane-vesicle transport assays

exposure

ATP-dependent GSSG uptake into vesicles

limitations

Vesicle uptake reflects cellular export; the GSH null result applies specifically to the tested 100 micromolar condition.

nutrient_topic

Glutathione research collection; topical membership is not evidence of a direct dietary effect. · GSH

organism

Human HL60 and HeLa systems

plain_language

Oxidized glutathione can be exported instead of recycled locally.

primary_references

[glutathione-p8670053] ATP-dependent glutathione disulphide transport mediated by the MRP gene-encoded conjugate export pump. (1996). https://pubmed.ncbi.nlm.nih.gov/8670053/ DOI: 10.1042/bj3140433

tissue_or_cell_type

MRP-overexpressing membranes

Glutathione: metabolism, signaling and nutrient connections (2026-09-17) · lines 723–734

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Membrane-vesicle transport assays · source_derived_draft · unverified_draft

### glutathione-mrp-gssg MRP1 mediated ATP-dependent GSSG transport; the HeLa-vesicle Km was 93 ± 26 micromolar. Condition category: normal nutrient_topic: Glutathione research collection; topical membership is not evidence of a direct dietary effect. plain_language: Oxidized glutathione can be exported instead of recycled locally. organism: Human HL60 and HeLa systems tissue_or_cell_type: MRP-overexpressing membranes experimental_model: Membrane-vesicle transport assays limitations: Vesicle uptake reflects cellular export; the GSH null result applies specifically to the tested 100 micromolar condition. exposure: ATP-dependent GSSG uptake into vesicles evidence_span: {"source_cache": "artifacts/glutathione-research/8670053.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9178e466ea8bd18f0957cc65594934ec1681ad7483e6ac64d79c4b8d8ca2afc3", "start_char": 0, "end_char": 1433, "text_sha256": "9178e466ea8bd18f0957cc65594934ec1681ad7483e6ac64d79c4b8d8ca2afc3"} [glutathione-p8670053] ATP-dependent glutathione disulphide transport mediated by the MRP gene-encoded conjugate export pump. (1996). https://pubmed.ncbi.nlm.nih.gov/8670053/ DOI: 10.1042/bj3140433

evidence_span

{"source_cache": "artifacts/molybdenum-research/23163752.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "909388cf5fb7bfa5d2f8444644e20773a7a8ec6a19b4ccb8a4bda78d9ad17c5d", "start_char": 0, "end_char": 1489, "text_sha256": "909388cf5fb7bfa5d2f8444644e20773a7a8ec6a19b4ccb8a4bda78d9ad17c5d"}

experimental_model

Purified mammalian gephyrin domains and full multidomain protein; in-vitro Moco reconstitution

exposure

MPT adenylation, molybdate insertion and domain-combination assays

limitations

No human dietary magnesium intervention; purified domain kinetics should not be turned into supplementation efficacy.

nutrient_topic

Molybdenum research collection; topical membership is not evidence of a direct dietary effect. · Molybdenum

organism

Mammalian protein system

plain_language

Gephyrin prepares the scaffold for metal insertion.

primary_references

[mo-p23163752] Metal insertion into the molybdenum cofactor: product-substrate channelling demonstrates the functional origin of domain fusion in gephyrin. (2013). https://pubmed.ncbi.nlm.nih.gov/23163752/ DOI: 10.1042/bj20121078

tissue_or_cell_type

Purified gephyrin

Molybdenum: cofactor assembly, sulfur metabolism and nutrient interactions (2026-09-17) · lines 482–493

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified mammalian gephyrin domains and full multidomain protein; in-vitro Moco reconstitution · source_derived_draft · unverified_draft

### mo-gphn-adenylation The gephyrin G domain produces adenylylated molybdopterin. Condition category: normal nutrient_topic: Molybdenum research collection; topical membership is not evidence of a direct dietary effect. plain_language: Gephyrin prepares the scaffold for metal insertion. organism: Mammalian protein system tissue_or_cell_type: Purified gephyrin experimental_model: Purified mammalian gephyrin domains and full multidomain protein; in-vitro Moco reconstitution limitations: No human dietary magnesium intervention; purified domain kinetics should not be turned into supplementation efficacy. exposure: MPT adenylation, molybdate insertion and domain-combination assays evidence_span: {"source_cache": "artifacts/molybdenum-research/23163752.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "909388cf5fb7bfa5d2f8444644e20773a7a8ec6a19b4ccb8a4bda78d9ad17c5d", "start_char": 0, "end_char": 1489, "text_sha256": "909388cf5fb7bfa5d2f8444644e20773a7a8ec6a19b4ccb8a4bda78d9ad17c5d"} [mo-p23163752] Metal insertion into the molybdenum cofactor: product-substrate channelling demonstrates the functional origin of domain fusion in gephyrin. (2013). https://pubmed.ncbi.nlm.nih.gov/23163752/ DOI: 10.1042/bj20121078

evidence_span

{"source_cache": "artifacts/molybdenum-research/22453920.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "700833295a22a72be9d0ee74144bfe9249d6266c7fcba7b48330a4b2f2bf9c64", "start_char": 0, "end_char": 1267, "text_sha256": "700833295a22a72be9d0ee74144bfe9249d6266c7fcba7b48330a4b2f2bf9c64"}

experimental_model

Human-cell interaction/localization and purified-protein adenylation/sulfuration

exposure

MOCS2A and URM1 terminal glycine variants

limitations

Shared enzyme does not prove competition for sulfur in ordinary nutrient deficiency.

nutrient_topic

Molybdenum research collection; topical membership is not evidence of a direct dietary effect. · Molybdenum

organism

Homo sapiens

plain_language

ATP-driven activation reloads the sulfur carrier.

primary_references

[mo-p22453920] Dual role of the molybdenum cofactor biosynthesis protein MOCS3 in tRNA thiolation and molybdenum cofactor biosynthesis in humans. (2012). https://pubmed.ncbi.nlm.nih.gov/22453920/ DOI: 10.1074/jbc.m112.351429

tissue_or_cell_type

Cytosolic sulfur-transfer pathways

Molybdenum: cofactor assembly, sulfur metabolism and nutrient interactions (2026-09-17) · lines 443–454

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human-cell interaction/localization and purified-protein adenylation/sulfuration · source_derived_draft · unverified_draft

### mo-mocs3-activate MOCS3 activates MOCS2A by adenylation followed by sulfur transfer, forming its C-terminal thiocarboxylate. Condition category: normal nutrient_topic: Molybdenum research collection; topical membership is not evidence of a direct dietary effect. plain_language: ATP-driven activation reloads the sulfur carrier. organism: Homo sapiens tissue_or_cell_type: Cytosolic sulfur-transfer pathways experimental_model: Human-cell interaction/localization and purified-protein adenylation/sulfuration limitations: Shared enzyme does not prove competition for sulfur in ordinary nutrient deficiency. exposure: MOCS2A and URM1 terminal glycine variants evidence_span: {"source_cache": "artifacts/molybdenum-research/22453920.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "700833295a22a72be9d0ee74144bfe9249d6266c7fcba7b48330a4b2f2bf9c64", "start_char": 0, "end_char": 1267, "text_sha256": "700833295a22a72be9d0ee74144bfe9249d6266c7fcba7b48330a4b2f2bf9c64"} [mo-p22453920] Dual role of the molybdenum cofactor biosynthesis protein MOCS3 in tRNA thiolation and molybdenum cofactor biosynthesis in humans. (2012). https://pubmed.ncbi.nlm.nih.gov/22453920/ DOI: 10.1074/jbc.m112.351429

evidence_span

{"source_cache": "artifacts/molybdenum-research/22453920.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "700833295a22a72be9d0ee74144bfe9249d6266c7fcba7b48330a4b2f2bf9c64", "start_char": 0, "end_char": 1267, "text_sha256": "700833295a22a72be9d0ee74144bfe9249d6266c7fcba7b48330a4b2f2bf9c64"}

experimental_model

Human-cell interaction/localization and purified-protein adenylation/sulfuration

exposure

MOCS2A and URM1 terminal glycine variants

limitations

Shared enzyme does not prove competition for sulfur in ordinary nutrient deficiency.

nutrient_topic

Molybdenum research collection; topical membership is not evidence of a direct dietary effect. · Molybdenum

organism

Homo sapiens

plain_language

The same sulfur-handling enzyme supplies a separate RNA-modification pathway.

primary_references

[mo-p22453920] Dual role of the molybdenum cofactor biosynthesis protein MOCS3 in tRNA thiolation and molybdenum cofactor biosynthesis in humans. (2012). https://pubmed.ncbi.nlm.nih.gov/22453920/ DOI: 10.1074/jbc.m112.351429

tissue_or_cell_type

Cytosolic sulfur-transfer pathways

Molybdenum: cofactor assembly, sulfur metabolism and nutrient interactions (2026-09-17) · lines 456–467

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human-cell interaction/localization and purified-protein adenylation/sulfuration · source_derived_draft · unverified_draft

### mo-mocs3-urm1 MOCS3 also activates URM1 by adenylation and sulfur transfer to its terminal glycine. Condition category: normal nutrient_topic: Molybdenum research collection; topical membership is not evidence of a direct dietary effect. plain_language: The same sulfur-handling enzyme supplies a separate RNA-modification pathway. organism: Homo sapiens tissue_or_cell_type: Cytosolic sulfur-transfer pathways experimental_model: Human-cell interaction/localization and purified-protein adenylation/sulfuration limitations: Shared enzyme does not prove competition for sulfur in ordinary nutrient deficiency. exposure: MOCS2A and URM1 terminal glycine variants evidence_span: {"source_cache": "artifacts/molybdenum-research/22453920.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "700833295a22a72be9d0ee74144bfe9249d6266c7fcba7b48330a4b2f2bf9c64", "start_char": 0, "end_char": 1267, "text_sha256": "700833295a22a72be9d0ee74144bfe9249d6266c7fcba7b48330a4b2f2bf9c64"} [mo-p22453920] Dual role of the molybdenum cofactor biosynthesis protein MOCS3 in tRNA thiolation and molybdenum cofactor biosynthesis in humans. (2012). https://pubmed.ncbi.nlm.nih.gov/22453920/ DOI: 10.1074/jbc.m112.351429

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/molybdenum-research/15273247.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d2f73a9ca41e4d51b85d3a66ada08511055ce6ff7462beb0e7eaf21aadf37279", "start_char": 0, "end_char": 1606, "text_sha256": "d2f73a9ca41e4d51b85d3a66ada08511055ce6ff7462beb0e7eaf21aadf37279"}

experimental_model

Rat brain mitochondria/extracts, purified enzyme and Neuro-2a/PC12 cells

exposure

Micromolar sulfite exposure

limitations

Experimental substrate dependence; not a measurement of these effects in people with ordinary low molybdenum intake.

nutrient_topic

Molybdenum research collection; topical membership is not evidence of a direct dietary effect. · Molybdenum

organism

Rattus norvegicus tissue; rodent cell lines

plain_language

The effect depended on which fuel route supplied the mitochondria.

primary_references

[mo-p15273247] A mechanism of sulfite neurotoxicity: direct inhibition of glutamate dehydrogenase. (2004). https://pubmed.ncbi.nlm.nih.gov/15273247/ DOI: 10.1074/jbc.m402759200

tissue_or_cell_type

Mitochondrial glutamate oxidation

trigger_kind

machinery_impairment Imported condition classification; unverified.

