NADPH

evidence_access

Primary abstract

experimental_model

Recombinant human FMO1 biochemistry.

limitations

NAD(P)H availability, FMO1 abundance and substrate availability are separate variables; no niacin repletion effect was tested.

nutrient_topic

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

plain_language

Niacin-derived electron carriers support this synthetic reaction.

primary_references

Flavin-Containing Monooxygenase 1 Catalyzes the Production of Taurine from Hypotaurine. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32156684/ · DOI 10.1124/dmd.119.089995

Taurine: synthesis, transport, mitochondrial decoding and nutrient interactions (2026-09-19) · lines 81–87

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Recombinant human FMO1 biochemistry. · source_derived_draft · unverified_draft

## taurine-fmo1-reducing-cofactors Niacin-derived electron carriers support this synthetic reaction. Human FMO1 converted hypotaurine to taurine with either NADPH or NADH as the reducing cofactor in the reported assays. Model: Recombinant human FMO1 biochemistry. Limitations: NAD(P)H availability, FMO1 abundance and substrate availability are separate variables; no niacin repletion effect was tested. Evidence access: Primary abstract Flavin-Containing Monooxygenase 1 Catalyzes the Production of Taurine from Hypotaurine. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32156684/ · DOI 10.1124/dmd.119.089995

evidence_access

Primary abstract

experimental_model

Cell-line NADPH intervention.

limitations

Changes support redox-dependent signaling but do not directly demonstrate each proposed vanadium intermediate.

nutrient_topic

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

plain_language

More reducing power did not necessarily protect against this metal exposure.

primary_references

Mechanisms of vanadate-induced cellular toxicity: role of cellular glutathione and NADPH. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12234491/ · DOI 10.1016/s0003-9861(02)00408-3

Vanadium: speciation, phosphate-sensitive enzymes and cross-nutrient mechanisms (2026-09-19) · lines 150–156

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Cell-line NADPH intervention. · source_derived_draft · unverified_draft

## vanadium-nadph-sensitization More reducing power did not necessarily protect against this metal exposure. NADPH sensitized vanadate-resistant cells and increased phosphotyrosine signals and Ras expression in the reported experiment. Model: Cell-line NADPH intervention. Limitations: Changes support redox-dependent signaling but do not directly demonstrate each proposed vanadium intermediate. Evidence access: Primary abstract Mechanisms of vanadate-induced cellular toxicity: role of cellular glutathione and NADPH. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12234491/ · DOI 10.1016/s0003-9861(02)00408-3

evidence_span

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experimental_model

Expression cloning and cell-death experiments

exposure

GPX4 deletion or inhibitors and FSP1 manipulation

limitations

Cancer-cell defense mechanism; preventing ferroptosis is not always a desirable disease outcome and oral CoQ benefit is not tested.

nutrient_topic

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

organism

Human cancer-cell models

plain_language

The antioxidant form must be regenerated using reducing power.

primary_references

[coq10-p31634899] FSP1 is a glutathione-independent ferroptosis suppressor. (2019). https://pubmed.ncbi.nlm.nih.gov/31634899/ DOI: 10.1038/s41586-019-1707-0

tissue_or_cell_type

FSP1-CoQ antioxidant pathway

Coenzyme Q10: biosynthesis, electron transfer, antioxidant recycling 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 · Expression cloning and cell-death experiments · source_derived_draft · unverified_draft

### coq10-fsp1-nadph FSP1 used NAD(P)H to regenerate the reduced CoQ pool that traps lipid peroxyl radicals. Condition category: normal nutrient_topic: Coenzyme Q10 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The antioxidant form must be regenerated using reducing power. organism: Human cancer-cell models tissue_or_cell_type: FSP1-CoQ antioxidant pathway experimental_model: Expression cloning and cell-death experiments limitations: Cancer-cell defense mechanism; preventing ferroptosis is not always a desirable disease outcome and oral CoQ benefit is not tested. exposure: GPX4 deletion or inhibitors and FSP1 manipulation evidence_span: {"source_cache": "artifacts/coq10-research/31634899.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1e96f6d5aed6def29533d907cd9ae90bc287d3f7beb6b9447aec3308d57a0dfe", "start_char": 0, "end_char": 1818, "text_sha256": "1e96f6d5aed6def29533d907cd9ae90bc287d3f7beb6b9447aec3308d57a0dfe"} [coq10-p31634899] FSP1 is a glutathione-independent ferroptosis suppressor. (2019). https://pubmed.ncbi.nlm.nih.gov/31634899/ DOI: 10.1038/s41586-019-1707-0

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/ceylon-research/26851241.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c2fb6b18a3ba708f060d53011ea0e198f98fe980930297e714c488a41413b5a2", "start_char": 0, "end_char": 1591, "text_sha256": "c2fb6b18a3ba708f060d53011ea0e198f98fe980930297e714c488a41413b5a2"}

experimental_model

Recombinant human CYP assays and mechanistic static modeling

exposure

Cinnamaldehyde, NADPH and glutathione; modeled inhibitor concentrations 0.1 and 1 micromolar

limitations

Enzyme inhibition and model predictions are not measured clinical drug interactions. NADPH omission is not dietary niacin deficiency.

nutrient_topic

Ceylon cinnamon research collection; topical membership is not evidence of a direct dietary effect. · Ceylon cinnamon / Cinnamomum verum bark preparations

organism

Human enzyme preparations; computational model

plain_language

The enzyme had to receive reducing power for this inactivation process to develop.

primary_references

[ceylon-p26851241] Inactivation of CYP2A6 by the Dietary Phenylpropanoid trans-Cinnamic Aldehyde (Cinnamaldehyde) and Estimation of Interactions with Nicotine and Letrozole. (2016). https://pubmed.ncbi.nlm.nih.gov/26851241/ DOI: 10.1124/dmd.115.067942

tissue_or_cell_type

CYP2A6 reaction system

trigger_kind

machinery_impairment Imported condition classification; unverified.

Ceylon cinnamon: metabolism, signaling and nutrient connections (2026-09-17) · lines 753–764

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human CYP assays and mechanistic static modeling · source_derived_draft · unverified_draft

### ceylon-nadph-dependence Cinnamaldehyde-dependent time-dependent inhibition of CYP2A6 required NADPH in the reconstituted assay. Condition category: machinery_impairment nutrient_topic: Ceylon cinnamon research collection; topical membership is not evidence of a direct dietary effect. plain_language: The enzyme had to receive reducing power for this inactivation process to develop. organism: Human enzyme preparations; computational model tissue_or_cell_type: CYP2A6 reaction system experimental_model: Recombinant human CYP assays and mechanistic static modeling limitations: Enzyme inhibition and model predictions are not measured clinical drug interactions. NADPH omission is not dietary niacin deficiency. exposure: Cinnamaldehyde, NADPH and glutathione; modeled inhibitor concentrations 0.1 and 1 micromolar evidence_span: {"source_cache": "artifacts/ceylon-research/26851241.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c2fb6b18a3ba708f060d53011ea0e198f98fe980930297e714c488a41413b5a2", "start_char": 0, "end_char": 1591, "text_sha256": "c2fb6b18a3ba708f060d53011ea0e198f98fe980930297e714c488a41413b5a2"} [ceylon-p26851241] Inactivation of CYP2A6 by the Dietary Phenylpropanoid trans-Cinnamic Aldehyde (Cinnamaldehyde) and Estimation of Interactions with Nicotine and Letrozole. (2016). https://pubmed.ncbi.nlm.nih.gov/26851241/ DOI: 10.1124/dmd.115.067942

evidence_span

{"source_cache": "artifacts/curcumin-research/21467222.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c4ff0be81d2a3b3bd5edb9902da02b1e599d45a5e60ab4787514e340bf63d757", "start_char": 0, "end_char": 1325, "text_sha256": "c4ff0be81d2a3b3bd5edb9902da02b1e599d45a5e60ab4787514e340bf63d757"}

experimental_model

Purification and characterization of a human-fecal bacterial enzyme

exposure

Curcumin and reduced intermediates; NADPH-dependent reactions

limitations

Bacterial biochemistry does not quantify a person's circulating metabolite concentrations or establish that dietary niacin increases this conversion.

nutrient_topic

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

organism

Escherichia coli isolate

plain_language

This bacterial reaction draws on NADPH reducing power.

primary_references

[curcumin-p21467222] Discovery of the curcumin metabolic pathway involving a unique enzyme in an intestinal microorganism. (2011). https://pubmed.ncbi.nlm.nih.gov/21467222/ DOI: 10.1073/pnas.1016217108

tissue_or_cell_type

Purified CurA

Curcumin: metabolism, signaling and nutrient connections (2026-09-17) · lines 229–240

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purification and characterization of a human-fecal bacterial enzyme · source_derived_draft · unverified_draft

### curcumin-cura-nadph The purified two-step reduction depended on NADPH. Condition category: normal nutrient_topic: Curcumin research collection; topical membership is not evidence of a direct dietary effect. plain_language: This bacterial reaction draws on NADPH reducing power. organism: Escherichia coli isolate tissue_or_cell_type: Purified CurA experimental_model: Purification and characterization of a human-fecal bacterial enzyme limitations: Bacterial biochemistry does not quantify a person's circulating metabolite concentrations or establish that dietary niacin increases this conversion. exposure: Curcumin and reduced intermediates; NADPH-dependent reactions evidence_span: {"source_cache": "artifacts/curcumin-research/21467222.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c4ff0be81d2a3b3bd5edb9902da02b1e599d45a5e60ab4787514e340bf63d757", "start_char": 0, "end_char": 1325, "text_sha256": "c4ff0be81d2a3b3bd5edb9902da02b1e599d45a5e60ab4787514e340bf63d757"} [curcumin-p21467222] Discovery of the curcumin metabolic pathway involving a unique enzyme in an intestinal microorganism. (2011). https://pubmed.ncbi.nlm.nih.gov/21467222/ DOI: 10.1073/pnas.1016217108

cross_nutrient

Nicotinamide-containing NADPH and B2-derived FAD perform distinct functions.

evidence_location

Results: NADPH binding; Fig 1 consensus cycle; GSH/GSSG complexes

experimental_model

Purified human glutathione reductase crystals with natural substrates, 0.95-1.1-A resolution, chemically reduced controls.

exposure

Purified-enzyme assay

limitations

Structural support for the established catalytic cycle; radiation reduction must be distinguished from natural catalysis.

nutrient_topic

Riboflavin research collection; topical membership is not evidence of a direct dietary effect. · Riboflavin (vitamin B2)

organism

Homo sapiens

plain_language

NADPH supplies electrons to the B2-derived cofactor.

primary_references

[berkholz2008] Catalytic cycle of human glutathione reductase near 1 A resolution. (2008). https://pubmed.ncbi.nlm.nih.gov/18638483/ DOI: 10.1016/j.jmb.2008.06.083

tissue_or_cell_type

Purified human erythrocyte-type GSR crystals

Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1304–1316

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human glutathione reductase crystals with natural substrates, 0.95-1.1-A resolution, chemically reduced controls. · source_derived_draft · unverified_draft

### b2-gsr-nadph-to-fad Human GSR substrate structures place NADPH for hydride transfer to bound FAD, the first redox step in glutathione recycling. Condition category: normal nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: NADPH supplies electrons to the B2-derived cofactor. organism: Homo sapiens tissue_or_cell_type: Purified human erythrocyte-type GSR crystals experimental_model: Purified human glutathione reductase crystals with natural substrates, 0.95-1.1-A resolution, chemically reduced controls. limitations: Structural support for the established catalytic cycle; radiation reduction must be distinguished from natural catalysis. exposure: Purified-enzyme assay cross_nutrient: Nicotinamide-containing NADPH and B2-derived FAD perform distinct functions. evidence_location: Results: NADPH binding; Fig 1 consensus cycle; GSH/GSSG complexes [berkholz2008] Catalytic cycle of human glutathione reductase near 1 A resolution. (2008). https://pubmed.ncbi.nlm.nih.gov/18638483/ DOI: 10.1016/j.jmb.2008.06.083

cross_nutrient

Nicotinamide-containing NADPH supplies electrons to B2-derived flavins.

evidence_location

Abstract

experimental_model

Recombinant human MTRR purification, flavin analysis, NADPH spectroscopy and methionine-synthase reconstitution.

exposure

Purified-enzyme assay

limitations

Biochemical evidence does not establish a dietary threshold or supplementation benefit.

nutrient_topic

Riboflavin research collection; topical membership is not evidence of a direct dietary effect. · Riboflavin (vitamin B2)

organism

Homo sapiens

plain_language

NADPH provides electrons to the flavin-containing reductase.

primary_references

[olteanu2001] Human methionine synthase reductase, a soluble P-450 reductase-like dual flavoprotein, is sufficient for NADPH-dependent methionine synthase activation. (2001). https://pubmed.ncbi.nlm.nih.gov/11466310/ DOI: 10.1074/jbc.m103707200

tissue_or_cell_type

Purified recombinant enzyme; no intact tissue

Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1108–1120

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human MTRR purification, flavin analysis, NADPH spectroscopy and methionine-synthase reconstitution. · source_derived_draft · unverified_draft