Molybdenum: cofactor assembly, sulfur metabolism and nutrient interactions (2026-09-17) · lines 1379–1390

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat brain mitochondria/extracts, purified enzyme and Neuro-2a/PC12 cells · source_derived_draft · unverified_draft

### mo-sulfite-atp Sulfite reduced glutamate-driven mitochondrial membrane potential and ATP synthesis, while malate- and succinate-supported membrane potential was not affected. Condition category: machinery_impairment nutrient_topic: Molybdenum research collection; topical membership is not evidence of a direct dietary effect. plain_language: The effect depended on which fuel route supplied the mitochondria. organism: Rattus norvegicus tissue; rodent cell lines tissue_or_cell_type: Mitochondrial glutamate oxidation experimental_model: Rat brain mitochondria/extracts, purified enzyme and Neuro-2a/PC12 cells limitations: Experimental substrate dependence; not a measurement of these effects in people with ordinary low molybdenum intake. exposure: Micromolar sulfite exposure evidence_span: {"source_cache": "artifacts/molybdenum-research/15273247.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d2f73a9ca41e4d51b85d3a66ada08511055ce6ff7462beb0e7eaf21aadf37279", "start_char": 0, "end_char": 1606, "text_sha256": "d2f73a9ca41e4d51b85d3a66ada08511055ce6ff7462beb0e7eaf21aadf37279"} [mo-p15273247] A mechanism of sulfite neurotoxicity: direct inhibition of glutamate dehydrogenase. (2004). https://pubmed.ncbi.nlm.nih.gov/15273247/ DOI: 10.1074/jbc.m402759200

experimental_model

Proteoliposomes and native disc transport assays

limitations

The assayed substrate is the adduct, not a requirement for free retinal diffusion.

nutrient_topic

Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A

organism

Bovine/mouse discs; recombinant transporter

plain_language

ABCA4 moves the trapped retinal-lipid adduct to the disposal side of the disc.

primary_references

[quazi-2012] ABCA4 is an N-retinylidene-phosphatidylethanolamine and phosphatidylethanolamine importer (2012). https://pmc.ncbi.nlm.nih.gov/articles/PMC3871175/ DOI: 10.1038/ncomms1927

tissue_or_cell_type

Photoreceptor disc membrane

transport_direction

disc lumen leaflet to cytoplasmic leaflet

transport_effect

raises Recorded as ATP-dependent transport from the disc lumen-facing leaflet toward the cytoplasmic leaflet.

transport_pool

the cytoplasmic leaflet of the disc membrane Recorded as ATP-dependent transport from the disc lumen-facing leaflet toward the cytoplasmic leaflet.

Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 801–811

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Proteoliposomes and native disc transport assays · source_derived_draft · unverified_draft

### a-vision-abca4-retinoid-flip ABCA4 drove ATP-dependent transport of retinal-PE adduct from the disc lumen-facing leaflet toward the cytoplasmic leaflet. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: ABCA4 moves the trapped retinal-lipid adduct to the disposal side of the disc. organism: Bovine/mouse discs; recombinant transporter tissue_or_cell_type: Photoreceptor disc membrane experimental_model: Proteoliposomes and native disc transport assays limitations: The assayed substrate is the adduct, not a requirement for free retinal diffusion. transport_direction: disc lumen leaflet to cytoplasmic leaflet [quazi-2012] ABCA4 is an N-retinylidene-phosphatidylethanolamine and phosphatidylethanolamine importer (2012). https://pmc.ncbi.nlm.nih.gov/articles/PMC3871175/ DOI: 10.1038/ncomms1927

evidence_access

Primary full text

experimental_model

Human recombinant ASNS structural and biochemical study; reaction characterized in the study framework.

limitations

A functioning reaction does not guarantee that adding substrate raises the product in every tissue. Correction record: The 2019 author correction added omitted author affiliations and funding acknowledgements; no mechanism or data change was stated. PMID 31799439; DOI 10.1038/s42003-019-0690-1. https://www.nature.com/articles/s42003-019-0690-1

nutrient_topic

L-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Aspartate

plain_language

Making asparagine needs both aspartate and a nitrogen donor, plus energy.

primary_references

High-resolution crystal structure of human asparagine synthetase enables analysis of inhibitor binding and selectivity. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31552298/ · DOI 10.1038/s42003-019-0587-z

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 186–192

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human recombinant ASNS structural and biochemical study; reaction characterized in the study framework. · source_derived_draft · unverified_draft

## l-aspartate-asns-reaction Making asparagine needs both aspartate and a nitrogen donor, plus energy. Human ASNS catalyzes ATP-dependent conversion of aspartate and glutamine to asparagine and glutamate through coupled glutaminase and synthetase chemistry. Model: Human recombinant ASNS structural and biochemical study; reaction characterized in the study framework. Limitations: A functioning reaction does not guarantee that adding substrate raises the product in every tissue. Correction record: The 2019 author correction added omitted author affiliations and funding acknowledgements; no mechanism or data change was stated. PMID 31799439; DOI 10.1038/s42003-019-0690-1. https://www.nature.com/articles/s42003-019-0690-1 Evidence access: Primary full text High-resolution crystal structure of human asparagine synthetase enables analysis of inhibitor binding and selectivity. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31552298/ · DOI 10.1038/s42003-019-0587-z

evidence_access

Primary full text

experimental_model

Human ASNS 1.85-angstrom structure and comparison with mechanistic data.

limitations

Structural interpretation is distinguished from measuring every transient chemical intermediate in intact cells. Correction record: The 2019 author correction added omitted author affiliations and funding acknowledgements; no mechanism or data change was stated. PMID 31799439; DOI 10.1038/s42003-019-0690-1. https://www.nature.com/articles/s42003-019-0690-1

nutrient_topic

L-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Aspartate

plain_language

The enzyme coordinates two reactions rather than attaching free glutamine directly to aspartate.

primary_references

High-resolution crystal structure of human asparagine synthetase enables analysis of inhibitor binding and selectivity. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31552298/ · DOI 10.1038/s42003-019-0587-z

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 194–200

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human ASNS 1.85-angstrom structure and comparison with mechanistic data. · source_derived_draft · unverified_draft

## l-aspartate-asns-two-sites The enzyme coordinates two reactions rather than attaching free glutamine directly to aspartate. The human ASNS structure separates glutamine-processing and ATP-dependent synthetase domains, with an internal path supporting nitrogen transfer toward activated aspartate. Model: Human ASNS 1.85-angstrom structure and comparison with mechanistic data. Limitations: Structural interpretation is distinguished from measuring every transient chemical intermediate in intact cells. Correction record: The 2019 author correction added omitted author affiliations and funding acknowledgements; no mechanism or data change was stated. PMID 31799439; DOI 10.1038/s42003-019-0690-1. https://www.nature.com/articles/s42003-019-0690-1 Evidence access: Primary full text High-resolution crystal structure of human asparagine synthetase enables analysis of inhibitor binding and selectivity. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31552298/ · DOI 10.1038/s42003-019-0587-z

evidence_access

Primary full text

experimental_model

Human HEK293E CAD expression, phosphosite mutation and kinase assays; complementary mouse cell tracing.

limitations

This is a signaling dependency, not evidence that a specific nutrient supplement necessarily increases CAD activity.

nutrient_topic

L-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Aspartate

plain_language

Growth signals can accelerate use of aspartate for nucleotide production.

primary_references

Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23429703/ · DOI 10.1126/science.1228792

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 154–160

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human HEK293E CAD expression, phosphosite mutation and kinase assays; complementary mouse cell tracing. · source_derived_draft · unverified_draft

## l-aspartate-cad-s6k1 Growth signals can accelerate use of aspartate for nucleotide production. S6K1 directly phosphorylated CAD at Ser1859, connecting mTORC1 signaling to increased de novo pyrimidine synthesis. Model: Human HEK293E CAD expression, phosphosite mutation and kinase assays; complementary mouse cell tracing. Limitations: This is a signaling dependency, not evidence that a specific nutrient supplement necessarily increases CAD activity. Evidence access: Primary full text Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23429703/ · DOI 10.1126/science.1228792

evidence_access

Primary full text

experimental_model

Human recombinant cytosolic enzyme structural study.

limitations

Structural suggestions about release from the multisynthetase complex are not treated as demonstrated nutrient signaling.

nutrient_topic

L-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Aspartate

plain_language

Aspartate must be placed on the correct transfer RNA to enter proteins.

primary_references

Crystal structure of human cytosolic aspartyl-tRNA synthetase, a component of multi-tRNA synthetase complex. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23609930/ · DOI 10.1002/prot.24306

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 354–360

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human recombinant cytosolic enzyme structural study. · source_derived_draft · unverified_draft