### b2-mtrr-nadph-reduction NADPH reduction of purified MTRR generated an air-stable flavin semiquinone detected spectroscopically. Condition category: normal nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: NADPH provides electrons to the flavin-containing reductase. organism: Homo sapiens tissue_or_cell_type: Purified recombinant enzyme; no intact tissue experimental_model: Recombinant human MTRR purification, flavin analysis, NADPH spectroscopy and methionine-synthase reconstitution. limitations: Biochemical evidence does not establish a dietary threshold or supplementation benefit. exposure: Purified-enzyme assay cross_nutrient: Nicotinamide-containing NADPH supplies electrons to B2-derived flavins. evidence_location: Abstract [olteanu2001] Human methionine synthase reductase, a soluble P-450 reductase-like dual flavoprotein, is sufficient for NADPH-dependent methionine synthase activation. (2001). https://pubmed.ncbi.nlm.nih.gov/11466310/ DOI: 10.1074/jbc.m103707200

dose

Tartrazine among tested substrates; exact substrate/cofactor concentrations unavailable in abstract

duration

Assay interval unavailable in primary abstract

evidence_access

Primary PubMed abstract; unrecovered method details explicitly retained.

evidence_scope

literature_reviewed; source-specific experimental curation

experimental_model

Purified Escherichia coli K12 azoreductases I and II

limitations

Both NADH and NADPH served as electron donors in enzyme characterization. This does not prove that niacin intake controls dye metabolism in humans. Protein genes and tartrazine-specific kinetic constants are unresolved.

nutrient_topic

Tartrazine food-colorant chapter; nutrient, drug and peptide interactions retain their models and limits. · Tartrazine

organism

Purified Escherichia coli K12 azoreductases I and II

plain_language

NADPH also functioned as an electron donor for the purified E. coli azoreductase preparations.

primary_references

Purification of two azoreductases from Escherichia coli K12. (1993). https://pubmed.ncbi.nlm.nih.gov/8112774/

route

In vitro enzyme/substrate incubation

tissue

Cell-free azo-reduction assays

Tartrazine: mechanisms, molecular forms and cross-actor connections (2026-09-20) · lines 50–59

Original AI-assisted curation of eighteen primary studies. Study-specific citations, negative findings and limitations retained. Not publisher full text. · supports · Purified Escherichia coli K12 azoreductases I and II · source_derived_draft · unverified_draft

## tartrazine-nadph-donor NADPH also functioned as an electron donor for the purified E. coli azoreductase preparations. Model/species: Purified Escherichia coli K12 azoreductases I and II Tissue: Cell-free azo-reduction assays Exposure: Tartrazine among tested substrates; exact substrate/cofactor concentrations unavailable in abstract Route: In vitro enzyme/substrate incubation Duration: Assay interval unavailable in primary abstract Limits: Both NADH and NADPH served as electron donors in enzyme characterization. This does not prove that niacin intake controls dye metabolism in humans. Protein genes and tartrazine-specific kinetic constants are unresolved. Primary reference: Purification of two azoreductases from Escherichia coli K12. (1993). https://pubmed.ncbi.nlm.nih.gov/8112774/ Access: Primary PubMed abstract; unrecovered method details explicitly retained.

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/glutathione-research/14676218.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a7399b7d035bd3815c30362449b7986dea08873c824e05506d7db627a71daa84", "start_char": 0, "end_char": 1398, "text_sha256": "a7399b7d035bd3815c30362449b7986dea08873c824e05506d7db627a71daa84"}

experimental_model

Purified human glutaredoxin kinetics and mutants

exposure

GSH or NADPH/thioredoxin-reductase donor systems

limitations

Thioredoxin-reductase isoform is not assigned from the indexed abstract; this is not a new selenium-dose response.

nutrient_topic

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

organism

Human GLRX1/GLRX2

plain_language

Glutaredoxin recovery also had an alternative donor route in the assay.

primary_references

[glutathione-p14676218] Human mitochondrial glutaredoxin reduces S-glutathionylated proteins with high affinity accepting electrons from either glutathione or thioredoxin reductase. (2004). https://pubmed.ncbi.nlm.nih.gov/14676218/ DOI: 10.1074/jbc.m312719200

tissue_or_cell_type

Glutathionylated substrates

Glutathione: metabolism, signaling and nutrient connections (2026-09-17) · lines 827–838

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

### glutathione-glrx2-alternative-donor A thioredoxin-reductase/NADPH system reduced GLRX2 disulfide and GSH-GLRX2 intermediates. Condition category: normal nutrient_topic: Glutathione research collection; topical membership is not evidence of a direct dietary effect. plain_language: Glutaredoxin recovery also had an alternative donor route in the assay. organism: Human GLRX1/GLRX2 tissue_or_cell_type: Glutathionylated substrates experimental_model: Purified human glutaredoxin kinetics and mutants limitations: Thioredoxin-reductase isoform is not assigned from the indexed abstract; this is not a new selenium-dose response. exposure: GSH or NADPH/thioredoxin-reductase donor systems evidence_span: {"source_cache": "artifacts/glutathione-research/14676218.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a7399b7d035bd3815c30362449b7986dea08873c824e05506d7db627a71daa84", "start_char": 0, "end_char": 1398, "text_sha256": "a7399b7d035bd3815c30362449b7986dea08873c824e05506d7db627a71daa84"} [glutathione-p14676218] Human mitochondrial glutaredoxin reduces S-glutathionylated proteins with high affinity accepting electrons from either glutathione or thioredoxin reductase. (2004). https://pubmed.ncbi.nlm.nih.gov/14676218/ DOI: 10.1074/jbc.m312719200

experimental_model

Purified-enzyme cofactor/substrate kinetics

limitations

Biochemical cofactor preference does not demonstrate a dietary niacin-deficiency visual phenotype.

nutrient_topic

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

organism

Homo sapiens protein

plain_language

The reductase uses NADPH reducing power to convert retinal into retinol.

primary_references

[belyaeva-2005] Biochemical properties of purified human retinol dehydrogenase 12 (RDH12): catalytic efficiency toward retinoids and C9 aldehydes and effects of cellular retinol-binding protein type I (CRBPI) and cellular retinaldehyde-binding protein (CRALBP) on the oxidation and reduction of retinoids (2005). https://pubmed.ncbi.nlm.nih.gov/15865448/ DOI: 10.1021/bi050226k

tissue_or_cell_type

Recombinant enzyme preparation

Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 778–787

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

### a-vision-rdh12-nadph Purified human RDH12 used NADPH for retinal reduction and had much lower apparent cofactor Km for NADP(H) than NAD(H). Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: The reductase uses NADPH reducing power to convert retinal into retinol. organism: Homo sapiens protein tissue_or_cell_type: Recombinant enzyme preparation experimental_model: Purified-enzyme cofactor/substrate kinetics limitations: Biochemical cofactor preference does not demonstrate a dietary niacin-deficiency visual phenotype. [belyaeva-2005] Biochemical properties of purified human retinol dehydrogenase 12 (RDH12): catalytic efficiency toward retinoids and C9 aldehydes and effects of cellular retinol-binding protein type I (CRBPI) and cellular retinaldehyde-binding protein (CRALBP) on the oxidation and reduction of retinoids (2005). https://pubmed.ncbi.nlm.nih.gov/15865448/ DOI: 10.1021/bi050226k

cross_nutrient

true

experimental_model

Cofactor omission/addition; Figure 6

exposure

0.5 mM NADPH; reaction followed for 80 minutes.

limitations

Direct NADPH dependence; no dietary niacin or riboflavin shortage, universal supplement combination or magnesium requirement was tested.

nutrient_topic

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

organism

Rattus norvegicus

plain_language

The initial microsomal oxidation required a reducing cofactor.

primary_references

[sontag2002] Cytochrome P450 omega-hydroxylase pathway of tocopherol catabolism. Novel mechanism of regulation of vitamin E status. (2002). https://pubmed.ncbi.nlm.nih.gov/11997390/ DOI: 10.1074/jbc.m201466200

tissue_or_cell_type

Liver microsomes

Vitamin E: transport, membrane protection and nutrient interactions (2026-09-17) · lines 441–452

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cofactor omission/addition; Figure 6 · source_derived_draft · unverified_draft

### ve-transport-nadph-microsomal-oxidation Rat liver microsomes formed initial alpha- and gamma-tocopherol side-chain oxidation products with NADPH but not without it. Condition category: normal nutrient_topic: Vitamin E research collection; topical membership is not evidence of a direct dietary effect. plain_language: The initial microsomal oxidation required a reducing cofactor. organism: Rattus norvegicus tissue_or_cell_type: Liver microsomes experimental_model: Cofactor omission/addition; Figure 6 limitations: Direct NADPH dependence; no dietary niacin or riboflavin shortage, universal supplement combination or magnesium requirement was tested. exposure: 0.5 mM NADPH; reaction followed for 80 minutes. cross_nutrient: true [sontag2002] Cytochrome P450 omega-hydroxylase pathway of tocopherol catabolism. Novel mechanism of regulation of vitamin E status. (2002). https://pubmed.ncbi.nlm.nih.gov/11997390/ DOI: 10.1074/jbc.m201466200

experimental_model

Purified chicken FAS kinetics.

limitations

This does not show that niacin supplementation cancels EGCG or improves a clinical outcome.

nutrient_topic

EGCG collection; comparator and shared-pathway records retain their actual intervention. · Epigallocatechin-3-gallate (EGCG)

plain_language

The enzyme’s reducing cofactor altered EGCG inhibition.

primary_references

Green tea epigallocatechin gallate: a natural inhibitor of fatty-acid synthase. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11700039/ · DOI 10.1006/bbrc.2001.5923

EGCG: receptor signaling, metabolism, nutrient interactions and discovery questions (2026-09-18) · lines 204–210

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Purified chicken FAS kinetics. · source_derived_draft · unverified_draft

## egcg-fasn-nadph The enzyme’s reducing cofactor altered EGCG inhibition. NADPH protected against inhibition, and ketoacyl-reductase experiments supported competition near the NADPH-binding function. Model: Purified chicken FAS kinetics. Limitations: This does not show that niacin supplementation cancels EGCG or improves a clinical outcome. Evidence access: primary abstract. Green tea epigallocatechin gallate: a natural inhibitor of fatty-acid synthase. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11700039/ · DOI 10.1006/bbrc.2001.5923

evidence_access

Primary PDF, p335 visually inspected

experimental_model

Rat liver reductase kinetics in the 1980 study.

limitations

Not evidence of NADPH depletion, niacin deficiency or reversal by niacin supplementation.

nutrient_topic

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

plain_language

The reducing cofactor and the competing substrate have different roles.

primary_references

[7380744] Monacolin K, a new hypocholesterolemic agent that specifically inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase. · 1980 · https://pubmed.ncbi.nlm.nih.gov/7380744/ · DOI 10.7164/antibiotics.33.334

Red yeast rice: constituents, mevalonate, CoQ and product-specific interactions (2026-09-20) · lines 60–66

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat liver reductase kinetics in the 1980 study. · source_derived_draft · unverified_draft

## red-yeast-rice-nadph-noncompetition The reducing cofactor and the competing substrate have different roles. The same monacolin K inhibition was noncompetitive with respect to NADPH. Model: Rat liver reductase kinetics in the 1980 study. Limitations: Not evidence of NADPH depletion, niacin deficiency or reversal by niacin supplementation. Evidence access: Primary PDF, p335 visually inspected [7380744] Monacolin K, a new hypocholesterolemic agent that specifically inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase. · 1980 · https://pubmed.ncbi.nlm.nih.gov/7380744/ · DOI 10.7164/antibiotics.33.334

experimental_model

Cell-free LPO/H2O2 reactions with nicotinamide nucleotides.

exposure_category

Study-specific exposure, including pharmacological and in-vitro conditions; normal is the schema fallback outside the three availability categories.

limitations

Chemical oxidation is not evidence that supplementation drains niacin in vivo; the authors expected thiocyanate oxidation to predominate in milk/saliva.

nutrient_topic

Potassium iodide research collection; shared-anion and comparator studies are not all KI interventions. · Potassium iodide

plain_language

The chemistry also reaches the NADPH reducing pool.

primary_references

The oxidation of reduced nicotinamide nucleotides by hydrogen peroside in the presence of lactoperoxidase and thiocyanate, iodide or bromide. · 1970 · https://pubmed.ncbi.nlm.nih.gov/4317722/ · DOI 10.1042/bj1170791

Potassium iodide: thyroid and non-thyroid mechanisms, interactions and discovery questions (2026-09-18) · lines 264–270

AI-assisted research curation; primary-study references, chemical references and label statements individually identified. Not publisher full text. · supports · Cell-free LPO/H2O2 reactions with nicotinamide nucleotides. · source_derived_draft · unverified_draft

## ki-nadph The chemistry also reaches the NADPH reducing pool. NADPH was also oxidized under the LPO/H2O2/iodide conditions. Model: Cell-free LPO/H2O2 reactions with nicotinamide nucleotides. Limitations: Chemical oxidation is not evidence that supplementation drains niacin in vivo; the authors expected thiocyanate oxidation to predominate in milk/saliva. Evidence location: Primary abstract The oxidation of reduced nicotinamide nucleotides by hydrogen peroside in the presence of lactoperoxidase and thiocyanate, iodide or bromide. · 1970 · https://pubmed.ncbi.nlm.nih.gov/4317722/ · DOI 10.1042/bj1170791

evidence_span

{"source_cache": "artifacts/niacin-redox-sources/nnt-structure-2019.abstract.txt", "locator": "Indexed abstract, reaction and structural mechanism", "start_char": 199, "end_char": 1759, "file_sha256": "edb35c2cdf2f57d604cb86da48665e5742d398f43c50f3e1622d161564c78a83", "text_sha256": "aa5063e57c35097c2fa2557ed9a7d61c3a411d90d0ded9b947525012520a5712"}

experimental_model

Cryo-EM of intact ovine NNT in different nucleotide states

exposure

Nucleotide-bound conformational states

limitations

Structural mechanism supported in ovine protein; forward flux is context dependent and not equivalent to adding phosphate to NAD. No human intake inference.

nutrient_topic

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

organism

Ovis aries

plain_language

NNT links the NADH and NADPH redox systems through membrane-coupled chemistry.

primary_references

[nnt-structure-2019] Structure and mechanism of mitochondrial proton-translocating transhydrogenase. (2019). https://pubmed.ncbi.nlm.nih.gov/31462775/ DOI: 10.1038/s41586-019-1519-2

tissue_or_cell_type

Purified mitochondrial protein

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 1003–1014

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cryo-EM of intact ovine NNT in different nucleotide states · source_derived_draft · unverified_draft

### b3-redox-nnt-coupling Structural analysis of mammalian NNT supported coupling of NADH-to-NADP+ hydride transfer to proton translocation across the mitochondrial membrane. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: NNT links the NADH and NADPH redox systems through membrane-coupled chemistry. organism: Ovis aries tissue_or_cell_type: Purified mitochondrial protein experimental_model: Cryo-EM of intact ovine NNT in different nucleotide states limitations: Structural mechanism supported in ovine protein; forward flux is context dependent and not equivalent to adding phosphate to NAD. No human intake inference. exposure: Nucleotide-bound conformational states evidence_span: {"source_cache": "artifacts/niacin-redox-sources/nnt-structure-2019.abstract.txt", "locator": "Indexed abstract, reaction and structural mechanism", "start_char": 199, "end_char": 1759, "file_sha256": "edb35c2cdf2f57d604cb86da48665e5742d398f43c50f3e1622d161564c78a83", "text_sha256": "aa5063e57c35097c2fa2557ed9a7d61c3a411d90d0ded9b947525012520a5712"} [nnt-structure-2019] Structure and mechanism of mitochondrial proton-translocating transhydrogenase. (2019). https://pubmed.ncbi.nlm.nih.gov/31462775/ DOI: 10.1038/s41586-019-1519-2

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_span

{"source_cache": "artifacts/glutathione-research/35858355.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "02c2d0e880b17ab304fab0854064813ffec5fa9e647b978a083aa88fbf8a38f0", "start_char": 0, "end_char": 1328, "text_sha256": "02c2d0e880b17ab304fab0854064813ffec5fa9e647b978a083aa88fbf8a38f0"}

experimental_model

Cryo-EM and structural comparison

exposure

Ligand-free and NADP/G6P-bound states

limitations

Structural NADP and catalytic NADP are different sites; enzyme activity is not a niacin-treatment trial.

nutrient_topic

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

organism

Human

plain_language

The reducing power used in glutathione recycling has to be replenished.

primary_references

[glutathione-p35858355] Allosteric role of a structural NADP+ molecule in glucose-6-phosphate dehydrogenase activity. (2022). https://pubmed.ncbi.nlm.nih.gov/35858355/ DOI: 10.1073/pnas.2119695119

tissue_or_cell_type

Purified wild-type G6PD and D200N

Glutathione: metabolism, signaling and nutrient connections (2026-09-17) · lines 762–773

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cryo-EM and structural comparison · source_derived_draft · unverified_draft

### glutathione-g6pd-nadph Human G6PD uses glucose-6-phosphate and catalytic NADP+ to generate NADPH. Condition category: normal nutrient_topic: Glutathione research collection; topical membership is not evidence of a direct dietary effect. plain_language: The reducing power used in glutathione recycling has to be replenished. organism: Human tissue_or_cell_type: Purified wild-type G6PD and D200N experimental_model: Cryo-EM and structural comparison limitations: Structural NADP and catalytic NADP are different sites; enzyme activity is not a niacin-treatment trial. exposure: Ligand-free and NADP/G6P-bound states evidence_span: {"source_cache": "artifacts/glutathione-research/35858355.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "02c2d0e880b17ab304fab0854064813ffec5fa9e647b978a083aa88fbf8a38f0", "start_char": 0, "end_char": 1328, "text_sha256": "02c2d0e880b17ab304fab0854064813ffec5fa9e647b978a083aa88fbf8a38f0"} [glutathione-p35858355] Allosteric role of a structural NADP+ molecule in glucose-6-phosphate dehydrogenase activity. (2022). https://pubmed.ncbi.nlm.nih.gov/35858355/ DOI: 10.1073/pnas.2119695119

cross_nutrient

Folate reduction uses nicotinamide reducing equivalents.

experimental_model

Recombinant human MTHFR; kinetics and structures.

limitations

Affinity does not quantify cellular flux.

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

MTHFR strongly preferred NADPH in this assay.

primary_references

[froese-2018] Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition (2018). https://pubmed.ncbi.nlm.nih.gov/29891918/ DOI: 10.1038/s41467-018-04735-2

tissue_or_cell_type

Purified protein

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 435–445

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

### folate-methyl-nadph-preference Purified full-length human MTHFR had apparent Km values of 35.5 micromolar for NADPH and 3760 micromolar for NADH. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: MTHFR strongly preferred NADPH in this assay. organism: Homo sapiens tissue_or_cell_type: Purified protein experimental_model: Recombinant human MTHFR; kinetics and structures. limitations: Affinity does not quantify cellular flux. cross_nutrient: Folate reduction uses nicotinamide reducing equivalents. [froese-2018] Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition (2018). https://pubmed.ncbi.nlm.nih.gov/29891918/ DOI: 10.1038/s41467-018-04735-2

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/biotin-research/31006591.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0dcedbfac623863bd4ae86ed1bb97cef0ef56bd417bd0d49507ef47d16af7b4e", "start_char": 0, "end_char": 1141, "text_sha256": "0dcedbfac623863bd4ae86ed1bb97cef0ef56bd417bd0d49507ef47d16af7b4e"}

experimental_model

Liver-specific Pcx-knockout mice

exposure

Genetic deletion of hepatic pyruvate carboxylase

limitations

Genetic enzyme deletion is not a dietary biotin experiment. Cross-nutrient implications identify pathway dependence rather than a proven supplement response.

nutrient_topic

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

organism

Mus musculus

plain_language

Failure of this carbon-supply step can affect the niacin-derived reducing-power pool.

primary_references

[b7-p31006591] Pyruvate-Carboxylase-Mediated Anaplerosis Promotes Antioxidant Capacity by Sustaining TCA Cycle and Redox Metabolism in Liver. (2019). https://pubmed.ncbi.nlm.nih.gov/31006591/ DOI: 10.1016/j.cmet.2019.03.014

tissue_or_cell_type

Liver and systemic metabolism

trigger_kind

machinery_impairment Imported condition classification; unverified.

Biotin: carboxylases, recycling, deficiency and nutrient interactions (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 · Liver-specific Pcx-knockout mice · source_derived_draft · unverified_draft

### b7-pc-null-nadph Liver-specific Pcx deletion depleted hepatic NADPH and worsened oxidative stress. Condition category: machinery_impairment nutrient_topic: Biotin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Failure of this carbon-supply step can affect the niacin-derived reducing-power pool. organism: Mus musculus tissue_or_cell_type: Liver and systemic metabolism experimental_model: Liver-specific Pcx-knockout mice limitations: Genetic enzyme deletion is not a dietary biotin experiment. Cross-nutrient implications identify pathway dependence rather than a proven supplement response. exposure: Genetic deletion of hepatic pyruvate carboxylase evidence_span: {"source_cache": "artifacts/biotin-research/31006591.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0dcedbfac623863bd4ae86ed1bb97cef0ef56bd417bd0d49507ef47d16af7b4e", "start_char": 0, "end_char": 1141, "text_sha256": "0dcedbfac623863bd4ae86ed1bb97cef0ef56bd417bd0d49507ef47d16af7b4e"} [b7-p31006591] Pyruvate-Carboxylase-Mediated Anaplerosis Promotes Antioxidant Capacity by Sustaining TCA Cycle and Redox Metabolism in Liver. (2019). https://pubmed.ncbi.nlm.nih.gov/31006591/ DOI: 10.1016/j.cmet.2019.03.014

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/dim-research/19884324.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3f702cc9af1528241d8572b8bcafc23dacb5ed3cacf6bb77403e8aa40d21a214", "start_char": 0, "end_char": 1738, "text_sha256": "3f702cc9af1528241d8572b8bcafc23dacb5ed3cacf6bb77403e8aa40d21a214"}

experimental_model

Recombinant protein and engineered bacterial coexpression

exposure

POR mutation and added FMN

limitations

In-vitro rescue of one mutant; not a dietary-riboflavin deficiency experiment or evidence that FMN reverses a DIM-drug interaction.

nutrient_topic

Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. · 3,3'-Diindolylmethane / DIM

organism

Human POR Y181D and human CYP1A2 in engineered systems

plain_language

Inducing an enzyme is not enough if its electron-supply machinery fails.

primary_references

[dim-p19884324] Human cytochrome P450 oxidoreductase deficiency caused by the Y181D mutation: molecular consequences and rescue of defect. (2010). https://pubmed.ncbi.nlm.nih.gov/19884324/ DOI: 10.1124/dmd.109.030445

tissue_or_cell_type

FMN-dependent electron transfer

trigger_kind

machinery_impairment Imported condition classification; unverified.

Diindolylmethane (DIM): formation, receptor signaling, metabolism and drug interactions (2026-09-17) · lines 272–283

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

### dim-por-fmn-loss POR Y181D lacked bound FMN and poorly supported CYP1A2-catalyzed reactions despite retaining FAD binding and NADPH utilization. Condition category: machinery_impairment nutrient_topic: Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. plain_language: Inducing an enzyme is not enough if its electron-supply machinery fails. organism: Human POR Y181D and human CYP1A2 in engineered systems tissue_or_cell_type: FMN-dependent electron transfer experimental_model: Recombinant protein and engineered bacterial coexpression limitations: In-vitro rescue of one mutant; not a dietary-riboflavin deficiency experiment or evidence that FMN reverses a DIM-drug interaction. exposure: POR mutation and added FMN evidence_span: {"source_cache": "artifacts/dim-research/19884324.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3f702cc9af1528241d8572b8bcafc23dacb5ed3cacf6bb77403e8aa40d21a214", "start_char": 0, "end_char": 1738, "text_sha256": "3f702cc9af1528241d8572b8bcafc23dacb5ed3cacf6bb77403e8aa40d21a214"} [dim-p19884324] Human cytochrome P450 oxidoreductase deficiency caused by the Y181D mutation: molecular consequences and rescue of defect. (2010). https://pubmed.ncbi.nlm.nih.gov/19884324/ DOI: 10.1124/dmd.109.030445

evidence_span

{"source_cache": "artifacts/dim-research/14998432.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "fa9fa0887ce5587c5c1894fd10a4afa651eac8220683d06745675a72f3e1ba2f", "start_char": 0, "end_char": 1208, "text_sha256": "fa9fa0887ce5587c5c1894fd10a4afa651eac8220683d06745675a72f3e1ba2f"}

experimental_model

Human microsomes and recombinant CYP comparison

exposure

NADPH-dependent substrate consumption and selective inhibition

limitations

Enzyme phenotyping; not a trial of DIM with tizanidine.

nutrient_topic

Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. · 3,3'-Diindolylmethane / DIM

organism

Human CYP enzymes

plain_language

Tizanidine has a strong pathway connection, while the size and direction of a DIM interaction remain unmeasured.

primary_references

[dim-p14998432] Tizanidine is mainly metabolized by cytochrome p450 1A2 in vitro. (2004). https://pubmed.ncbi.nlm.nih.gov/14998432/ DOI: 10.1046/j.1365-2125.2003.02028.x

tissue_or_cell_type

Tizanidine metabolism

Diindolylmethane (DIM): formation, receptor signaling, metabolism and drug interactions (2026-09-17) · lines 779–790

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human microsomes and recombinant CYP comparison · source_derived_draft · unverified_draft

### dim-tizanidine-1a2 CYP1A2 was the predominant tested catalyst of tizanidine metabolism. Condition category: normal nutrient_topic: Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. plain_language: Tizanidine has a strong pathway connection, while the size and direction of a DIM interaction remain unmeasured. organism: Human CYP enzymes tissue_or_cell_type: Tizanidine metabolism experimental_model: Human microsomes and recombinant CYP comparison limitations: Enzyme phenotyping; not a trial of DIM with tizanidine. exposure: NADPH-dependent substrate consumption and selective inhibition evidence_span: {"source_cache": "artifacts/dim-research/14998432.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "fa9fa0887ce5587c5c1894fd10a4afa651eac8220683d06745675a72f3e1ba2f", "start_char": 0, "end_char": 1208, "text_sha256": "fa9fa0887ce5587c5c1894fd10a4afa651eac8220683d06745675a72f3e1ba2f"} [dim-p14998432] Tizanidine is mainly metabolized by cytochrome p450 1A2 in vitro. (2004). https://pubmed.ncbi.nlm.nih.gov/14998432/ DOI: 10.1046/j.1365-2125.2003.02028.x

cross_nutrient

false

evidence_location

Primary Tables 3-5, Figure 6A and Experimental procedures; full text retrieved.

experimental_model

Partially purified human CYP27B1 membrane assay

exposure

5-40 nM CYP27B1; 15 micromolar FDX1, 0.4 micromolar FDXR, 50 micromolar NADPH; 2 min at 37 C. Table 5/Figure 6A.

limitations

D2 kinetic data came from one experiment; results do not establish human dosing equivalence.

nutrient

Vitamin D2 and D3 · Vitamin D2 and D3

nutrient_topic

Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin D2 and D3

organism

Homo sapiens proteins

plain_language

CYP27B1 completes activation of the D2 precursor.