## l-aspartate-dars1-translation Aspartate must be placed on the correct transfer RNA to enter proteins. Human cytosolic DARS1 catalyzes attachment of aspartate to its cognate tRNA; its 2.25-angstrom homodimer structure defines the cytosolic enzyme separately from mitochondrial DARS2. Model: Human recombinant cytosolic enzyme structural study. Limitations: Structural suggestions about release from the multisynthetase complex are not treated as demonstrated nutrient signaling. Evidence access: Primary full text Crystal structure of human cytosolic aspartyl-tRNA synthetase, a component of multi-tRNA synthetase complex. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23609930/ · DOI 10.1002/prot.24306

evidence_access

Primary full text

experimental_model

Purified human mitochondrial DARS2, crystallography and isothermal titration calorimetry.

limitations

Bacterial structural comparison is not a human aspartate-deficiency model or proof of supplement rescue.

nutrient_topic

L-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Aspartate

plain_language

Mitochondrial translation has its own aspartate-handling machinery.

primary_references

Thermodynamic properties distinguish human mitochondrial aspartyl-tRNA synthetase from bacterial homolog with same 3D architecture. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23275545/ · DOI 10.1093/nar/gks1322

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 362–368

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Purified human mitochondrial DARS2, crystallography and isothermal titration calorimetry. · source_derived_draft · unverified_draft

## l-aspartate-dars2-compartment Mitochondrial translation has its own aspartate-handling machinery. Human mitochondrial aspartyl-tRNA synthetase showed a broader catalytic groove and distinct tRNA-binding thermodynamics compared with its bacterial structural homologue. Model: Purified human mitochondrial DARS2, crystallography and isothermal titration calorimetry. Limitations: Bacterial structural comparison is not a human aspartate-deficiency model or proof of supplement rescue. Evidence access: Primary full text Thermodynamic properties distinguish human mitochondrial aspartyl-tRNA synthetase from bacterial homolog with same 3D architecture. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23275545/ · DOI 10.1093/nar/gks1322

evidence_span

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experimental_model

Biochemical Akt regulation and targeted mouse Ip6k1 deletion

exposure

5-InsP7 and Ip6k1 knockout

limitations

Whole-gene deletion is not equivalent to adding or withdrawing free myo-inositol; the reported therapeutic proposal is not established treatment.

nutrient_topic

Inositol research collection; topical membership is not evidence of a direct dietary effect. · Inositol (stereoisomer family)

organism

Mammalian enzymology and Mus musculus

plain_language

Adding a phosphate onto an existing phosphate makes an inositol pyrophosphate.

primary_references

[ino-p21145457] Inositol pyrophosphates inhibit Akt signaling, thereby regulating insulin sensitivity and weight gain. (2010). https://pubmed.ncbi.nlm.nih.gov/21145457/ DOI: 10.1016/j.cell.2010.11.032

tissue_or_cell_type

Muscle, adipose tissue and liver

Inositol: synthesis, signaling, mineral interactions and conditional deficiency (2026-09-17) · lines 769–780

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Biochemical Akt regulation and targeted mouse Ip6k1 deletion · source_derived_draft · unverified_draft

### ino-ip6k-ip7 IP6K enzymes form 5-InsP7 from InsP6. Condition category: normal nutrient_topic: Inositol research collection; topical membership is not evidence of a direct dietary effect. plain_language: Adding a phosphate onto an existing phosphate makes an inositol pyrophosphate. organism: Mammalian enzymology and Mus musculus tissue_or_cell_type: Muscle, adipose tissue and liver experimental_model: Biochemical Akt regulation and targeted mouse Ip6k1 deletion limitations: Whole-gene deletion is not equivalent to adding or withdrawing free myo-inositol; the reported therapeutic proposal is not established treatment. exposure: 5-InsP7 and Ip6k1 knockout evidence_span: {"source_cache": "artifacts/inositol-research/21145457.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0de0a9c3ea11cd8ce59bccff69a41139b11e11182fd9fd66016ec72ba329a5ce", "start_char": 0, "end_char": 889, "text_sha256": "0de0a9c3ea11cd8ce59bccff69a41139b11e11182fd9fd66016ec72ba329a5ce"} [ino-p21145457] Inositol pyrophosphates inhibit Akt signaling, thereby regulating insulin sensitivity and weight gain. (2010). https://pubmed.ncbi.nlm.nih.gov/21145457/ DOI: 10.1016/j.cell.2010.11.032

evidence_span

{"source_cache": "artifacts/inositol-research/12084730.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7e44dbc7039048a53bffd92fd69dfa1f35f1dc762389c8d810f913ea70e10c80", "start_char": 0, "end_char": 1407, "text_sha256": "7e44dbc7039048a53bffd92fd69dfa1f35f1dc762389c8d810f913ea70e10c80"}

experimental_model

Recombinant kinase and yeast complementation

exposure

Inositol pentakisphosphate and ATP assays

limitations

Human enzyme activity; yeast rescue is not a clinical supplementation trial.

nutrient_topic

Inositol research collection; topical membership is not evidence of a direct dietary effect. · Inositol (stereoisomer family)

organism

Human IPPK expressed in Sf21 cells

plain_language

The cell can make the six-phosphate inositol molecule inside itself.

primary_references

[ino-p12084730] The synthesis of inositol hexakisphosphate. Characterization of human inositol 1,3,4,5,6-pentakisphosphate 2-kinase. (2002). https://pubmed.ncbi.nlm.nih.gov/12084730/ DOI: 10.1074/jbc.m205682200

tissue_or_cell_type

Purified kinase

Inositol: synthesis, signaling, mineral interactions and conditional deficiency (2026-09-17) · lines 743–754

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant kinase and yeast complementation · source_derived_draft · unverified_draft

### ino-ippk-ip6 Human IPPK used ATP to phosphorylate inositol 1,3,4,5,6-pentakisphosphate at position 2, producing InsP6. Condition category: normal nutrient_topic: Inositol research collection; topical membership is not evidence of a direct dietary effect. plain_language: The cell can make the six-phosphate inositol molecule inside itself. organism: Human IPPK expressed in Sf21 cells tissue_or_cell_type: Purified kinase experimental_model: Recombinant kinase and yeast complementation limitations: Human enzyme activity; yeast rescue is not a clinical supplementation trial. exposure: Inositol pentakisphosphate and ATP assays evidence_span: {"source_cache": "artifacts/inositol-research/12084730.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7e44dbc7039048a53bffd92fd69dfa1f35f1dc762389c8d810f913ea70e10c80", "start_char": 0, "end_char": 1407, "text_sha256": "7e44dbc7039048a53bffd92fd69dfa1f35f1dc762389c8d810f913ea70e10c80"} [ino-p12084730] The synthesis of inositol hexakisphosphate. Characterization of human inositol 1,3,4,5,6-pentakisphosphate 2-kinase. (2002). https://pubmed.ncbi.nlm.nih.gov/12084730/ DOI: 10.1074/jbc.m205682200

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/inositol-research/28126903.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6f5c96ed7d02591d5fe475d0e26aa2f21dc93f0c86c12998debb417f98254d2f", "start_char": 0, "end_char": 1981, "text_sha256": "6f5c96ed7d02591d5fe475d0e26aa2f21dc93f0c86c12998debb417f98254d2f"}

experimental_model

Cellular phosphate withdrawal/repletion and bifunctional enzyme kinetics

exposure

Phosphate availability and PPIP5K kinase/phosphatase assays

limitations

Cell-culture nutrient withdrawal is not a measured human dietary threshold; PPIP5K isoforms are not identical.

nutrient_topic

Inositol research collection; topical membership is not evidence of a direct dietary effect. · Inositol (stereoisomer family)

organism

Human HCT116 cells and human PPIP5K proteins

plain_language

The signaling network detects phosphate supply instead of depending only on the amount of free inositol.

primary_references

[ino-p28126903] The Significance of the Bifunctional Kinase/Phosphatase Activities of Diphosphoinositol Pentakisphosphate Kinases (PPIP5Ks) for Coupling Inositol Pyrophosphate Cell Signaling to Cellular Phosphate Homeostasis. (2017). https://pubmed.ncbi.nlm.nih.gov/28126903/ DOI: 10.1074/jbc.m116.765743

tissue_or_cell_type

Intestinal tumor-derived cell line; purified enzymes

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Inositol: synthesis, signaling, mineral interactions and conditional deficiency (2026-09-17) · lines 860–871

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cellular phosphate withdrawal/repletion and bifunctional enzyme kinetics · source_derived_draft · unverified_draft

### ino-phosphate-ip8 Phosphate starvation lowered ATP and 5-InsP7, while InsP8 showed a larger and more sensitive response; levels recovered with phosphate replenishment. Condition category: nutrient_deficiency nutrient_topic: Inositol research collection; topical membership is not evidence of a direct dietary effect. plain_language: The signaling network detects phosphate supply instead of depending only on the amount of free inositol. organism: Human HCT116 cells and human PPIP5K proteins tissue_or_cell_type: Intestinal tumor-derived cell line; purified enzymes experimental_model: Cellular phosphate withdrawal/repletion and bifunctional enzyme kinetics limitations: Cell-culture nutrient withdrawal is not a measured human dietary threshold; PPIP5K isoforms are not identical. exposure: Phosphate availability and PPIP5K kinase/phosphatase assays evidence_span: {"source_cache": "artifacts/inositol-research/28126903.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6f5c96ed7d02591d5fe475d0e26aa2f21dc93f0c86c12998debb417f98254d2f", "start_char": 0, "end_char": 1981, "text_sha256": "6f5c96ed7d02591d5fe475d0e26aa2f21dc93f0c86c12998debb417f98254d2f"} [ino-p28126903] The Significance of the Bifunctional Kinase/Phosphatase Activities of Diphosphoinositol Pentakisphosphate Kinases (PPIP5Ks) for Coupling Inositol Pyrophosphate Cell Signaling to Cellular Phosphate Homeostasis. (2017). https://pubmed.ncbi.nlm.nih.gov/28126903/ DOI: 10.1074/jbc.m116.765743

evidence_span

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experimental_model

Recombinant human PI4K230 enzyme characterization

exposure

ATP-dependent kinase assays

limitations

An enzyme reaction does not establish that free inositol supplementation increases signaling.

nutrient_topic

Inositol research collection; topical membership is not evidence of a direct dietary effect. · Inositol (stereoisomer family)

organism

Human protein expressed in Sf9 cells

plain_language

An enzyme adds a phosphate at position 4 of the PI head group.