primary_references

[tang2012] Expression of human CYP27B1 in Escherichia coli and characterization in phospholipid vesicles. (2012). https://pubmed.ncbi.nlm.nih.gov/22862690/ DOI: 10.1111/j.1742-4658.2012.08736.x

tissue_or_cell_type

reconstituted inner-mitochondrial-membrane model

Vitamin D2 and D3: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 437–450

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Partially purified human CYP27B1 membrane assay · source_derived_draft · unverified_draft

### vd-act-cyp27b1-d2 Human CYP27B1 1alpha-hydroxylated 25-hydroxyvitamin D2 in phospholipid vesicles; low-substrate catalytic efficiency was similar to that measured for calcifediol. Condition category: normal nutrient_topic: Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect. plain_language: CYP27B1 completes activation of the D2 precursor. organism: Homo sapiens proteins tissue_or_cell_type: reconstituted inner-mitochondrial-membrane model experimental_model: Partially purified human CYP27B1 membrane assay limitations: D2 kinetic data came from one experiment; results do not establish human dosing equivalence. exposure: 5-40 nM CYP27B1; 15 micromolar FDX1, 0.4 micromolar FDXR, 50 micromolar NADPH; 2 min at 37 C. Table 5/Figure 6A. cross_nutrient: false evidence_location: Primary Tables 3-5, Figure 6A and Experimental procedures; full text retrieved. nutrient: Vitamin D2 and D3 [tang2012] Expression of human CYP27B1 in Escherichia coli and characterization in phospholipid vesicles. (2012). https://pubmed.ncbi.nlm.nih.gov/22862690/ DOI: 10.1111/j.1742-4658.2012.08736.x

cross_nutrient

true

evidence_location

Primary Tables 3-5, Figure 6A and Experimental procedures; full text retrieved.

experimental_model

Human CYP27B1/FDX1/FDXR kinetic reconstitution

exposure

FDX1 1-30 micromolar; 2-min incubations with calcifediol; Table 4.

limitations

The experiment varies intact FDX1, not dietary iron. Reciprocal changes of apparent Km and turnover prevent interpreting FDX1 level as a universal limiting factor.

nutrient

Vitamin D2 and D3 · Vitamin D2 and D3

nutrient_topic

Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin D2 and D3

organism

Homo sapiens proteins

plain_language

An iron-sulfur electron carrier supports the final D3 activation step.

primary_references

[tang2012] Expression of human CYP27B1 in Escherichia coli and characterization in phospholipid vesicles. (2012). https://pubmed.ncbi.nlm.nih.gov/22862690/ DOI: 10.1111/j.1742-4658.2012.08736.x

tissue_or_cell_type

reconstituted mitochondrial membrane

Vitamin D2 and D3: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 452–465

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human CYP27B1/FDX1/FDXR kinetic reconstitution · source_derived_draft · unverified_draft

### vd-act-fdx1-cyp27b1 Human adrenodoxin supported CYP27B1 activity in reconstituted vesicles; varying adrenodoxin changed apparent kinetic parameters for calcifediol hydroxylation. Condition category: normal nutrient_topic: Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect. plain_language: An iron-sulfur electron carrier supports the final D3 activation step. organism: Homo sapiens proteins tissue_or_cell_type: reconstituted mitochondrial membrane experimental_model: Human CYP27B1/FDX1/FDXR kinetic reconstitution limitations: The experiment varies intact FDX1, not dietary iron. Reciprocal changes of apparent Km and turnover prevent interpreting FDX1 level as a universal limiting factor. exposure: FDX1 1-30 micromolar; 2-min incubations with calcifediol; Table 4. cross_nutrient: true evidence_location: Primary Tables 3-5, Figure 6A and Experimental procedures; full text retrieved. nutrient: Vitamin D2 and D3 [tang2012] Expression of human CYP27B1 in Escherichia coli and characterization in phospholipid vesicles. (2012). https://pubmed.ncbi.nlm.nih.gov/22862690/ DOI: 10.1111/j.1742-4658.2012.08736.x

cross_nutrient

true

evidence_location

Primary Tables 3-5, Figure 6A and Experimental procedures; full text retrieved.

experimental_model

Human protein reconstitution and substrate turnover

exposure

0.4 micromolar FDXR, 15 micromolar FDX1 and 50 micromolar NADPH; Experimental procedures.

limitations

This record reports the supported redox chain; FDXR omission or dietary niacin/riboflavin intervention was not reported in the extracted experiment.

nutrient

Vitamin D2 and D3 · Vitamin D2 and D3

nutrient_topic

Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin D2 and D3

organism

Homo sapiens proteins

plain_language

A reductase feeds the electron carrier used during vitamin D activation.

primary_references

[tang2012] Expression of human CYP27B1 in Escherichia coli and characterization in phospholipid vesicles. (2012). https://pubmed.ncbi.nlm.nih.gov/22862690/ DOI: 10.1111/j.1742-4658.2012.08736.x

tissue_or_cell_type

mitochondrial redox-partner assay

Vitamin D2 and D3: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 467–480

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human protein reconstitution and substrate turnover · source_derived_draft · unverified_draft

### vd-act-fdxr-cyp27b1-system The active human CYP27B1 reconstitution supplied human adrenodoxin reductase and NADPH upstream of human adrenodoxin. Condition category: normal nutrient_topic: Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect. plain_language: A reductase feeds the electron carrier used during vitamin D activation. organism: Homo sapiens proteins tissue_or_cell_type: mitochondrial redox-partner assay experimental_model: Human protein reconstitution and substrate turnover limitations: This record reports the supported redox chain; FDXR omission or dietary niacin/riboflavin intervention was not reported in the extracted experiment. exposure: 0.4 micromolar FDXR, 15 micromolar FDX1 and 50 micromolar NADPH; Experimental procedures. cross_nutrient: true evidence_location: Primary Tables 3-5, Figure 6A and Experimental procedures; full text retrieved. nutrient: Vitamin D2 and D3 [tang2012] Expression of human CYP27B1 in Escherichia coli and characterization in phospholipid vesicles. (2012). https://pubmed.ncbi.nlm.nih.gov/22862690/ DOI: 10.1111/j.1742-4658.2012.08736.x

cross_nutrient

true

evidence_location

Primary Figure 2C; Methods 2.3 and reconstitution assays.

experimental_model

Purified enzyme and phospholipid-vesicle reconstitution

exposure

0.25 micromolar CYP2R1; varied POR; 30 min at 37 C; Figure 2C.

limitations

Assay optimum is not a tissue expression target or a vitamin dosing requirement.

nutrient

Vitamin D2 and D3 · Vitamin D2 and D3

nutrient_topic

Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin D2 and D3

organism

Homo sapiens proteins

plain_language

CYP2R1 needs an electron-supplying partner.

primary_references

[cheng2018] Properties of purified CYP2R1 in a reconstituted membrane environment and its 25-hydroxylation of 20-hydroxyvitamin D3. (2018). https://pubmed.ncbi.nlm.nih.gov/28716760/ DOI: 10.1016/j.jsbmb.2017.07.011

tissue_or_cell_type

reconstituted membrane

Vitamin D2 and D3: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 392–405

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

### vd-act-por-support Human POR supported CYP2R1-mediated cholecalciferol 25-hydroxylation, with maximal measured activity near a 4:1 POR:CYP2R1 molar ratio. Condition category: normal nutrient_topic: Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect. plain_language: CYP2R1 needs an electron-supplying partner. organism: Homo sapiens proteins tissue_or_cell_type: reconstituted membrane experimental_model: Purified enzyme and phospholipid-vesicle reconstitution limitations: Assay optimum is not a tissue expression target or a vitamin dosing requirement. exposure: 0.25 micromolar CYP2R1; varied POR; 30 min at 37 C; Figure 2C. cross_nutrient: true evidence_location: Primary Figure 2C; Methods 2.3 and reconstitution assays. nutrient: Vitamin D2 and D3 [cheng2018] Properties of purified CYP2R1 in a reconstituted membrane environment and its 25-hydroxylation of 20-hydroxyvitamin D3. (2018). https://pubmed.ncbi.nlm.nih.gov/28716760/ DOI: 10.1016/j.jsbmb.2017.07.011

evidence_span

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experimental_model

Recombinant P450 screen and mouse brain comparisons

exposure

Eleven P450 isozymes; NADPH-dependent 6-hydroxylation/O-demethylation

limitations

Catalytic capacity in an enzyme assay is not whole-body contribution. CYP1B1 is an extrahepatic route; human proteins are not substituted for mouse knockout identity.

nutrient_topic

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

organism

Human recombinant enzymes; separate mouse knockout experiment

plain_language

Melatonin has multiple metabolic routes whose importance depends on enzyme and tissue.

primary_references

[melatonin-p15616152] Metabolism of melatonin by human cytochromes p450. (2005). https://pubmed.ncbi.nlm.nih.gov/15616152/ DOI: 10.1124/dmd.104.002410

tissue_or_cell_type

Oxidative melatonin metabolism

Melatonin: synthesis, receptors, circadian timing and nutrient interactions (2026-09-17) · lines 565–576

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant P450 screen and mouse brain comparisons · source_derived_draft · unverified_draft

### melatonin-cyp-1a1-hydroxylation Recombinant human CYP1A1 catalyzed melatonin 6-hydroxylation. Condition category: normal nutrient_topic: Melatonin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Melatonin has multiple metabolic routes whose importance depends on enzyme and tissue. organism: Human recombinant enzymes; separate mouse knockout experiment tissue_or_cell_type: Oxidative melatonin metabolism experimental_model: Recombinant P450 screen and mouse brain comparisons limitations: Catalytic capacity in an enzyme assay is not whole-body contribution. CYP1B1 is an extrahepatic route; human proteins are not substituted for mouse knockout identity. exposure: Eleven P450 isozymes; NADPH-dependent 6-hydroxylation/O-demethylation evidence_span: {"source_cache": "artifacts/melatonin-research/15616152.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "482334074e10503323360f236e00b5b837c5b082a7cda4df000a23d491bff8a2", "start_char": 0, "end_char": 1733, "text_sha256": "482334074e10503323360f236e00b5b837c5b082a7cda4df000a23d491bff8a2"} [melatonin-p15616152] Metabolism of melatonin by human cytochromes p450. (2005). https://pubmed.ncbi.nlm.nih.gov/15616152/ DOI: 10.1124/dmd.104.002410

evidence_span

{"source_cache": "artifacts/melatonin-research/15616152.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "482334074e10503323360f236e00b5b837c5b082a7cda4df000a23d491bff8a2", "start_char": 0, "end_char": 1733, "text_sha256": "482334074e10503323360f236e00b5b837c5b082a7cda4df000a23d491bff8a2"}

experimental_model

Recombinant P450 screen and mouse brain comparisons

exposure

Eleven P450 isozymes; NADPH-dependent 6-hydroxylation/O-demethylation

limitations

Catalytic capacity in an enzyme assay is not whole-body contribution. CYP1B1 is an extrahepatic route; human proteins are not substituted for mouse knockout identity.

nutrient_topic

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

organism

Human recombinant enzymes; separate mouse knockout experiment

plain_language

Removing the methyl group returns a molecule with the identity of a synthetic precursor.

primary_references

[melatonin-p15616152] Metabolism of melatonin by human cytochromes p450. (2005). https://pubmed.ncbi.nlm.nih.gov/15616152/ DOI: 10.1124/dmd.104.002410

tissue_or_cell_type

Oxidative melatonin metabolism

Melatonin: synthesis, receptors, circadian timing and nutrient interactions (2026-09-17) · lines 617–628

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant P450 screen and mouse brain comparisons · source_derived_draft · unverified_draft

### melatonin-cyp-1a2-demethylation Human CYP1A2 catalyzed melatonin O-demethylation to a lesser extent than CYP2C19 in the study. Condition category: normal nutrient_topic: Melatonin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Removing the methyl group returns a molecule with the identity of a synthetic precursor. organism: Human recombinant enzymes; separate mouse knockout experiment tissue_or_cell_type: Oxidative melatonin metabolism experimental_model: Recombinant P450 screen and mouse brain comparisons limitations: Catalytic capacity in an enzyme assay is not whole-body contribution. CYP1B1 is an extrahepatic route; human proteins are not substituted for mouse knockout identity. exposure: Eleven P450 isozymes; NADPH-dependent 6-hydroxylation/O-demethylation evidence_span: {"source_cache": "artifacts/melatonin-research/15616152.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "482334074e10503323360f236e00b5b837c5b082a7cda4df000a23d491bff8a2", "start_char": 0, "end_char": 1733, "text_sha256": "482334074e10503323360f236e00b5b837c5b082a7cda4df000a23d491bff8a2"} [melatonin-p15616152] Metabolism of melatonin by human cytochromes p450. (2005). https://pubmed.ncbi.nlm.nih.gov/15616152/ DOI: 10.1124/dmd.104.002410

evidence_span

{"source_cache": "artifacts/melatonin-research/15616152.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "482334074e10503323360f236e00b5b837c5b082a7cda4df000a23d491bff8a2", "start_char": 0, "end_char": 1733, "text_sha256": "482334074e10503323360f236e00b5b837c5b082a7cda4df000a23d491bff8a2"}

experimental_model

Recombinant P450 screen and mouse brain comparisons

exposure

Eleven P450 isozymes; NADPH-dependent 6-hydroxylation/O-demethylation

limitations

Catalytic capacity in an enzyme assay is not whole-body contribution. CYP1B1 is an extrahepatic route; human proteins are not substituted for mouse knockout identity.

nutrient_topic

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

organism

Human recombinant enzymes; separate mouse knockout experiment

plain_language

Melatonin has multiple metabolic routes whose importance depends on enzyme and tissue.

primary_references

[melatonin-p15616152] Metabolism of melatonin by human cytochromes p450. (2005). https://pubmed.ncbi.nlm.nih.gov/15616152/ DOI: 10.1124/dmd.104.002410

tissue_or_cell_type

Oxidative melatonin metabolism

Melatonin: synthesis, receptors, circadian timing and nutrient interactions (2026-09-17) · lines 578–589

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant P450 screen and mouse brain comparisons · source_derived_draft · unverified_draft

### melatonin-cyp-1b1-hydroxylation Recombinant human CYP1B1 catalyzed melatonin 6-hydroxylation. Condition category: normal nutrient_topic: Melatonin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Melatonin has multiple metabolic routes whose importance depends on enzyme and tissue. organism: Human recombinant enzymes; separate mouse knockout experiment tissue_or_cell_type: Oxidative melatonin metabolism experimental_model: Recombinant P450 screen and mouse brain comparisons limitations: Catalytic capacity in an enzyme assay is not whole-body contribution. CYP1B1 is an extrahepatic route; human proteins are not substituted for mouse knockout identity. exposure: Eleven P450 isozymes; NADPH-dependent 6-hydroxylation/O-demethylation evidence_span: {"source_cache": "artifacts/melatonin-research/15616152.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "482334074e10503323360f236e00b5b837c5b082a7cda4df000a23d491bff8a2", "start_char": 0, "end_char": 1733, "text_sha256": "482334074e10503323360f236e00b5b837c5b082a7cda4df000a23d491bff8a2"} [melatonin-p15616152] Metabolism of melatonin by human cytochromes p450. (2005). https://pubmed.ncbi.nlm.nih.gov/15616152/ DOI: 10.1124/dmd.104.002410

evidence_span

{"source_cache": "artifacts/melatonin-research/15616152.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "482334074e10503323360f236e00b5b837c5b082a7cda4df000a23d491bff8a2", "start_char": 0, "end_char": 1733, "text_sha256": "482334074e10503323360f236e00b5b837c5b082a7cda4df000a23d491bff8a2"}

experimental_model

Recombinant P450 screen and mouse brain comparisons

exposure

Eleven P450 isozymes; NADPH-dependent 6-hydroxylation/O-demethylation

limitations

Catalytic capacity in an enzyme assay is not whole-body contribution. CYP1B1 is an extrahepatic route; human proteins are not substituted for mouse knockout identity.

nutrient_topic

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

organism

Human recombinant enzymes; separate mouse knockout experiment

plain_language

Removing the methyl group returns a molecule with the identity of a synthetic precursor.

primary_references

[melatonin-p15616152] Metabolism of melatonin by human cytochromes p450. (2005). https://pubmed.ncbi.nlm.nih.gov/15616152/ DOI: 10.1124/dmd.104.002410

tissue_or_cell_type

Oxidative melatonin metabolism

Melatonin: synthesis, receptors, circadian timing and nutrient interactions (2026-09-17) · lines 604–615

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant P450 screen and mouse brain comparisons · source_derived_draft · unverified_draft

### melatonin-cyp-2c19-demethylation Human CYP2C19 catalyzed melatonin O-demethylation. Condition category: normal nutrient_topic: Melatonin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Removing the methyl group returns a molecule with the identity of a synthetic precursor. organism: Human recombinant enzymes; separate mouse knockout experiment tissue_or_cell_type: Oxidative melatonin metabolism experimental_model: Recombinant P450 screen and mouse brain comparisons limitations: Catalytic capacity in an enzyme assay is not whole-body contribution. CYP1B1 is an extrahepatic route; human proteins are not substituted for mouse knockout identity. exposure: Eleven P450 isozymes; NADPH-dependent 6-hydroxylation/O-demethylation evidence_span: {"source_cache": "artifacts/melatonin-research/15616152.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "482334074e10503323360f236e00b5b837c5b082a7cda4df000a23d491bff8a2", "start_char": 0, "end_char": 1733, "text_sha256": "482334074e10503323360f236e00b5b837c5b082a7cda4df000a23d491bff8a2"} [melatonin-p15616152] Metabolism of melatonin by human cytochromes p450. (2005). https://pubmed.ncbi.nlm.nih.gov/15616152/ DOI: 10.1124/dmd.104.002410

evidence_span

{"source_cache": "artifacts/melatonin-research/15616152.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "482334074e10503323360f236e00b5b837c5b082a7cda4df000a23d491bff8a2", "start_char": 0, "end_char": 1733, "text_sha256": "482334074e10503323360f236e00b5b837c5b082a7cda4df000a23d491bff8a2"}

experimental_model

Recombinant P450 screen and mouse brain comparisons

exposure

Eleven P450 isozymes; NADPH-dependent 6-hydroxylation/O-demethylation

limitations

Catalytic capacity in an enzyme assay is not whole-body contribution. CYP1B1 is an extrahepatic route; human proteins are not substituted for mouse knockout identity.

nutrient_topic

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

organism

Human recombinant enzymes; separate mouse knockout experiment

plain_language

Melatonin has multiple metabolic routes whose importance depends on enzyme and tissue.

primary_references

[melatonin-p15616152] Metabolism of melatonin by human cytochromes p450. (2005). https://pubmed.ncbi.nlm.nih.gov/15616152/ DOI: 10.1124/dmd.104.002410

tissue_or_cell_type

Oxidative melatonin metabolism

Melatonin: synthesis, receptors, circadian timing and nutrient interactions (2026-09-17) · lines 591–602

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant P450 screen and mouse brain comparisons · source_derived_draft · unverified_draft

### melatonin-cyp-2c19-hydroxylation Recombinant human CYP2C19 catalyzed melatonin 6-hydroxylation to a minor extent in this screen. Condition category: normal nutrient_topic: Melatonin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Melatonin has multiple metabolic routes whose importance depends on enzyme and tissue. organism: Human recombinant enzymes; separate mouse knockout experiment tissue_or_cell_type: Oxidative melatonin metabolism experimental_model: Recombinant P450 screen and mouse brain comparisons limitations: Catalytic capacity in an enzyme assay is not whole-body contribution. CYP1B1 is an extrahepatic route; human proteins are not substituted for mouse knockout identity. exposure: Eleven P450 isozymes; NADPH-dependent 6-hydroxylation/O-demethylation evidence_span: {"source_cache": "artifacts/melatonin-research/15616152.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "482334074e10503323360f236e00b5b837c5b082a7cda4df000a23d491bff8a2", "start_char": 0, "end_char": 1733, "text_sha256": "482334074e10503323360f236e00b5b837c5b082a7cda4df000a23d491bff8a2"} [melatonin-p15616152] Metabolism of melatonin by human cytochromes p450. (2005). https://pubmed.ncbi.nlm.nih.gov/15616152/ DOI: 10.1124/dmd.104.002410

evidence_access

Primary abstract

experimental_model

Cell-free NADH/NADPH oxidation experiments.

limitations

Not evidence of a measured whole-body NAD shortage.

nutrient_topic

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

plain_language

Reducing equivalents can be consumed by a metal-dependent reaction.

primary_references

Vanadate-mediated oxidation of NADH: description of an in vitro system requiring ascorbate and phosphate. · 1989 · https://pubmed.ncbi.nlm.nih.gov/2735768/ · DOI 10.1016/0003-9861(89)90196-3

Vanadium: speciation, phosphate-sensitive enzymes 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 · Cell-free NADH/NADPH oxidation experiments. · source_derived_draft · unverified_draft

## vanadium-nadh-oxidation Reducing equivalents can be consumed by a metal-dependent reaction. A vanadate/ascorbate/phosphate system oxidized NADH, with similar results for NADPH, through a proposed superoxide-initiated chain reaction. Model: Cell-free NADH/NADPH oxidation experiments. Limitations: Not evidence of a measured whole-body NAD shortage. Evidence access: Primary abstract Vanadate-mediated oxidation of NADH: description of an in vitro system requiring ascorbate and phosphate. · 1989 · https://pubmed.ncbi.nlm.nih.gov/2735768/ · DOI 10.1016/0003-9861(89)90196-3

evidence_span

{"source_cache": "artifacts/coq10-research/38425362.fulltext.txt", "locator": "Primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7d25af4ecd7340649536b8fea3b8a0a308a1611bbf8c57f6a79b362f443f1cba", "start_char": 9067, "end_char": 13813, "text_sha256": "49612ae4d3a59a75a02fe3fb132abd8aeb7ef8b7cae3b0f79b5557503c55ad51"}

experimental_model

Purified reconstructed COQ metabolon with short-chain substrates

exposure

Enzyme combinations, methyl donors, reductants and metal additions

limitations

Ancestral proteins and CoQ1 analogues; no clinical cofactor dose or proof of nutritional rate limitation. Reaction order need not be universal across species.

nutrient_topic

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

organism

Reconstructed ancestral tetrapod proteins

plain_language

The monooxygenase needed its electron-supplying partners.

primary_references

[coq10-p38425362] In vitro construction of the COQ metabolon unveils the molecular determinants of coenzyme Q biosynthesis. (2024). https://pubmed.ncbi.nlm.nih.gov/38425362/ DOI: 10.1038/s41929-023-01087-z

tissue_or_cell_type

Stepwise CoQ head-group assembly

Coenzyme Q10: biosynthesis, electron transfer, antioxidant recycling and nutrient interactions (2026-09-17) · lines 632–643

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified reconstructed COQ metabolon with short-chain substrates · source_derived_draft · unverified_draft

### coq10-fdx2-coq6 COQ6 substrate conversion required the FDXR-FDX2 pair in the reconstructed assay. Condition category: normal nutrient_topic: Coenzyme Q10 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The monooxygenase needed its electron-supplying partners. organism: Reconstructed ancestral tetrapod proteins tissue_or_cell_type: Stepwise CoQ head-group assembly experimental_model: Purified reconstructed COQ metabolon with short-chain substrates limitations: Ancestral proteins and CoQ1 analogues; no clinical cofactor dose or proof of nutritional rate limitation. Reaction order need not be universal across species. exposure: Enzyme combinations, methyl donors, reductants and metal additions evidence_span: {"source_cache": "artifacts/coq10-research/38425362.fulltext.txt", "locator": "Primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7d25af4ecd7340649536b8fea3b8a0a308a1611bbf8c57f6a79b362f443f1cba", "start_char": 9067, "end_char": 13813, "text_sha256": "49612ae4d3a59a75a02fe3fb132abd8aeb7ef8b7cae3b0f79b5557503c55ad51"} [coq10-p38425362] In vitro construction of the COQ metabolon unveils the molecular determinants of coenzyme Q biosynthesis. (2024). https://pubmed.ncbi.nlm.nih.gov/38425362/ DOI: 10.1038/s41929-023-01087-z

evidence_span

{"source_cache": "artifacts/coq10-research/38425362.fulltext.txt", "locator": "Primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7d25af4ecd7340649536b8fea3b8a0a308a1611bbf8c57f6a79b362f443f1cba", "start_char": 9067, "end_char": 13813, "text_sha256": "49612ae4d3a59a75a02fe3fb132abd8aeb7ef8b7cae3b0f79b5557503c55ad51"}

experimental_model

Purified reconstructed COQ metabolon with short-chain substrates

exposure

Enzyme combinations, methyl donors, reductants and metal additions

limitations

Ancestral proteins and CoQ1 analogues; no clinical cofactor dose or proof of nutritional rate limitation. Reaction order need not be universal across species.

nutrient_topic

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

organism

Reconstructed ancestral tetrapod proteins

plain_language

The synthesis pathway has a separate relay supplying reducing power.

primary_references

[coq10-p38425362] In vitro construction of the COQ metabolon unveils the molecular determinants of coenzyme Q biosynthesis. (2024). https://pubmed.ncbi.nlm.nih.gov/38425362/ DOI: 10.1038/s41929-023-01087-z

tissue_or_cell_type

Stepwise CoQ head-group assembly

Coenzyme Q10: biosynthesis, electron transfer, antioxidant recycling and nutrient interactions (2026-09-17) · lines 619–630

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified reconstructed COQ metabolon with short-chain substrates · source_derived_draft · unverified_draft

### coq10-fdxr-fdx2 FDX2 accepted electrons from reduced FDXR in the reconstructed system. Condition category: normal nutrient_topic: Coenzyme Q10 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The synthesis pathway has a separate relay supplying reducing power. organism: Reconstructed ancestral tetrapod proteins tissue_or_cell_type: Stepwise CoQ head-group assembly experimental_model: Purified reconstructed COQ metabolon with short-chain substrates limitations: Ancestral proteins and CoQ1 analogues; no clinical cofactor dose or proof of nutritional rate limitation. Reaction order need not be universal across species. exposure: Enzyme combinations, methyl donors, reductants and metal additions evidence_span: {"source_cache": "artifacts/coq10-research/38425362.fulltext.txt", "locator": "Primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7d25af4ecd7340649536b8fea3b8a0a308a1611bbf8c57f6a79b362f443f1cba", "start_char": 9067, "end_char": 13813, "text_sha256": "49612ae4d3a59a75a02fe3fb132abd8aeb7ef8b7cae3b0f79b5557503c55ad51"} [coq10-p38425362] In vitro construction of the COQ metabolon unveils the molecular determinants of coenzyme Q biosynthesis. (2024). https://pubmed.ncbi.nlm.nih.gov/38425362/ DOI: 10.1038/s41929-023-01087-z

evidence_span

{"source_cache": "artifacts/coq10-research/12435734.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "929e8de2bc15ea62eb4a3814995fd289de759d721f16b848174ad65f95847c55", "start_char": 0, "end_char": 1340, "text_sha256": "929e8de2bc15ea62eb4a3814995fd289de759d721f16b848174ad65f95847c55"}

experimental_model

Enzyme kinetics, mutants and overexpressing-cell homogenates

exposure

NADPH or NADH; selenite and selenium-deprived enzyme variants

limitations

Biochemical selenium dependence; not proof that all CoQ recycling stops with low selenium or that combined supplements are synergistic clinically.