primary_references

[ino-p10101268] Functional expression and characterisation of a new human phosphatidylinositol 4-kinase PI4K230. (1999). https://pubmed.ncbi.nlm.nih.gov/10101268/ DOI: 10.1016/s1388-1981(99)00029-3

tissue_or_cell_type

Recombinant PI4KA

Inositol: synthesis, signaling, mineral interactions and conditional deficiency (2026-09-17) · lines 561–572

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human PI4K230 enzyme characterization · source_derived_draft · unverified_draft

### ino-pi4ka-pi4p Recombinant human PI4K230, now designated PI4KA, showed phosphatidylinositol 4-kinase activity. Condition category: normal nutrient_topic: Inositol research collection; topical membership is not evidence of a direct dietary effect. plain_language: An enzyme adds a phosphate at position 4 of the PI head group. organism: Human protein expressed in Sf9 cells tissue_or_cell_type: Recombinant PI4KA experimental_model: Recombinant human PI4K230 enzyme characterization limitations: An enzyme reaction does not establish that free inositol supplementation increases signaling. exposure: ATP-dependent kinase assays evidence_span: {"source_cache": "artifacts/inositol-research/10101268.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "fa5bbd801387ed6401fcba3b21ddc260a21a089c33818db5abcfea346b3db5d0", "start_char": 0, "end_char": 1101, "text_sha256": "fa5bbd801387ed6401fcba3b21ddc260a21a089c33818db5abcfea346b3db5d0"} [ino-p10101268] Functional expression and characterisation of a new human phosphatidylinositol 4-kinase PI4K230. (1999). https://pubmed.ncbi.nlm.nih.gov/10101268/ DOI: 10.1016/s1388-1981(99)00029-3

evidence_span

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experimental_model

Human splice-isoform expression, localization and kinase assay

exposure

PIP5K1C_i4 and i5 characterization

limitations

Isoforms have different localizations; a bulk lipid concentration cannot describe every local pool.

nutrient_topic

Inositol research collection; topical membership is not evidence of a direct dietary effect. · Inositol (stereoisomer family)

organism

Human proteins in cellular expression assays

plain_language

This isoform can make PI(4,5)P2 from PI4P.

primary_references

[ino-p19548880] Two novel phosphatidylinositol-4-phosphate 5-kinase type Igamma splice variants expressed in human cells display distinctive cellular targeting. (2009). https://pubmed.ncbi.nlm.nih.gov/19548880/ DOI: 10.1042/bj20090638

tissue_or_cell_type

Nuclear and vesicular compartments

Inositol: synthesis, signaling, mineral interactions and conditional deficiency (2026-09-17) · lines 574–585

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human splice-isoform expression, localization and kinase assay · source_derived_draft · unverified_draft

### ino-pip5k-i4 Human PIP5K1C_i4 displayed PI4P 5-kinase activity in vitro. Condition category: normal nutrient_topic: Inositol research collection; topical membership is not evidence of a direct dietary effect. plain_language: This isoform can make PI(4,5)P2 from PI4P. organism: Human proteins in cellular expression assays tissue_or_cell_type: Nuclear and vesicular compartments experimental_model: Human splice-isoform expression, localization and kinase assay limitations: Isoforms have different localizations; a bulk lipid concentration cannot describe every local pool. exposure: PIP5K1C_i4 and i5 characterization evidence_span: {"source_cache": "artifacts/inositol-research/19548880.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5ae150d47bf139d7352c8a5a128e0d6b071340f8c47d78700d5f398a549d3cd8", "start_char": 0, "end_char": 1766, "text_sha256": "5ae150d47bf139d7352c8a5a128e0d6b071340f8c47d78700d5f398a549d3cd8"} [ino-p19548880] Two novel phosphatidylinositol-4-phosphate 5-kinase type Igamma splice variants expressed in human cells display distinctive cellular targeting. (2009). https://pubmed.ncbi.nlm.nih.gov/19548880/ DOI: 10.1042/bj20090638

evidence_span

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experimental_model

Human splice-isoform expression, localization and kinase assay

exposure

PIP5K1C_i4 and i5 characterization

limitations

Isoforms have different localizations; a bulk lipid concentration cannot describe every local pool.

nutrient_topic

Inositol research collection; topical membership is not evidence of a direct dietary effect. · Inositol (stereoisomer family)

organism

Human proteins in cellular expression assays

plain_language

A separately identified isoform can carry out the same chemical step.

primary_references

[ino-p19548880] Two novel phosphatidylinositol-4-phosphate 5-kinase type Igamma splice variants expressed in human cells display distinctive cellular targeting. (2009). https://pubmed.ncbi.nlm.nih.gov/19548880/ DOI: 10.1042/bj20090638

tissue_or_cell_type

Nuclear and vesicular compartments

Inositol: synthesis, signaling, mineral interactions and conditional deficiency (2026-09-17) · lines 587–598

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human splice-isoform expression, localization and kinase assay · source_derived_draft · unverified_draft

### ino-pip5k-i5 Human PIP5K1C_i5 also displayed PI4P 5-kinase activity in vitro. Condition category: normal nutrient_topic: Inositol research collection; topical membership is not evidence of a direct dietary effect. plain_language: A separately identified isoform can carry out the same chemical step. organism: Human proteins in cellular expression assays tissue_or_cell_type: Nuclear and vesicular compartments experimental_model: Human splice-isoform expression, localization and kinase assay limitations: Isoforms have different localizations; a bulk lipid concentration cannot describe every local pool. exposure: PIP5K1C_i4 and i5 characterization evidence_span: {"source_cache": "artifacts/inositol-research/19548880.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5ae150d47bf139d7352c8a5a128e0d6b071340f8c47d78700d5f398a549d3cd8", "start_char": 0, "end_char": 1766, "text_sha256": "5ae150d47bf139d7352c8a5a128e0d6b071340f8c47d78700d5f398a549d3cd8"} [ino-p19548880] Two novel phosphatidylinositol-4-phosphate 5-kinase type Igamma splice variants expressed in human cells display distinctive cellular targeting. (2009). https://pubmed.ncbi.nlm.nih.gov/19548880/ DOI: 10.1042/bj20090638

evidence_span

{"source_cache": "artifacts/inositol-research/28126903.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6f5c96ed7d02591d5fe475d0e26aa2f21dc93f0c86c12998debb417f98254d2f", "start_char": 0, "end_char": 1981, "text_sha256": "6f5c96ed7d02591d5fe475d0e26aa2f21dc93f0c86c12998debb417f98254d2f"}

experimental_model

Cellular phosphate withdrawal/repletion and bifunctional enzyme kinetics

exposure

Phosphate availability and PPIP5K kinase/phosphatase assays

limitations

Cell-culture nutrient withdrawal is not a measured human dietary threshold; PPIP5K isoforms are not identical.

nutrient_topic

Inositol research collection; topical membership is not evidence of a direct dietary effect. · Inositol (stereoisomer family)

organism

Human HCT116 cells and human PPIP5K proteins

plain_language

A further phosphorylation step creates another distinct phosphate signal.

primary_references

[ino-p28126903] The Significance of the Bifunctional Kinase/Phosphatase Activities of Diphosphoinositol Pentakisphosphate Kinases (PPIP5Ks) for Coupling Inositol Pyrophosphate Cell Signaling to Cellular Phosphate Homeostasis. (2017). https://pubmed.ncbi.nlm.nih.gov/28126903/ DOI: 10.1074/jbc.m116.765743

tissue_or_cell_type

Intestinal tumor-derived cell line; purified enzymes

Inositol: synthesis, signaling, mineral interactions and conditional deficiency (2026-09-17) · lines 808–819

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cellular phosphate withdrawal/repletion and bifunctional enzyme kinetics · source_derived_draft · unverified_draft

### ino-ppip5k-ip8 PPIP5K kinase activity converts 5-InsP7 to 1,5-InsP8. Condition category: normal nutrient_topic: Inositol research collection; topical membership is not evidence of a direct dietary effect. plain_language: A further phosphorylation step creates another distinct phosphate signal. organism: Human HCT116 cells and human PPIP5K proteins tissue_or_cell_type: Intestinal tumor-derived cell line; purified enzymes experimental_model: Cellular phosphate withdrawal/repletion and bifunctional enzyme kinetics limitations: Cell-culture nutrient withdrawal is not a measured human dietary threshold; PPIP5K isoforms are not identical. exposure: Phosphate availability and PPIP5K kinase/phosphatase assays evidence_span: {"source_cache": "artifacts/inositol-research/28126903.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6f5c96ed7d02591d5fe475d0e26aa2f21dc93f0c86c12998debb417f98254d2f", "start_char": 0, "end_char": 1981, "text_sha256": "6f5c96ed7d02591d5fe475d0e26aa2f21dc93f0c86c12998debb417f98254d2f"} [ino-p28126903] The Significance of the Bifunctional Kinase/Phosphatase Activities of Diphosphoinositol Pentakisphosphate Kinases (PPIP5Ks) for Coupling Inositol Pyrophosphate Cell Signaling to Cellular Phosphate Homeostasis. (2017). https://pubmed.ncbi.nlm.nih.gov/28126903/ DOI: 10.1074/jbc.m116.765743

evidence_access

Primary abstract

experimental_model

Nine healthy men; six-day creatine loading 0.5 g/kg/day, with or without caffeine 5 mg/kg/day; intermittent knee-extensor testing.

limitations

Small protocol-specific trial. Creatine accumulation and performance were separate endpoints.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

Caffeine did not block the measured phosphocreatine increase.

primary_references

Caffeine counteracts the ergogenic action of muscle creatine loading. · 1996 · https://pubmed.ncbi.nlm.nih.gov/8929583/ · DOI 10.1152/jappl.1996.80.2.452

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 444–450

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Nine healthy men; six-day creatine loading 0.5 g/kg/day, with or without caffeine 5 mg/kg/day; intermittent knee-extensor testing. · source_derived_draft · unverified_draft