nutrient_topic

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

organism

Mammalian TrxR1 and human HEK293 cells

plain_language

A selenium-dependent enzyme can regenerate the antioxidant form of CoQ.

primary_references

[coq10-p12435734] The mammalian cytosolic selenoenzyme thioredoxin reductase reduces ubiquinone. A novel mechanism for defense against oxidative stress. (2003). https://pubmed.ncbi.nlm.nih.gov/12435734/ DOI: 10.1074/jbc.m210456200

tissue_or_cell_type

Ubiquinone reduction

Coenzyme Q10: biosynthesis, electron transfer, antioxidant recycling and nutrient interactions (2026-09-17) · lines 762–773

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Enzyme kinetics, mutants and overexpressing-cell homogenates · source_derived_draft · unverified_draft

### coq10-txnrd1-coq Mammalian TrxR1 reduced ubiquinone-10 to ubiquinol-10. Condition category: normal nutrient_topic: Coenzyme Q10 research collection; topical membership is not evidence of a direct dietary effect. plain_language: A selenium-dependent enzyme can regenerate the antioxidant form of CoQ. organism: Mammalian TrxR1 and human HEK293 cells tissue_or_cell_type: Ubiquinone reduction experimental_model: Enzyme kinetics, mutants and overexpressing-cell homogenates limitations: Biochemical selenium dependence; not proof that all CoQ recycling stops with low selenium or that combined supplements are synergistic clinically. exposure: NADPH or NADH; selenite and selenium-deprived enzyme variants evidence_span: {"source_cache": "artifacts/coq10-research/12435734.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "929e8de2bc15ea62eb4a3814995fd289de759d721f16b848174ad65f95847c55", "start_char": 0, "end_char": 1340, "text_sha256": "929e8de2bc15ea62eb4a3814995fd289de759d721f16b848174ad65f95847c55"} [coq10-p12435734] The mammalian cytosolic selenoenzyme thioredoxin reductase reduces ubiquinone. A novel mechanism for defense against oxidative stress. (2003). https://pubmed.ncbi.nlm.nih.gov/12435734/ DOI: 10.1074/jbc.m210456200

evidence_access

Primary full text

experimental_model

Mouse macrophage genetic comparison.

limitations

Does not exclude every ROS source or establish NADPH depletion. Correction record: A 2026 author correction replaces an erroneously duplicated lower-left Fig. 8c micrograph with the retrieved original. This is a figure correction, not a scientific contradiction or retraction. https://www.nature.com/articles/s41590-026-02468-9

nutrient_topic

Silica collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Silica and soluble silicon

plain_language

The phagocyte NADPH oxidase burst was not obligatory in this model.

primary_references

Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18604214/ · DOI 10.1038/ni.1631

Silica: soluble silicon, cellular transport and particle-specific mechanisms (2026-09-19) · lines 456–462

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse macrophage genetic comparison. · source_derived_draft · unverified_draft

## silica-nox2-null The phagocyte NADPH oxidase burst was not obligatory in this model. Cybb/gp91phox-deficient macrophages retained silica-triggered inflammasome responses. Model: Mouse macrophage genetic comparison. Limitations: Does not exclude every ROS source or establish NADPH depletion. Correction record: A 2026 author correction replaces an erroneously duplicated lower-left Fig. 8c micrograph with the retrieved original. This is a figure correction, not a scientific contradiction or retraction. https://www.nature.com/articles/s41590-026-02468-9 Evidence access: Primary full text Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18604214/ · DOI 10.1038/ni.1631

cross_nutrient

false

evidence_location

Figure 1A; STAR Methods: Expression of RGR and RDH10

experimental_model

Recombinant bovine RGR/RDH10 coexpression

exposure

30-minute illumination; 5 micromolar all-trans-retinol; assay medium contained 250 micromolar NADPH.

limitations

Coupled output does not prove every proposed intermediate reaction or RDH10 necessity in intact retina. Added NADPH is an assay component, not a demonstrated dietary requirement.

nutrient

Vitamin A · Vitamin A

nutrient_topic

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

organism

Bos taurus proteins in Homo sapiens cells

plain_language

The two proteins supported light-dependent retinol recycling together in cultured cells.

primary_references

[vav-morshedian2019] Light-Driven Regeneration of Cone Visual Pigments through a Mechanism Involving RGR Opsin in Müller Glial Cells. (2019). https://pubmed.ncbi.nlm.nih.gov/31056353/ DOI: 10.1016/j.neuron.2019.04.004

tissue_or_cell_type

HEK293T culture

Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17) · lines 468–481

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant bovine RGR/RDH10 coexpression · source_derived_draft · unverified_draft

### vae-rgr-rdh10-coupled-retinol HEK293T cells coexpressing bovine RGR and RDH10 generated more 11-cis-retinol from all-trans-retinol during illumination than cells expressing either protein alone. Condition category: normal nutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. plain_language: The two proteins supported light-dependent retinol recycling together in cultured cells. organism: Bos taurus proteins in Homo sapiens cells tissue_or_cell_type: HEK293T culture experimental_model: Recombinant bovine RGR/RDH10 coexpression limitations: Coupled output does not prove every proposed intermediate reaction or RDH10 necessity in intact retina. Added NADPH is an assay component, not a demonstrated dietary requirement. exposure: 30-minute illumination; 5 micromolar all-trans-retinol; assay medium contained 250 micromolar NADPH. cross_nutrient: false evidence_location: Figure 1A; STAR Methods: Expression of RGR and RDH10 nutrient: Vitamin A [vav-morshedian2019] Light-Driven Regeneration of Cone Visual Pigments through a Mechanism Involving RGR Opsin in Müller Glial Cells. (2019). https://pubmed.ncbi.nlm.nih.gov/31056353/ DOI: 10.1016/j.neuron.2019.04.004

evidence_span

{"source_cache": "artifacts/ceylon-research/26851241.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c2fb6b18a3ba708f060d53011ea0e198f98fe980930297e714c488a41413b5a2", "start_char": 0, "end_char": 1591, "text_sha256": "c2fb6b18a3ba708f060d53011ea0e198f98fe980930297e714c488a41413b5a2"}

experimental_model

Recombinant human CYP assays and mechanistic static modeling

exposure

Cinnamaldehyde, NADPH and glutathione; modeled inhibitor concentrations 0.1 and 1 micromolar

limitations

Enzyme inhibition and model predictions are not measured clinical drug interactions. NADPH omission is not dietary niacin deficiency.

nutrient_topic

Ceylon cinnamon research collection; topical membership is not evidence of a direct dietary effect. · Ceylon cinnamon / Cinnamomum verum bark preparations

organism

Human enzyme preparations; computational model

plain_language

The chemical interfered with a drug-metabolizing enzyme when its catalytic system was operating.

primary_references

[ceylon-p26851241] Inactivation of CYP2A6 by the Dietary Phenylpropanoid trans-Cinnamic Aldehyde (Cinnamaldehyde) and Estimation of Interactions with Nicotine and Letrozole. (2016). https://pubmed.ncbi.nlm.nih.gov/26851241/ DOI: 10.1124/dmd.115.067942

tissue_or_cell_type

CYP2A6 reaction system

Ceylon cinnamon: metabolism, signaling and nutrient connections (2026-09-17) · lines 727–738

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human CYP assays and mechanistic static modeling · source_derived_draft · unverified_draft

### ceylon-cyp2a6 Cinnamaldehyde inhibited recombinant human CYP2A6, with reported IC50 6.1 micromolar; inhibition increased with time and required NADPH. Condition category: normal nutrient_topic: Ceylon cinnamon research collection; topical membership is not evidence of a direct dietary effect. plain_language: The chemical interfered with a drug-metabolizing enzyme when its catalytic system was operating. organism: Human enzyme preparations; computational model tissue_or_cell_type: CYP2A6 reaction system experimental_model: Recombinant human CYP assays and mechanistic static modeling limitations: Enzyme inhibition and model predictions are not measured clinical drug interactions. NADPH omission is not dietary niacin deficiency. exposure: Cinnamaldehyde, NADPH and glutathione; modeled inhibitor concentrations 0.1 and 1 micromolar evidence_span: {"source_cache": "artifacts/ceylon-research/26851241.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c2fb6b18a3ba708f060d53011ea0e198f98fe980930297e714c488a41413b5a2", "start_char": 0, "end_char": 1591, "text_sha256": "c2fb6b18a3ba708f060d53011ea0e198f98fe980930297e714c488a41413b5a2"} [ceylon-p26851241] Inactivation of CYP2A6 by the Dietary Phenylpropanoid trans-Cinnamic Aldehyde (Cinnamaldehyde) and Estimation of Interactions with Nicotine and Letrozole. (2016). https://pubmed.ncbi.nlm.nih.gov/26851241/ DOI: 10.1124/dmd.115.067942

evidence_access

Primary full text PMC3513969, CYP methods and results

experimental_model

Human liver microsomes; product concentrations normalized to 0.5–25 micromolar lovastatin, with an NADPH-generating system.

limitations

In-vitro inhibition is not a measured interaction with every drug using this enzyme; the additional responsible constituent was not identified.

nutrient_topic

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

plain_language

The mixture changed an enzyme assay beyond its lovastatin content.

primary_references

[23227093] Interaction between Red Yeast Rice and CYP450 Enzymes/P-Glycoprotein and Its Implication for the Clinical Pharmacokinetics of Lovastatin. · 2012 · https://pubmed.ncbi.nlm.nih.gov/23227093/ · DOI 10.1155/2012/127043

Red yeast rice: constituents, mevalonate, CoQ and product-specific interactions (2026-09-20) · lines 108–114

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human liver microsomes; product concentrations normalized to 0.5–25 micromolar lovastatin, with an NADPH-generating system. · source_derived_draft · unverified_draft

## red-yeast-rice-extract-cyp1a2 The mixture changed an enzyme assay beyond its lovastatin content. The three 2012 red yeast rice product extracts inhibited human microsomal CYP1A2 more potently than pure lovastatin at matched nominal lovastatin concentrations. Model: Human liver microsomes; product concentrations normalized to 0.5–25 micromolar lovastatin, with an NADPH-generating system. Limitations: In-vitro inhibition is not a measured interaction with every drug using this enzyme; the additional responsible constituent was not identified. Evidence access: Primary full text PMC3513969, CYP methods and results [23227093] Interaction between Red Yeast Rice and CYP450 Enzymes/P-Glycoprotein and Its Implication for the Clinical Pharmacokinetics of Lovastatin. · 2012 · https://pubmed.ncbi.nlm.nih.gov/23227093/ · DOI 10.1155/2012/127043

evidence_access

Primary full text PMC3513969, CYP methods and results

experimental_model

Human liver microsomes; product concentrations normalized to 0.5–25 micromolar lovastatin, with an NADPH-generating system.

limitations

In-vitro inhibition is not a measured interaction with every drug using this enzyme; the additional responsible constituent was not identified.

nutrient_topic

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

plain_language

The mixture changed an enzyme assay beyond its lovastatin content.

primary_references

[23227093] Interaction between Red Yeast Rice and CYP450 Enzymes/P-Glycoprotein and Its Implication for the Clinical Pharmacokinetics of Lovastatin. · 2012 · https://pubmed.ncbi.nlm.nih.gov/23227093/ · DOI 10.1155/2012/127043

Red yeast rice: constituents, mevalonate, CoQ and product-specific interactions (2026-09-20) · lines 116–122

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human liver microsomes; product concentrations normalized to 0.5–25 micromolar lovastatin, with an NADPH-generating system. · source_derived_draft · unverified_draft

## red-yeast-rice-extract-cyp2c19 The mixture changed an enzyme assay beyond its lovastatin content. The three 2012 red yeast rice product extracts inhibited human microsomal CYP2C19 more potently than pure lovastatin at matched nominal lovastatin concentrations. Model: Human liver microsomes; product concentrations normalized to 0.5–25 micromolar lovastatin, with an NADPH-generating system. Limitations: In-vitro inhibition is not a measured interaction with every drug using this enzyme; the additional responsible constituent was not identified. Evidence access: Primary full text PMC3513969, CYP methods and results [23227093] Interaction between Red Yeast Rice and CYP450 Enzymes/P-Glycoprotein and Its Implication for the Clinical Pharmacokinetics of Lovastatin. · 2012 · https://pubmed.ncbi.nlm.nih.gov/23227093/ · DOI 10.1155/2012/127043

evidence_access

Primary full text PMC3513969, CYP methods and results

experimental_model

Human liver microsomes; product concentrations normalized to 0.5–25 micromolar lovastatin, with an NADPH-generating system.

limitations

In-vitro inhibition is not a measured interaction with every drug using this enzyme; the additional responsible constituent was not identified.

nutrient_topic

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

plain_language

The mixture changed an enzyme assay beyond its lovastatin content.

primary_references

[23227093] Interaction between Red Yeast Rice and CYP450 Enzymes/P-Glycoprotein and Its Implication for the Clinical Pharmacokinetics of Lovastatin. · 2012 · https://pubmed.ncbi.nlm.nih.gov/23227093/ · DOI 10.1155/2012/127043

Red yeast rice: constituents, mevalonate, CoQ and product-specific interactions (2026-09-20) · lines 124–130

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human liver microsomes; product concentrations normalized to 0.5–25 micromolar lovastatin, with an NADPH-generating system. · source_derived_draft · unverified_draft

## red-yeast-rice-extract-cyp3a4 The mixture changed an enzyme assay beyond its lovastatin content. The three 2012 red yeast rice product extracts inhibited human microsomal CYP3A4 more potently than pure lovastatin at matched nominal lovastatin concentrations. Model: Human liver microsomes; product concentrations normalized to 0.5–25 micromolar lovastatin, with an NADPH-generating system. Limitations: In-vitro inhibition is not a measured interaction with every drug using this enzyme; the additional responsible constituent was not identified. Evidence access: Primary full text PMC3513969, CYP methods and results [23227093] Interaction between Red Yeast Rice and CYP450 Enzymes/P-Glycoprotein and Its Implication for the Clinical Pharmacokinetics of Lovastatin. · 2012 · https://pubmed.ncbi.nlm.nih.gov/23227093/ · DOI 10.1155/2012/127043

evidence_access

Primary abstract

experimental_model

Human recombinant catalytic-domain crystallography and biochemical background.

limitations

Shared human machinery; the source is not an experiment administering red yeast rice.

nutrient_topic

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

plain_language

This enzyme supplies a shared precursor pathway.

primary_references

[10698924] Crystal structure of the catalytic portion of human HMG-CoA reductase: insights into regulation of activity and catalysis. · 2000 · https://pubmed.ncbi.nlm.nih.gov/10698924/ · DOI 10.1093/emboj/19.5.819

Red yeast rice: constituents, mevalonate, CoQ and product-specific interactions (2026-09-20) · lines 76–82

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human recombinant catalytic-domain crystallography and biochemical background. · source_derived_draft · unverified_draft

## red-yeast-rice-human-mevalonate-machinery This enzyme supplies a shared precursor pathway. Human HMG-CoA reductase catalyzes mevalonate formation; substrate/cofactor-bound structures locate HMG-CoA and the nicotinamide cofactor in the catalytic domain. Model: Human recombinant catalytic-domain crystallography and biochemical background. Limitations: Shared human machinery; the source is not an experiment administering red yeast rice. Evidence access: Primary abstract [10698924] Crystal structure of the catalytic portion of human HMG-CoA reductase: insights into regulation of activity and catalysis. · 2000 · https://pubmed.ncbi.nlm.nih.gov/10698924/ · DOI 10.1093/emboj/19.5.819

evidence_span

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experimental_model

Enzyme/liposome chemistry, knockout cells and warfarin-exposed mice

exposure

MK-4/K1, NAD(P)H, FSP1 loss and inhibitors

limitations

Preclinical experiments; not a demonstrated oral MK-7 treatment for ferroptosis-related disease or a self-treatment regimen for anticoagulant poisoning.

nutrient_topic

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

organism

Human recombinant FSP1, mammalian cells and mice

plain_language

A niacin-derived electron donor helps regenerate the reduced antioxidant form.

primary_references

[k2-p35922516] A non-canonical vitamin K cycle is a potent ferroptosis suppressor. (2022). https://pubmed.ncbi.nlm.nih.gov/35922516/ DOI: 10.1038/s41586-022-05022-3

tissue_or_cell_type

Lipid peroxidation and vitamin K reduction

Vitamin K2: menaquinone forms, carboxylation, recycling and nutrient interactions (2026-09-17) · lines 773–784

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Enzyme/liposome chemistry, knockout cells and warfarin-exposed mice · source_derived_draft · unverified_draft

### k2-fsp1-k-reduction FSP1 reduced vitamin K quinones to radical-trapping hydroquinones using NAD(P)H. Condition category: normal nutrient_topic: Vitamin K2 research collection; topical membership is not evidence of a direct dietary effect. plain_language: A niacin-derived electron donor helps regenerate the reduced antioxidant form. organism: Human recombinant FSP1, mammalian cells and mice tissue_or_cell_type: Lipid peroxidation and vitamin K reduction experimental_model: Enzyme/liposome chemistry, knockout cells and warfarin-exposed mice limitations: Preclinical experiments; not a demonstrated oral MK-7 treatment for ferroptosis-related disease or a self-treatment regimen for anticoagulant poisoning. exposure: MK-4/K1, NAD(P)H, FSP1 loss and inhibitors evidence_span: {"source_cache": "artifacts/k2-research/35922516.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3bd5750fd2d12a754ad4237018851391c6b5b80bac6ad58307321fb7c3042c5a", "start_char": 0, "end_char": 1403, "text_sha256": "3bd5750fd2d12a754ad4237018851391c6b5b80bac6ad58307321fb7c3042c5a"} [k2-p35922516] A non-canonical vitamin K cycle is a potent ferroptosis suppressor. (2022). https://pubmed.ncbi.nlm.nih.gov/35922516/ DOI: 10.1038/s41586-022-05022-3

evidence_span

{"source_cache": "artifacts/curcumin-research/21467222.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c4ff0be81d2a3b3bd5edb9902da02b1e599d45a5e60ab4787514e340bf63d757", "start_char": 0, "end_char": 1325, "text_sha256": "c4ff0be81d2a3b3bd5edb9902da02b1e599d45a5e60ab4787514e340bf63d757"}

experimental_model

Purification and characterization of a human-fecal bacterial enzyme

exposure

Curcumin and reduced intermediates; NADPH-dependent reactions

limitations

Bacterial biochemistry does not quantify a person's circulating metabolite concentrations or establish that dietary niacin increases this conversion.

nutrient_topic

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

organism

Escherichia coli isolate

plain_language

A gut bacterial enzyme performs the first reduction step.

primary_references

[curcumin-p21467222] Discovery of the curcumin metabolic pathway involving a unique enzyme in an intestinal microorganism. (2011). https://pubmed.ncbi.nlm.nih.gov/21467222/ DOI: 10.1073/pnas.1016217108

tissue_or_cell_type

Purified CurA

Curcumin: metabolism, signaling and nutrient connections (2026-09-17) · lines 203–214

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purification and characterization of a human-fecal bacterial enzyme · source_derived_draft · unverified_draft

### curcumin-cura-first CurA catalyzed the first reduction of curcumin to dihydrocurcumin. Condition category: normal nutrient_topic: Curcumin research collection; topical membership is not evidence of a direct dietary effect. plain_language: A gut bacterial enzyme performs the first reduction step. organism: Escherichia coli isolate tissue_or_cell_type: Purified CurA experimental_model: Purification and characterization of a human-fecal bacterial enzyme limitations: Bacterial biochemistry does not quantify a person's circulating metabolite concentrations or establish that dietary niacin increases this conversion. exposure: Curcumin and reduced intermediates; NADPH-dependent reactions evidence_span: {"source_cache": "artifacts/curcumin-research/21467222.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c4ff0be81d2a3b3bd5edb9902da02b1e599d45a5e60ab4787514e340bf63d757", "start_char": 0, "end_char": 1325, "text_sha256": "c4ff0be81d2a3b3bd5edb9902da02b1e599d45a5e60ab4787514e340bf63d757"} [curcumin-p21467222] Discovery of the curcumin metabolic pathway involving a unique enzyme in an intestinal microorganism. (2011). https://pubmed.ncbi.nlm.nih.gov/21467222/ DOI: 10.1073/pnas.1016217108

evidence_span

{"source_cache": "artifacts/curcumin-research/21467222.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c4ff0be81d2a3b3bd5edb9902da02b1e599d45a5e60ab4787514e340bf63d757", "start_char": 0, "end_char": 1325, "text_sha256": "c4ff0be81d2a3b3bd5edb9902da02b1e599d45a5e60ab4787514e340bf63d757"}

experimental_model

Purification and characterization of a human-fecal bacterial enzyme

exposure

Curcumin and reduced intermediates; NADPH-dependent reactions

limitations

Bacterial biochemistry does not quantify a person's circulating metabolite concentrations or establish that dietary niacin increases this conversion.

nutrient_topic

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

organism

Escherichia coli isolate

plain_language

The same enzyme can carry out the next step.

primary_references

[curcumin-p21467222] Discovery of the curcumin metabolic pathway involving a unique enzyme in an intestinal microorganism. (2011). https://pubmed.ncbi.nlm.nih.gov/21467222/ DOI: 10.1073/pnas.1016217108

tissue_or_cell_type

Purified CurA

Curcumin: metabolism, signaling and nutrient connections (2026-09-17) · lines 216–227

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purification and characterization of a human-fecal bacterial enzyme · source_derived_draft · unverified_draft

### curcumin-cura-second CurA then reduced dihydrocurcumin to tetrahydrocurcumin. Condition category: normal nutrient_topic: Curcumin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The same enzyme can carry out the next step. organism: Escherichia coli isolate tissue_or_cell_type: Purified CurA experimental_model: Purification and characterization of a human-fecal bacterial enzyme limitations: Bacterial biochemistry does not quantify a person's circulating metabolite concentrations or establish that dietary niacin increases this conversion. exposure: Curcumin and reduced intermediates; NADPH-dependent reactions evidence_span: {"source_cache": "artifacts/curcumin-research/21467222.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c4ff0be81d2a3b3bd5edb9902da02b1e599d45a5e60ab4787514e340bf63d757", "start_char": 0, "end_char": 1325, "text_sha256": "c4ff0be81d2a3b3bd5edb9902da02b1e599d45a5e60ab4787514e340bf63d757"} [curcumin-p21467222] Discovery of the curcumin metabolic pathway involving a unique enzyme in an intestinal microorganism. (2011). https://pubmed.ncbi.nlm.nih.gov/21467222/ DOI: 10.1073/pnas.1016217108

evidence_span

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experimental_model

Purified rat enzyme and separate HeLa-cell assays

exposure

Rat enzyme: two-hour incubation, IC50 3.6 micromolar; HeLa activity IC50 about 15 micromolar

limitations

Rat residue numbering Cys496/Sec497 is source-specific and must not replace numbering in other TrxR constructs. Cellular enzyme activity does not prove clinical cancer benefit.

nutrient_topic

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

organism

Rattus norvegicus

plain_language

The interaction included the selenium-containing active-site residue.

primary_references

[curcumin-p15879598] Thioredoxin reductase is irreversibly modified by curcumin: a novel molecular mechanism for its anticancer activity. (2005). https://pubmed.ncbi.nlm.nih.gov/15879598/ DOI: 10.1074/jbc.m414645200

tissue_or_cell_type

Purified enzyme

Curcumin: metabolism, signaling and nutrient connections (2026-09-17) · lines 515–526

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

### curcumin-trx-adduct Mass spectrometry and blotting supported modification of Cys496 and Sec497 in the rat enzyme. Condition category: normal nutrient_topic: Curcumin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The interaction included the selenium-containing active-site residue. organism: Rattus norvegicus tissue_or_cell_type: Purified enzyme experimental_model: Purified rat enzyme and separate HeLa-cell assays limitations: Rat residue numbering Cys496/Sec497 is source-specific and must not replace numbering in other TrxR constructs. Cellular enzyme activity does not prove clinical cancer benefit. exposure: Rat enzyme: two-hour incubation, IC50 3.6 micromolar; HeLa activity IC50 about 15 micromolar evidence_span: {"source_cache": "artifacts/curcumin-research/15879598.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "be68f9ed2b0741db356a6bc020304fe832121f92dfd9c423ce8a305e984e995c", "start_char": 0, "end_char": 1659, "text_sha256": "be68f9ed2b0741db356a6bc020304fe832121f92dfd9c423ce8a305e984e995c"} [curcumin-p15879598] Thioredoxin reductase is irreversibly modified by curcumin: a novel molecular mechanism for its anticancer activity. (2005). https://pubmed.ncbi.nlm.nih.gov/15879598/ DOI: 10.1074/jbc.m414645200

evidence_span

{"source_cache": "artifacts/curcumin-research/15879598.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "be68f9ed2b0741db356a6bc020304fe832121f92dfd9c423ce8a305e984e995c", "start_char": 0, "end_char": 1659, "text_sha256": "be68f9ed2b0741db356a6bc020304fe832121f92dfd9c423ce8a305e984e995c"}

experimental_model

Purified rat enzyme and separate HeLa-cell assays

exposure

Rat enzyme: two-hour incubation, IC50 3.6 micromolar; HeLa activity IC50 about 15 micromolar

limitations

Rat residue numbering Cys496/Sec497 is source-specific and must not replace numbering in other TrxR constructs. Cellular enzyme activity does not prove clinical cancer benefit.

nutrient_topic

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

organism

Rattus norvegicus

plain_language

An enzyme that normally helps control oxidation was inhibited.

primary_references

[curcumin-p15879598] Thioredoxin reductase is irreversibly modified by curcumin: a novel molecular mechanism for its anticancer activity. (2005). https://pubmed.ncbi.nlm.nih.gov/15879598/ DOI: 10.1074/jbc.m414645200

tissue_or_cell_type

Purified enzyme

Curcumin: metabolism, signaling and nutrient connections (2026-09-17) · lines 502–513