## caf-creatine-pcr Caffeine did not block the measured phosphocreatine increase. Creatine alone and creatine plus caffeine each increased muscle phosphocreatine by 4–6%; measured ATP stayed constant. Model: Nine healthy men; six-day creatine loading 0.5 g/kg/day, with or without caffeine 5 mg/kg/day; intermittent knee-extensor testing. Limitations: Small protocol-specific trial. Creatine accumulation and performance were separate endpoints. Evidence access: Primary abstract Caffeine counteracts the ergogenic action of muscle creatine loading. · 1996 · https://pubmed.ncbi.nlm.nih.gov/8929583/ · DOI 10.1152/jappl.1996.80.2.452

experimental_model

Formate rescue and metabolomics

exposure

Carbon-13 formate tracer in wild-type cells; Figure 2d.

limitations

Tracing supports pathway use but is not an isolated enzyme assay or dietary recommendation.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

Cells incorporate formate carbon into purine nucleotides.

primary_references

[ducker-2016] Reversal of Cytosolic One-Carbon Flux Compensates for Loss of the Mitochondrial Folate Pathway (2016). https://pubmed.ncbi.nlm.nih.gov/27211901/ DOI: 10.1016/j.cmet.2016.04.016

tissue_or_cell_type

HEK293T cells

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 911–921

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Formate rescue and metabolomics · source_derived_draft · unverified_draft

### formate-mthfd1-assimilation Provided carbon-13 formate entered cytosolic 10-formyl-THF and ATP in wild-type HEK293T cells through the MTHFD1 assimilation route. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Cells incorporate formate carbon into purine nucleotides. organism: Homo sapiens tissue_or_cell_type: HEK293T cells experimental_model: Formate rescue and metabolomics limitations: Tracing supports pathway use but is not an isolated enzyme assay or dietary recommendation. exposure: Carbon-13 formate tracer in wild-type cells; Figure 2d. [ducker-2016] Reversal of Cytosolic One-Carbon Flux Compensates for Loss of the Mitochondrial Folate Pathway (2016). https://pubmed.ncbi.nlm.nih.gov/27211901/ DOI: 10.1016/j.cmet.2016.04.016

cross_nutrient

ATP and NADPH support folate-mediated carbon use.

experimental_model

Localization and folate-pathway experiments

exposure

Assay conditions described in the linked primary study.

limitations

Compartmental flux varies with cell cycle.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

Formate can feed DNA-base production inside the nucleus.

primary_references

[field-2014] Nuclear enrichment of folate cofactors and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) protect de novo thymidylate biosynthesis during folate deficiency (2014). https://pubmed.ncbi.nlm.nih.gov/25213861/ DOI: 10.1074/jbc.m114.599589

tissue_or_cell_type

HeLa and MCF7 cells

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 936–947

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Localization and folate-pathway experiments · source_derived_draft · unverified_draft

### mthfd1-formate-nuclear-carbon Nuclear MTHFD1 supplies formate-derived one-carbon units for thymidylate synthesis through its folate-interconversion activities. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Formate can feed DNA-base production inside the nucleus. organism: Homo sapiens tissue_or_cell_type: HeLa and MCF7 cells experimental_model: Localization and folate-pathway experiments limitations: Compartmental flux varies with cell cycle. exposure: Assay conditions described in the linked primary study. cross_nutrient: ATP and NADPH support folate-mediated carbon use. [field-2014] Nuclear enrichment of folate cofactors and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) protect de novo thymidylate biosynthesis during folate deficiency (2014). https://pubmed.ncbi.nlm.nih.gov/25213861/ DOI: 10.1074/jbc.m114.599589

availability_state

biomarker_context Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/aspirin-research/25256746.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e8cd347665e1de7dc2cadee06da087e2526d4fc11aefef6f7ce15cb33f6234c2", "start_char": 0, "end_char": 1171, "text_sha256": "e8cd347665e1de7dc2cadee06da087e2526d4fc11aefef6f7ce15cb33f6234c2"}

experimental_model

Incubation of rat fast-twitch epitrochlearis and slow-twitch soleus muscle with salicylate

exposure

Salicylate applied to isolated muscle with glucose transport and nucleotide measurements

limitations

Adds the tissue and the energy measurements. Isolated muscle at concentrations set by the incubation buffer, which is not a plasma concentration.

nutrient_topic

Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. · Aspirin / acetylsalicylic acid

organism

Rat

plain_language

Muscle takes up more glucose without any help from insulin, and its energy stores fall while it happens.

primary_references

[asa-p25256746] Salicylate acutely stimulates 5'-AMP-activated protein kinase and insulin-independent glucose transport in rat skeletal muscles. (2014). https://pubmed.ncbi.nlm.nih.gov/25256746/ DOI: 10.1016/j.bbrc.2014.09.066

tissue_or_cell_type

Skeletal muscle

trigger_kind

biomarker_context Imported condition classification; unverified.

Aspirin: the serine it acetylates, the enzyme that acetylation creates, the dose that separates platelet from vessel wall, and the metabolite that is a different drug (2026-09-22) · lines 507–518

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Incubation of rat fast-twitch epitrochlearis and slow-twitch soleus muscle with salicylate · source_derived_draft · unverified_draft

### asa-muscle-glucose-uptake Intracellular salicylate concentrations increased within five minutes in both rat fast-twitch and slow-twitch muscle, threonine-172 phosphorylation of the AMP-activated protein kinase alpha subunit increased dose- and time-dependently with increases in both alpha-1 and alpha-2 activity, and these were accompanied by increased 3-O-methyl-D-glucose transport and decreases in ATP, phosphocreatine and glycogen, while phosphorylation of insulin receptor substrate 1, Akt and p70 S6 kinase was unchanged. Condition category: biomarker_context nutrient_topic: Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. plain_language: Muscle takes up more glucose without any help from insulin, and its energy stores fall while it happens. organism: Rat tissue_or_cell_type: Skeletal muscle experimental_model: Incubation of rat fast-twitch epitrochlearis and slow-twitch soleus muscle with salicylate limitations: Adds the tissue and the energy measurements. Isolated muscle at concentrations set by the incubation buffer, which is not a plasma concentration. exposure: Salicylate applied to isolated muscle with glucose transport and nucleotide measurements evidence_span: {"source_cache": "artifacts/aspirin-research/25256746.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e8cd347665e1de7dc2cadee06da087e2526d4fc11aefef6f7ce15cb33f6234c2", "start_char": 0, "end_char": 1171, "text_sha256": "e8cd347665e1de7dc2cadee06da087e2526d4fc11aefef6f7ce15cb33f6234c2"} [asa-p25256746] Salicylate acutely stimulates 5'-AMP-activated protein kinase and insulin-independent glucose transport in rat skeletal muscles. (2014). https://pubmed.ncbi.nlm.nih.gov/25256746/ DOI: 10.1016/j.bbrc.2014.09.066

cross_nutrient

false

experimental_model

Recombinant human PPCS, PPCDC and COASY expressed in Escherichia coli; coupled enzyme assays and HPLC reconstitution

exposure

Forward PPAT assays: 5–500 micromolar phosphopantetheine and 5 mM ATP; 0.15–0.3 micrograms/mL recombinant COASY.

limitations

Direct biochemical reaction, distinct from the final phosphorylation; does not establish efficient entry of an oral intermediate into human cells.

nutrient_topic

Pantothenic acid (vitamin B5) research collection; topical membership is not evidence of a direct dietary effect. · Pantothenate (vitamin B5)

organism

Homo sapiens

plain_language

COASY adds the adenosine-containing portion of CoA.

primary_references

[b5-bio-daugherty2002] Complete reconstitution of the human coenzyme A biosynthetic pathway via comparative genomics. (2002). https://pubmed.ncbi.nlm.nih.gov/11923312/ DOI: 10.1074/jbc.m201708200

tissue_or_cell_type

Purified recombinant protein; no intact tissue

Pantothenic acid (vitamin B5): coenzyme A, deficiency and nutrient interactions (2026-09-17) · lines 574–585

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human PPCS, PPCDC and COASY expressed in Escherichia coli; coupled enzyme assays and HPLC reconstitution · source_derived_draft · unverified_draft

### b5-bio-coasy-adenylylation Human COASY phosphopantetheine adenylyltransferase activity used ATP and 4′-phosphopantetheine to form dephospho-CoA. Condition category: normal nutrient_topic: Pantothenic acid (vitamin B5) research collection; topical membership is not evidence of a direct dietary effect. plain_language: COASY adds the adenosine-containing portion of CoA. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Recombinant human PPCS, PPCDC and COASY expressed in Escherichia coli; coupled enzyme assays and HPLC reconstitution limitations: Direct biochemical reaction, distinct from the final phosphorylation; does not establish efficient entry of an oral intermediate into human cells. exposure: Forward PPAT assays: 5–500 micromolar phosphopantetheine and 5 mM ATP; 0.15–0.3 micrograms/mL recombinant COASY. cross_nutrient: false [b5-bio-daugherty2002] Complete reconstitution of the human coenzyme A biosynthetic pathway via comparative genomics. (2002). https://pubmed.ncbi.nlm.nih.gov/11923312/ DOI: 10.1074/jbc.m201708200

cross_nutrient

false

experimental_model

Recombinant human PPCS, PPCDC and COASY expressed in Escherichia coli; coupled enzyme assays and HPLC reconstitution

exposure

DPCK assay: 5–100 micromolar dephospho-CoA, 1 mM ATP; coupled ADP readout and direct HPLC product analysis.

limitations

Recombinant enzyme and truncation studies define two distinct COASY activities; no whole-body nutritional threshold is measured.

nutrient_topic

Pantothenic acid (vitamin B5) research collection; topical membership is not evidence of a direct dietary effect. · Pantothenate (vitamin B5)

organism

Homo sapiens

plain_language

The final COASY reaction completes CoA.

primary_references

[b5-bio-daugherty2002] Complete reconstitution of the human coenzyme A biosynthetic pathway via comparative genomics. (2002). https://pubmed.ncbi.nlm.nih.gov/11923312/ DOI: 10.1074/jbc.m201708200

tissue_or_cell_type

Purified recombinant protein; no intact tissue

Pantothenic acid (vitamin B5): coenzyme A, deficiency and nutrient interactions (2026-09-17) · lines 587–598

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human PPCS, PPCDC and COASY expressed in Escherichia coli; coupled enzyme assays and HPLC reconstitution · source_derived_draft · unverified_draft

### b5-bio-coasy-phosphorylation Human COASY dephospho-CoA kinase activity phosphorylated dephospho-CoA to CoA using ATP; deleting the C-terminal domain retained PPAT but removed DPCK activity. Condition category: normal nutrient_topic: Pantothenic acid (vitamin B5) research collection; topical membership is not evidence of a direct dietary effect. plain_language: The final COASY reaction completes CoA. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Recombinant human PPCS, PPCDC and COASY expressed in Escherichia coli; coupled enzyme assays and HPLC reconstitution limitations: Recombinant enzyme and truncation studies define two distinct COASY activities; no whole-body nutritional threshold is measured. exposure: DPCK assay: 5–100 micromolar dephospho-CoA, 1 mM ATP; coupled ADP readout and direct HPLC product analysis. cross_nutrient: false [b5-bio-daugherty2002] Complete reconstitution of the human coenzyme A biosynthetic pathway via comparative genomics. (2002). https://pubmed.ncbi.nlm.nih.gov/11923312/ DOI: 10.1074/jbc.m201708200

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

experimental_model

Two unrelated human NBIA cases, primary fibroblasts, recombinant wild-type and variant COASY DPCK domains and yeast studies

exposure

HPLC assays with 1 microgram recombinant wild-type or p.Arg499Cys DPCK protein, ATP and dephospho-CoA; substrate concentrations not extracted.

limitations

Loss of detectable isolated-domain activity does not mean that every patient cell has no CoA. Wild-type and variant domains were recombinantly produced in bacteria.

nutrient_topic

Pantothenic acid (vitamin B5) research collection; topical membership is not evidence of a direct dietary effect. · Pantothenate (vitamin B5)

organism

Homo sapiens

plain_language

This COASY variant disabled the final reaction in the isolated-enzyme test.

primary_references

[b5-bio-coasy2014] Exome sequence reveals mutations in CoA synthase as a cause of neurodegeneration with brain iron accumulation. (2014). https://pubmed.ncbi.nlm.nih.gov/24360804/ DOI: 10.1016/j.ajhg.2013.11.008

tissue_or_cell_type

Purified recombinant protein; no intact tissue

trigger_kind

machinery_impairment Imported condition classification; unverified.

Pantothenic acid (vitamin B5): coenzyme A, deficiency and nutrient interactions (2026-09-17) · lines 730–741

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Two unrelated human NBIA cases, primary fibroblasts, recombinant wild-type and variant COASY DPCK domains and yeast studies · source_derived_draft · unverified_draft

### b5-bio-coasy-r499c-activity The recombinant COASY DPCK domain carrying p.Arg499Cys did not produce a detectable CoA HPLC peak, whereas wild-type DPCK converted dephospho-CoA to CoA. Condition category: machinery_impairment nutrient_topic: Pantothenic acid (vitamin B5) research collection; topical membership is not evidence of a direct dietary effect. plain_language: This COASY variant disabled the final reaction in the isolated-enzyme test. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Two unrelated human NBIA cases, primary fibroblasts, recombinant wild-type and variant COASY DPCK domains and yeast studies limitations: Loss of detectable isolated-domain activity does not mean that every patient cell has no CoA. Wild-type and variant domains were recombinantly produced in bacteria. exposure: HPLC assays with 1 microgram recombinant wild-type or p.Arg499Cys DPCK protein, ATP and dephospho-CoA; substrate concentrations not extracted. cross_nutrient: false [b5-bio-coasy2014] Exome sequence reveals mutations in CoA synthase as a cause of neurodegeneration with brain iron accumulation. (2014). https://pubmed.ncbi.nlm.nih.gov/24360804/ DOI: 10.1016/j.ajhg.2013.11.008

cross_nutrient

false

experimental_model

Human PANK2 in 293T-cell lysates and purified enzyme assays

exposure

293T-cell-lysate inhibition IC50 was 0.3 micromolar acetyl-CoA; purified-enzyme assays established ATP competition.

limitations

The lysate IC50 is preparation-specific and is not a intracellular or dietary adequacy threshold. Purified-enzyme competition and lysate potency are separately identified.

nutrient_topic

Pantothenic acid (vitamin B5) research collection; topical membership is not evidence of a direct dietary effect. · Pantothenate (vitamin B5)

organism

Homo sapiens

plain_language

An existing CoA derivative feeds back to restrain PANK2.

primary_references

[b5-bio-pank2reg] Activation of human mitochondrial pantothenate kinase 2 by palmitoylcarnitine. (2007). https://pubmed.ncbi.nlm.nih.gov/17242360/ DOI: 10.1073/pnas.0607621104

tissue_or_cell_type

Purified recombinant protein; no intact tissue

Pantothenic acid (vitamin B5): coenzyme A, deficiency and nutrient interactions (2026-09-17) · lines 600–611

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human PANK2 in 293T-cell lysates and purified enzyme assays · source_derived_draft · unverified_draft

### b5-bio-pank2-acetyl-inhibition Acetyl-CoA inhibited purified human PANK2 competitively with ATP; PANK2 inhibition was submicromolar in the reported preparations. Condition category: normal nutrient_topic: Pantothenic acid (vitamin B5) research collection; topical membership is not evidence of a direct dietary effect. plain_language: An existing CoA derivative feeds back to restrain PANK2. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Human PANK2 in 293T-cell lysates and purified enzyme assays limitations: The lysate IC50 is preparation-specific and is not a intracellular or dietary adequacy threshold. Purified-enzyme competition and lysate potency are separately identified. exposure: 293T-cell-lysate inhibition IC50 was 0.3 micromolar acetyl-CoA; purified-enzyme assays established ATP competition. cross_nutrient: false [b5-bio-pank2reg] Activation of human mitochondrial pantothenate kinase 2 by palmitoylcarnitine. (2007). https://pubmed.ncbi.nlm.nih.gov/17242360/ DOI: 10.1073/pnas.0607621104

cross_nutrient

true

experimental_model

Human PANK2 in 293T-cell lysates and purified enzyme assays

exposure

Human PANK2 in 293T lysates and purified-enzyme assays; indexed Fig. 1 used 0.2 micromolar acetyl-CoA.

limitations

Acylcarnitine is a specific molecule; this does not show that free-carnitine supplements activate PANK2 in people. Intact-organism fatty-acid-demand interpretation was proposed.

nutrient_topic

Pantothenic acid (vitamin B5) research collection; topical membership is not evidence of a direct dietary effect. · Pantothenate (vitamin B5)

organism

Homo sapiens

plain_language

A long-chain acylcarnitine can release the brake on PANK2.

primary_references

[b5-bio-pank2reg] Activation of human mitochondrial pantothenate kinase 2 by palmitoylcarnitine. (2007). https://pubmed.ncbi.nlm.nih.gov/17242360/ DOI: 10.1073/pnas.0607621104

tissue_or_cell_type

Purified recombinant protein; no intact tissue

Pantothenic acid (vitamin B5): coenzyme A, deficiency and nutrient interactions (2026-09-17) · lines 613–624

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human PANK2 in 293T-cell lysates and purified enzyme assays · source_derived_draft · unverified_draft

### b5-bio-pank2-palmitoylcarnitine Palmitoylcarnitine antagonized acetyl-CoA inhibition of human PANK2, providing a positive regulatory input in biochemical assays. Condition category: normal nutrient_topic: Pantothenic acid (vitamin B5) research collection; topical membership is not evidence of a direct dietary effect. plain_language: A long-chain acylcarnitine can release the brake on PANK2. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Human PANK2 in 293T-cell lysates and purified enzyme assays limitations: Acylcarnitine is a specific molecule; this does not show that free-carnitine supplements activate PANK2 in people. Intact-organism fatty-acid-demand interpretation was proposed. exposure: Human PANK2 in 293T lysates and purified-enzyme assays; indexed Fig. 1 used 0.2 micromolar acetyl-CoA. cross_nutrient: true [b5-bio-pank2reg] Activation of human mitochondrial pantothenate kinase 2 by palmitoylcarnitine. (2007). https://pubmed.ncbi.nlm.nih.gov/17242360/ DOI: 10.1073/pnas.0607621104

cross_nutrient

false

experimental_model

Purified recombinant human PANK3, crystallography and biochemical ligand-binding/heterodimer experiments

exposure

In-vitro biochemical exposure; concentrations not extracted.

limitations

Abstract-level structural and biochemical findings; no diet or Mg-repletion experiment. Substrate concentrations not established here.

nutrient_topic

Pantothenic acid (vitamin B5) research collection; topical membership is not evidence of a direct dietary effect. · Pantothenate (vitamin B5)

organism

Homo sapiens

plain_language

Accumulated acyl-CoA can slow the first step of new CoA production.

primary_references

[b5-bio-pank3allosteric] Allosteric Regulation of Mammalian Pantothenate Kinase. (2016). https://pubmed.ncbi.nlm.nih.gov/27555321/ DOI: 10.1074/jbc.m116.748061

tissue_or_cell_type

Purified recombinant protein; no intact tissue

Pantothenic acid (vitamin B5): coenzyme A, deficiency and nutrient interactions (2026-09-17) · lines 509–520

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant human PANK3, crystallography and biochemical ligand-binding/heterodimer experiments · source_derived_draft · unverified_draft

### b5-bio-pank3-feedback Acetyl-CoA stabilizes an inactive human PANK3 dimer conformation, whereas ATP–Mg favors the active state; biochemical analyses showed coordinated switching of its two active sites. Condition category: normal nutrient_topic: Pantothenic acid (vitamin B5) research collection; topical membership is not evidence of a direct dietary effect. plain_language: Accumulated acyl-CoA can slow the first step of new CoA production. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Purified recombinant human PANK3, crystallography and biochemical ligand-binding/heterodimer experiments limitations: Abstract-level structural and biochemical findings; no diet or Mg-repletion experiment. Substrate concentrations not established here. exposure: In-vitro biochemical exposure; concentrations not extracted. cross_nutrient: false [b5-bio-pank3allosteric] Allosteric Regulation of Mammalian Pantothenate Kinase. (2016). https://pubmed.ncbi.nlm.nih.gov/27555321/ DOI: 10.1074/jbc.m116.748061

cross_nutrient

true

experimental_model

Purified recombinant human PANK3, crystallography and biochemical ligand-binding/heterodimer experiments

exposure

In-vitro biochemical exposure; concentrations not extracted.

limitations

Structures used AMPPNP, ADP and related nucleotide complexes; ATP–Mg binding was assessed biochemically. This demonstrates catalytic-complex participation, not a dietary magnesium threshold or supplementation requirement.

nutrient_topic

Pantothenic acid (vitamin B5) research collection; topical membership is not evidence of a direct dietary effect. · Pantothenate (vitamin B5)

organism

Homo sapiens

plain_language

Magnesium is part of the nucleotide complex used by PANK3.

primary_references

[b5-bio-pank3allosteric] Allosteric Regulation of Mammalian Pantothenate Kinase. (2016). https://pubmed.ncbi.nlm.nih.gov/27555321/ DOI: 10.1074/jbc.m116.748061

tissue_or_cell_type

Purified recombinant protein; no intact tissue

Pantothenic acid (vitamin B5): coenzyme A, deficiency and nutrient interactions (2026-09-17) · lines 496–507

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant human PANK3, crystallography and biochemical ligand-binding/heterodimer experiments · source_derived_draft · unverified_draft

### b5-bio-pank3-magnesium Human PANK3 structures resolved Mg2+ in nucleotide-bound substrate and product complexes, directly connecting magnesium to the B5-phosphorylation machinery. Condition category: normal nutrient_topic: Pantothenic acid (vitamin B5) research collection; topical membership is not evidence of a direct dietary effect. plain_language: Magnesium is part of the nucleotide complex used by PANK3. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Purified recombinant human PANK3, crystallography and biochemical ligand-binding/heterodimer experiments limitations: Structures used AMPPNP, ADP and related nucleotide complexes; ATP–Mg binding was assessed biochemically. This demonstrates catalytic-complex participation, not a dietary magnesium threshold or supplementation requirement. exposure: In-vitro biochemical exposure; concentrations not extracted. cross_nutrient: true [b5-bio-pank3allosteric] Allosteric Regulation of Mammalian Pantothenate Kinase. (2016). https://pubmed.ncbi.nlm.nih.gov/27555321/ DOI: 10.1074/jbc.m116.748061

cross_nutrient

true

experimental_model

Purified recombinant human PANK3, crystallography and biochemical ligand-binding/heterodimer experiments

exposure

In-vitro biochemical exposure; concentrations not extracted.

limitations

Abstract-level structural and biochemical findings; no diet or Mg-repletion experiment. Substrate concentrations not established here.

nutrient_topic

Pantothenic acid (vitamin B5) research collection; topical membership is not evidence of a direct dietary effect. · Pantothenate (vitamin B5)

organism

Homo sapiens

plain_language

PANK3 starts vitamin B5 activation by adding phosphate.

primary_references

[b5-bio-pank3allosteric] Allosteric Regulation of Mammalian Pantothenate Kinase. (2016). https://pubmed.ncbi.nlm.nih.gov/27555321/ DOI: 10.1074/jbc.m116.748061

tissue_or_cell_type

Purified recombinant protein; no intact tissue

Pantothenic acid (vitamin B5): coenzyme A, deficiency and nutrient interactions (2026-09-17) · lines 483–494

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant human PANK3, crystallography and biochemical ligand-binding/heterodimer experiments · source_derived_draft · unverified_draft

### b5-bio-pank3-phosphorylation Human PANK3 catalyzes ATP-dependent conversion of pantothenate to 4′-phosphopantothenate. Condition category: normal nutrient_topic: Pantothenic acid (vitamin B5) research collection; topical membership is not evidence of a direct dietary effect. plain_language: PANK3 starts vitamin B5 activation by adding phosphate. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Purified recombinant human PANK3, crystallography and biochemical ligand-binding/heterodimer experiments limitations: Abstract-level structural and biochemical findings; no diet or Mg-repletion experiment. Substrate concentrations not established here. exposure: In-vitro biochemical exposure; concentrations not extracted. cross_nutrient: true [b5-bio-pank3allosteric] Allosteric Regulation of Mammalian Pantothenate Kinase. (2016). https://pubmed.ncbi.nlm.nih.gov/27555321/ DOI: 10.1074/jbc.m116.748061

cross_nutrient

true

experimental_model

Recombinant human PPCS, PPCDC and COASY expressed in Escherichia coli; coupled enzyme assays and HPLC reconstitution

exposure

Coupled PPCS assay: 1.5 mM phosphopantothenate, 5 mM cysteine and 1 mM ATP or CTP; 2 mM MgCl2, pH 8.0, 37°C.

limitations

Human enzyme expressed in E. coli; assay substrate supply is not evidence that oral cysteine raises human CoA or that low blood cysteine gates B5 repletion.

nutrient_topic

Pantothenic acid (vitamin B5) research collection; topical membership is not evidence of a direct dietary effect. · Pantothenate (vitamin B5)

organism

Homo sapiens

plain_language

Cysteine supplies the sulfur-containing portion of the developing CoA molecule.

primary_references

[b5-bio-daugherty2002] Complete reconstitution of the human coenzyme A biosynthetic pathway via comparative genomics. (2002). https://pubmed.ncbi.nlm.nih.gov/11923312/ DOI: 10.1074/jbc.m201708200

tissue_or_cell_type

Purified recombinant protein; no intact tissue

Pantothenic acid (vitamin B5): coenzyme A, deficiency and nutrient interactions (2026-09-17) · lines 522–533

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human PPCS, PPCDC and COASY expressed in Escherichia coli; coupled enzyme assays and HPLC reconstitution · source_derived_draft · unverified_draft

### b5-bio-ppcs-ligation Recombinant human PPCS ligated L-cysteine to 4′-phosphopantothenate in a nucleotide-dependent reaction forming 4′-phosphopantothenoylcysteine. Condition category: normal nutrient_topic: Pantothenic acid (vitamin B5) research collection; topical membership is not evidence of a direct dietary effect. plain_language: Cysteine supplies the sulfur-containing portion of the developing CoA molecule. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Recombinant human PPCS, PPCDC and COASY expressed in Escherichia coli; coupled enzyme assays and HPLC reconstitution limitations: Human enzyme expressed in E. coli; assay substrate supply is not evidence that oral cysteine raises human CoA or that low blood cysteine gates B5 repletion. exposure: Coupled PPCS assay: 1.5 mM phosphopantothenate, 5 mM cysteine and 1 mM ATP or CTP; 2 mM MgCl2, pH 8.0, 37°C. cross_nutrient: true [b5-bio-daugherty2002] Complete reconstitution of the human coenzyme A biosynthetic pathway via comparative genomics. (2002). https://pubmed.ncbi.nlm.nih.gov/11923312/ DOI: 10.1074/jbc.m201708200

evidence_span

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experimental_model

Freeze-clamped liver metabolite measurement in starved rats after ethanol

exposure

Single ethanol dose, sampled over 30 minutes in fed and starved animals

limitations

The classic redox measurement. Metabolite ratios are calculated from near-equilibrium assumptions rather than measured directly, which the authors state.

nutrient_topic

Alcohol research collection; topical membership is not evidence of a direct clinical effect, and ethanol is recorded separately from the acetaldehyde it becomes. · Ethanol

organism

Rat

plain_language

Two other energy ratios move as well, and they recover on different timescales.

primary_references

[alcohol-p4342558] The time-course of the effects of ethanol on the redox and phosphorylation states of rat liver. (1972). https://pubmed.ncbi.nlm.nih.gov/4342558/ DOI: 10.1042/bj1270387

tissue_or_cell_type

Liver

Alcohol: ethanol clearance, acetaldehyde, the channels it binds, organ injury and nutrient collisions (2026-09-21) · lines 111–122

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Freeze-clamped liver metabolite measurement in starved rats after ethanol · source_derived_draft · unverified_draft

### alcohol-nadp-and-phosphorylation The free cytosolic NADP+/NADPH ratio fell immediately and returned nearly to control by 15 minutes, while the cytosolic ATP/ADP phosphate ratio was elevated at 15 minutes in starved rats. Condition category: normal nutrient_topic: Alcohol research collection; topical membership is not evidence of a direct clinical effect, and ethanol is recorded separately from the acetaldehyde it becomes. plain_language: Two other energy ratios move as well, and they recover on different timescales. organism: Rat tissue_or_cell_type: Liver experimental_model: Freeze-clamped liver metabolite measurement in starved rats after ethanol limitations: The classic redox measurement. Metabolite ratios are calculated from near-equilibrium assumptions rather than measured directly, which the authors state. exposure: Single ethanol dose, sampled over 30 minutes in fed and starved animals evidence_span: {"source_cache": "artifacts/alcohol-research/4342558.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "dce57aa8128b432a841f087e3c4e70963b8fe318e462df980e6cdd66ed4af79d", "start_char": 0, "end_char": 959, "text_sha256": "dce57aa8128b432a841f087e3c4e70963b8fe318e462df980e6cdd66ed4af79d"} [alcohol-p4342558] The time-course of the effects of ethanol on the redox and phosphorylation states of rat liver. (1972). https://pubmed.ncbi.nlm.nih.gov/4342558/ DOI: 10.1042/bj1270387

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_span

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experimental_model

31P-MRS ATP-flux measurements, repletion and cellular/mitochondrial experiments

exposure

Diet-induced low phosphate, NaPi-IIa knockout, phosphate repletion; one SLC34A3-associated human case

limitations

ATP synthetic flux is not ATP pool size or direct proof that all measured flux is mitochondrial oxidative phosphorylation. One human case cannot define a population threshold.

nutrient_topic

Phosphorus research collection; topical membership is not evidence of a direct dietary effect. · Phosphorus

organism

Mouse

plain_language

In this mouse experiment, phosphate shortage limited the measured ATP-making flux.

primary_references

[phosphorus-p27338702] Hypophosphatemia promotes lower rates of muscle ATP synthesis. (2016). https://pubmed.ncbi.nlm.nih.gov/27338702/ DOI: 10.1096/fj.201600473r

tissue_or_cell_type

Skeletal muscle

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Phosphorus: metabolism, signaling and nutrient connections (2026-09-17) · lines 568–579

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · 31P-MRS ATP-flux measurements, repletion and cellular/mitochondrial experiments · source_derived_draft · unverified_draft

### phosphorus-diet-atp Diet-induced hypophosphatemic mice had approximately 50% lower basal and insulin-stimulated muscle ATP synthetic flux. Condition category: nutrient_deficiency nutrient_topic: Phosphorus research collection; topical membership is not evidence of a direct dietary effect. plain_language: In this mouse experiment, phosphate shortage limited the measured ATP-making flux. organism: Mouse tissue_or_cell_type: Skeletal muscle experimental_model: 31P-MRS ATP-flux measurements, repletion and cellular/mitochondrial experiments limitations: ATP synthetic flux is not ATP pool size or direct proof that all measured flux is mitochondrial oxidative phosphorylation. One human case cannot define a population threshold. exposure: Diet-induced low phosphate, NaPi-IIa knockout, phosphate repletion; one SLC34A3-associated human case evidence_span: {"source_cache": "artifacts/phosphorus-research/27338702.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "634bc9a26ebb8d6a911692bcb98a05432db2bc08455c0a02f1ef5e4b953150fe", "start_char": 0, "end_char": 1786, "text_sha256": "634bc9a26ebb8d6a911692bcb98a05432db2bc08455c0a02f1ef5e4b953150fe"} [phosphorus-p27338702] Hypophosphatemia promotes lower rates of muscle ATP synthesis. (2016). https://pubmed.ncbi.nlm.nih.gov/27338702/ DOI: 10.1096/fj.201600473r

evidence_span

{"source_cache": "artifacts/phosphorus-research/33656855.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1d45073f7187a06cfb9b2d630f94fa651239f0a9a5ae353b37d9af90750f2f38", "start_char": 0, "end_char": 1520, "text_sha256": "1d45073f7187a06cfb9b2d630f94fa651239f0a9a5ae353b37d9af90750f2f38"}

experimental_model

Human MAT2A kinetics, isotope exchange and inhibitor-bound crystallography

exposure

ATP/methionine reactions and PNPNP ligand complexes

limitations

Phosphoryl chemistry is not evidence that phosphate supplements boost methylation. Metal contacts were resolved with an experimental ATP-site ligand.

nutrient_topic

Phosphorus research collection; topical membership is not evidence of a direct dietary effect. · Phosphorus

organism

Human recombinant enzyme

plain_language

Making the methyl donor SAM is coupled to ATP-derived phosphate chemistry.

primary_references

[phosphorus-p33656855] Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. (2021). https://pubmed.ncbi.nlm.nih.gov/33656855/ DOI: 10.1021/acs.biochem.0c00998

tissue_or_cell_type

Purified MAT2A active site

Phosphorus: metabolism, signaling and nutrient connections (2026-09-17) · lines 633–644

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human MAT2A kinetics, isotope exchange and inhibitor-bound crystallography · source_derived_draft · unverified_draft

### phosphorus-mat-sam Human MAT2A formed S-adenosylmethionine before rapid triphosphate hydrolysis and product release in the kinetic study. Condition category: normal nutrient_topic: Phosphorus research collection; topical membership is not evidence of a direct dietary effect. plain_language: Making the methyl donor SAM is coupled to ATP-derived phosphate chemistry. organism: Human recombinant enzyme tissue_or_cell_type: Purified MAT2A active site experimental_model: Human MAT2A kinetics, isotope exchange and inhibitor-bound crystallography limitations: Phosphoryl chemistry is not evidence that phosphate supplements boost methylation. Metal contacts were resolved with an experimental ATP-site ligand. exposure: ATP/methionine reactions and PNPNP ligand complexes evidence_span: {"source_cache": "artifacts/phosphorus-research/33656855.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1d45073f7187a06cfb9b2d630f94fa651239f0a9a5ae353b37d9af90750f2f38", "start_char": 0, "end_char": 1520, "text_sha256": "1d45073f7187a06cfb9b2d630f94fa651239f0a9a5ae353b37d9af90750f2f38"} [phosphorus-p33656855] Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. (2021). https://pubmed.ncbi.nlm.nih.gov/33656855/ DOI: 10.1021/acs.biochem.0c00998

evidence_span

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experimental_model

Human family genetics, mitochondrial functional assay and yeast complementation

exposure

Two siblings with homozygous SLC25A3 exon-3A c.215G>A, p.Gly72Glu

limitations

Isoform- and tissue-specific inherited transport defect; normal dietary phosphorus cannot be assumed to repair the carrier.

nutrient_topic

Phosphorus research collection; topical membership is not evidence of a direct dietary effect. · Phosphorus

organism

Human; yeast functional complementation

plain_language

Phosphate must enter the mitochondrion before it can support ATP production.

primary_references

[phosphorus-p17273968] Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation. (2007). https://pubmed.ncbi.nlm.nih.gov/17273968/ DOI: 10.1086/511788

tissue_or_cell_type

Muscle compared with fibroblasts

transport_effect

raises Recorded as supplying inorganic phosphate to the matrix.

transport_pool

the mitochondrial matrix Recorded as supplying inorganic phosphate to the matrix.

Phosphorus: metabolism, signaling and nutrient connections (2026-09-17) · lines 529–540

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human family genetics, mitochondrial functional assay and yeast complementation · source_derived_draft · unverified_draft

### phosphorus-mitochondrial-entry SLC25A3 supplies inorganic phosphate to the mitochondrial matrix for aerobic ATP synthesis; the family study localized the defect to the muscle-expressed isoform. Condition category: normal nutrient_topic: Phosphorus research collection; topical membership is not evidence of a direct dietary effect. plain_language: Phosphate must enter the mitochondrion before it can support ATP production. organism: Human; yeast functional complementation tissue_or_cell_type: Muscle compared with fibroblasts experimental_model: Human family genetics, mitochondrial functional assay and yeast complementation limitations: Isoform- and tissue-specific inherited transport defect; normal dietary phosphorus cannot be assumed to repair the carrier. exposure: Two siblings with homozygous SLC25A3 exon-3A c.215G>A, p.Gly72Glu evidence_span: {"source_cache": "artifacts/phosphorus-research/17273968.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ff20a374b5c0a96a013cb9dd52c86c9dcc63d157e35e8aac58266dd26da9c0a2", "start_char": 0, "end_char": 805, "text_sha256": "ff20a374b5c0a96a013cb9dd52c86c9dcc63d157e35e8aac58266dd26da9c0a2"} [phosphorus-p17273968] Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation. (2007). https://pubmed.ncbi.nlm.nih.gov/17273968/ DOI: 10.1086/511788

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

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experimental_model

Human family genetics, mitochondrial functional assay and yeast complementation

exposure

Two siblings with homozygous SLC25A3 exon-3A c.215G>A, p.Gly72Glu

limitations

Isoform- and tissue-specific inherited transport defect; normal dietary phosphorus cannot be assumed to repair the carrier.

nutrient_topic

Phosphorus research collection; topical membership is not evidence of a direct dietary effect. · Phosphorus

organism

Human; yeast functional complementation

plain_language

The defect appeared in the tissue using the affected carrier isoform.

primary_references

[phosphorus-p17273968] Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation. (2007). https://pubmed.ncbi.nlm.nih.gov/17273968/ DOI: 10.1086/511788

tissue_or_cell_type

Muscle compared with fibroblasts

trigger_kind

machinery_impairment Imported condition classification; unverified.

Phosphorus: metabolism, signaling and nutrient connections (2026-09-17) · lines 542–553

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human family genetics, mitochondrial functional assay and yeast complementation · source_derived_draft · unverified_draft

### phosphorus-slc25a3-muscle Intact muscle mitochondria from the affected siblings showed deficient ATP synthesis. Condition category: machinery_impairment nutrient_topic: Phosphorus research collection; topical membership is not evidence of a direct dietary effect. plain_language: The defect appeared in the tissue using the affected carrier isoform. organism: Human; yeast functional complementation tissue_or_cell_type: Muscle compared with fibroblasts experimental_model: Human family genetics, mitochondrial functional assay and yeast complementation limitations: Isoform- and tissue-specific inherited transport defect; normal dietary phosphorus cannot be assumed to repair the carrier. exposure: Two siblings with homozygous SLC25A3 exon-3A c.215G>A, p.Gly72Glu evidence_span: {"source_cache": "artifacts/phosphorus-research/17273968.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ff20a374b5c0a96a013cb9dd52c86c9dcc63d157e35e8aac58266dd26da9c0a2", "start_char": 0, "end_char": 805, "text_sha256": "ff20a374b5c0a96a013cb9dd52c86c9dcc63d157e35e8aac58266dd26da9c0a2"} [phosphorus-p17273968] Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation. (2007). https://pubmed.ncbi.nlm.nih.gov/17273968/ DOI: 10.1086/511788

cell_type

experimental cells

experimental_model

Biochemical AMPylation assays

limitations

Substrate identification does not establish every tissue context.

organism

mammalian

Selenium: literature corrections and mechanism additions · lines 486–496

Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Biochemical AMPylation assays · secondary_verified · secondary_verified

## selenoo-ampylates-glud1 SELENOO can modify the metabolic enzyme GLUD1 with AMP. SELENOO catalyzes AMP attachment to GLUD1. Organism: mammalian Cell type: experimental cells Experimental model: Biochemical AMPylation assays Limitations: Substrate identification does not establish every tissue context. Primary reference: [A repurposed AMP binding domain reveals mitochondrial protein AMPylation as a regulator of cellular metabolism](https://www.nature.com/articles/s41467-025-63014-z)

cell_type

melanoma-related assays

experimental_model

Biochemical substrate experiments

limitations

Keep this reaction separate from NAD hydrolysis.

organism

mammalian

Selenium: literature corrections and mechanism additions · lines 462–472

Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Biochemical substrate experiments · secondary_verified · secondary_verified

## selenoo-ampylates-sdha SELENOO can attach an AMP group to a respiratory enzyme. SELENOO transfers AMP from ATP onto SDHA in the reported AMPylation experiments. Organism: mammalian Cell type: melanoma-related assays Experimental model: Biochemical substrate experiments Limitations: Keep this reaction separate from NAD hydrolysis. Primary reference: [Selenoprotein O Promotes Melanoma Metastasis and Regulates Mitochondrial Complex II Activity](https://pubmed.ncbi.nlm.nih.gov/39700395/)