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

### curcumin-trx-inhibition Curcumin inhibited NADPH-reduced rat TrxR1 and inhibition persisted after curcumin removal. Condition category: normal nutrient_topic: Curcumin research collection; topical membership is not evidence of a direct dietary effect. plain_language: An enzyme that normally helps control oxidation was inhibited. organism: Rattus norvegicus tissue_or_cell_type: Purified enzyme experimental_model: Purified rat enzyme and separate HeLa-cell assays limitations: Rat residue numbering Cys496/Sec497 is source-specific and must not replace numbering in other TrxR constructs. Cellular enzyme activity does not prove clinical cancer benefit. exposure: Rat enzyme: two-hour incubation, IC50 3.6 micromolar; HeLa activity IC50 about 15 micromolar evidence_span: {"source_cache": "artifacts/curcumin-research/15879598.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "be68f9ed2b0741db356a6bc020304fe832121f92dfd9c423ce8a305e984e995c", "start_char": 0, "end_char": 1659, "text_sha256": "be68f9ed2b0741db356a6bc020304fe832121f92dfd9c423ce8a305e984e995c"} [curcumin-p15879598] Thioredoxin reductase is irreversibly modified by curcumin: a novel molecular mechanism for its anticancer activity. (2005). https://pubmed.ncbi.nlm.nih.gov/15879598/ DOI: 10.1074/jbc.m414645200

evidence_span

{"source_cache": "artifacts/curcumin-research/15879598.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "be68f9ed2b0741db356a6bc020304fe832121f92dfd9c423ce8a305e984e995c", "start_char": 0, "end_char": 1659, "text_sha256": "be68f9ed2b0741db356a6bc020304fe832121f92dfd9c423ce8a305e984e995c"}

experimental_model

Purified rat enzyme and separate HeLa-cell assays

exposure

Rat enzyme: two-hour incubation, IC50 3.6 micromolar; HeLa activity IC50 about 15 micromolar

limitations

Rat residue numbering Cys496/Sec497 is source-specific and must not replace numbering in other TrxR constructs. Cellular enzyme activity does not prove clinical cancer benefit.

nutrient_topic

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

organism

Rattus norvegicus

plain_language

The modified protein could consume reducing power while promoting oxidation.

primary_references

[curcumin-p15879598] Thioredoxin reductase is irreversibly modified by curcumin: a novel molecular mechanism for its anticancer activity. (2005). https://pubmed.ncbi.nlm.nih.gov/15879598/ DOI: 10.1074/jbc.m414645200

tissue_or_cell_type

Purified enzyme

Curcumin: metabolism, signaling and nutrient connections (2026-09-17) · lines 528–539

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

### curcumin-trx-oxidase The modified enzyme acquired increased NADPH oxidase activity associated with reactive oxygen species production. Condition category: normal nutrient_topic: Curcumin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The modified protein could consume reducing power while promoting oxidation. organism: Rattus norvegicus tissue_or_cell_type: Purified enzyme experimental_model: Purified rat enzyme and separate HeLa-cell assays limitations: Rat residue numbering Cys496/Sec497 is source-specific and must not replace numbering in other TrxR constructs. Cellular enzyme activity does not prove clinical cancer benefit. exposure: Rat enzyme: two-hour incubation, IC50 3.6 micromolar; HeLa activity IC50 about 15 micromolar evidence_span: {"source_cache": "artifacts/curcumin-research/15879598.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "be68f9ed2b0741db356a6bc020304fe832121f92dfd9c423ce8a305e984e995c", "start_char": 0, "end_char": 1659, "text_sha256": "be68f9ed2b0741db356a6bc020304fe832121f92dfd9c423ce8a305e984e995c"} [curcumin-p15879598] Thioredoxin reductase is irreversibly modified by curcumin: a novel molecular mechanism for its anticancer activity. (2005). https://pubmed.ncbi.nlm.nih.gov/15879598/ DOI: 10.1074/jbc.m414645200

cross_nutrient

B2-FAD supports GSH recycling; selenium-dependent GPX use of GSH is a separate reaction.

evidence_location

Results: NADPH binding; Fig 1 consensus cycle; GSH/GSSG complexes

experimental_model

Purified human glutathione reductase crystals with natural substrates, 0.95-1.1-A resolution, chemically reduced controls.

exposure

Purified-enzyme assay

limitations

GSR is not glutathione peroxidase; this record does not show that B2 improves selenium repletion.

nutrient_topic

Riboflavin research collection; topical membership is not evidence of a direct dietary effect. · Riboflavin (vitamin B2)

organism

Homo sapiens

plain_language

This enzyme recycles glutathione after oxidation.

primary_references

[berkholz2008] Catalytic cycle of human glutathione reductase near 1 A resolution. (2008). https://pubmed.ncbi.nlm.nih.gov/18638483/ DOI: 10.1016/j.jmb.2008.06.083

tissue_or_cell_type

Purified human GSR

Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1332–1344

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human glutathione reductase crystals with natural substrates, 0.95-1.1-A resolution, chemically reduced controls. · source_derived_draft · unverified_draft

### b2-gsr-gssg-to-gsh GSR reduces one glutathione-disulfide molecule to two reduced glutathione molecules using the NADPH/FAD catalytic relay. Condition category: normal nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: This enzyme recycles glutathione after oxidation. organism: Homo sapiens tissue_or_cell_type: Purified human GSR experimental_model: Purified human glutathione reductase crystals with natural substrates, 0.95-1.1-A resolution, chemically reduced controls. limitations: GSR is not glutathione peroxidase; this record does not show that B2 improves selenium repletion. exposure: Purified-enzyme assay cross_nutrient: B2-FAD supports GSH recycling; selenium-dependent GPX use of GSH is a separate reaction. evidence_location: Results: NADPH binding; Fig 1 consensus cycle; GSH/GSSG complexes [berkholz2008] Catalytic cycle of human glutathione reductase near 1 A resolution. (2008). https://pubmed.ncbi.nlm.nih.gov/18638483/ DOI: 10.1016/j.jmb.2008.06.083

cross_nutrient

B2-FAD and nicotinamide-containing NADPH support a branch upstream of de novo niacin synthesis.

evidence_location

Fig 2f and Methods: kinetic assays; interpret species separately

experimental_model

Human KMO in Sf9 membrane preparations; mass-spectrometry kinetics; separate P. fluorescens KMO crystallography.

exposure

Purified-enzyme assay

limitations

Human functional assays and bacterial structures are distinct evidence; this experiment did not test dietary B2 restriction or total NAD synthesis.

nutrient_topic

Riboflavin research collection; topical membership is not evidence of a direct dietary effect. · Riboflavin (vitamin B2)

organism

Homo sapiens

plain_language

A flavin enzyme directs tryptophan-derived kynurenine into the hydroxylated branch.

primary_references

[hutchinson2017] Structural and mechanistic basis of differentiated inhibitors of the acute pancreatitis target kynurenine-3-monooxygenase. (2017). https://pubmed.ncbi.nlm.nih.gov/28604669/ DOI: 10.1038/ncomms15827

tissue_or_cell_type

Sf9 membrane fraction expressing human KMO

Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1234–1246

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human KMO in Sf9 membrane preparations; mass-spectrometry kinetics; separate P. fluorescens KMO crystallography. · source_derived_draft · unverified_draft

### b2-kmo-kynurenine-hydroxylation Human KMO membrane assays measured kynurenine conversion to 3-hydroxykynurenine with NADPH; at 200 micromolar NADPH, kynurenine Km was 2 micromolar. Condition category: normal nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: A flavin enzyme directs tryptophan-derived kynurenine into the hydroxylated branch. organism: Homo sapiens tissue_or_cell_type: Sf9 membrane fraction expressing human KMO experimental_model: Human KMO in Sf9 membrane preparations; mass-spectrometry kinetics; separate P. fluorescens KMO crystallography. limitations: Human functional assays and bacterial structures are distinct evidence; this experiment did not test dietary B2 restriction or total NAD synthesis. exposure: Purified-enzyme assay cross_nutrient: B2-FAD and nicotinamide-containing NADPH support a branch upstream of de novo niacin synthesis. evidence_location: Fig 2f and Methods: kinetic assays; interpret species separately [hutchinson2017] Structural and mechanistic basis of differentiated inhibitors of the acute pancreatitis target kynurenine-3-monooxygenase. (2017). https://pubmed.ncbi.nlm.nih.gov/28604669/ DOI: 10.1038/ncomms15827

cross_nutrient

B2-FAD, folate and nicotinamide-containing NADPH participate in one reaction.

evidence_location

Results: kinetics, FAD occupancy and SAM inhibition; Table 1; Figs 2-4, 6

experimental_model

Recombinant human MTHFR expressed in Sf9 cells; mass spectrometry, 2.5-A structure, HPLC activity assays.

exposure

Purified-enzyme assay

limitations

Biochemical evidence does not establish a dietary threshold or supplementation benefit.

nutrient_topic

Riboflavin research collection; topical membership is not evidence of a direct dietary effect. · Riboflavin (vitamin B2)

organism

Homo sapiens

plain_language

The enzyme makes the methylfolate used in homocysteine recycling.

primary_references

[froese2018] Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition. (2018). https://pubmed.ncbi.nlm.nih.gov/29891918/ DOI: 10.1038/s41467-018-04735-2

tissue_or_cell_type

Purified recombinant enzyme; no intact tissue

Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1010–1022

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human MTHFR expressed in Sf9 cells; mass spectrometry, 2.5-A structure, HPLC activity assays. · source_derived_draft · unverified_draft

### b2-mthfr-methylfolate-production HPLC assays measured human MTHFR reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate using NADPH. Condition category: normal nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The enzyme makes the methylfolate used in homocysteine recycling. organism: Homo sapiens tissue_or_cell_type: Purified recombinant enzyme; no intact tissue experimental_model: Recombinant human MTHFR expressed in Sf9 cells; mass spectrometry, 2.5-A structure, HPLC activity assays. limitations: Biochemical evidence does not establish a dietary threshold or supplementation benefit. exposure: Purified-enzyme assay cross_nutrient: B2-FAD, folate and nicotinamide-containing NADPH participate in one reaction. evidence_location: Results: kinetics, FAD occupancy and SAM inhibition; Table 1; Figs 2-4, 6 [froese2018] Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition. (2018). https://pubmed.ncbi.nlm.nih.gov/29891918/ DOI: 10.1038/s41467-018-04735-2

cross_nutrient

B2 flavins support reactivation of B12-dependent folate/homocysteine metabolism.

evidence_location

Abstract

experimental_model

Recombinant human MTRR purification, flavin analysis, NADPH spectroscopy and methionine-synthase reconstitution.

exposure

Purified-enzyme assay

limitations

Reconstituted biochemistry; the accessible abstract identifies human MTRR but not the target MTR species. No dietary B2/B12 synergy was tested.

nutrient_topic

Riboflavin research collection; topical membership is not evidence of a direct dietary effect. · Riboflavin (vitamin B2)

organism

Homo sapiens

plain_language

The flavin reductase helps restore an enzyme that uses B12 and methylfolate.

primary_references

[olteanu2001] Human methionine synthase reductase, a soluble P-450 reductase-like dual flavoprotein, is sufficient for NADPH-dependent methionine synthase activation. (2001). https://pubmed.ncbi.nlm.nih.gov/11466310/ DOI: 10.1074/jbc.m103707200

tissue_or_cell_type

Purified recombinant enzyme; no intact tissue

Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1122–1134

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human MTRR purification, flavin analysis, NADPH spectroscopy and methionine-synthase reconstitution. · source_derived_draft · unverified_draft

### b2-mtrr-mtr-reactivation Reconstituted assays showed human MTRR sufficient to support NADPH-dependent activity of cobalamin-dependent methionine synthase. Condition category: normal nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The flavin reductase helps restore an enzyme that uses B12 and methylfolate. organism: Homo sapiens tissue_or_cell_type: Purified recombinant enzyme; no intact tissue experimental_model: Recombinant human MTRR purification, flavin analysis, NADPH spectroscopy and methionine-synthase reconstitution. limitations: Reconstituted biochemistry; the accessible abstract identifies human MTRR but not the target MTR species. No dietary B2/B12 synergy was tested. exposure: Purified-enzyme assay cross_nutrient: B2 flavins support reactivation of B12-dependent folate/homocysteine metabolism. evidence_location: Abstract [olteanu2001] Human methionine synthase reductase, a soluble P-450 reductase-like dual flavoprotein, is sufficient for NADPH-dependent methionine synthase activation. (2001). https://pubmed.ncbi.nlm.nih.gov/11466310/ DOI: 10.1074/jbc.m103707200

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

Distinct B2-cofactor and selenium-site functions cannot substitute for one another.

evidence_location

Abstract

experimental_model

Rat TXNRD1 Sec498Cys, Sec498Ser and C-terminal truncation expressed in E. coli; FAD analysis, NADPH titration and thioredoxin assays.

exposure

Purified-enzyme assay

limitations

Includes Sec498Cys, Sec498Ser and terminal truncation; engineered proteins, not nutrient-depleted animals.

nutrient_topic

Riboflavin research collection; topical membership is not evidence of a direct dietary effect. · Riboflavin (vitamin B2)

organism

Rattus norvegicus protein expressed in Escherichia coli

plain_language

A defective terminal center can leave upstream flavin reduction intact.

primary_references

[zhong2000] Essential role of selenium in the catalytic activities of mammalian thioredoxin reductase revealed by characterization of recombinant enzymes with selenocysteine mutations. (2000). https://pubmed.ncbi.nlm.nih.gov/10849437/ DOI: 10.1074/jbc.m000690200

tissue_or_cell_type

Purified recombinant enzyme; no intact tissue

trigger_kind

machinery_impairment Imported condition classification; unverified.

Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1374–1386

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat TXNRD1 Sec498Cys, Sec498Ser and C-terminal truncation expressed in E. coli; FAD analysis, NADPH titration and thioredoxin assays. · source_derived_draft · unverified_draft

### b2-txnrd-mutants-upstream-retained Engineered rat TXNRD1 terminal mutants retained one FAD per subunit and rapidly formed a thiolate-flavin charge-transfer signal upon NADPH titration. Condition category: machinery_impairment nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: A defective terminal center can leave upstream flavin reduction intact. organism: Rattus norvegicus protein expressed in Escherichia coli tissue_or_cell_type: Purified recombinant enzyme; no intact tissue experimental_model: Rat TXNRD1 Sec498Cys, Sec498Ser and C-terminal truncation expressed in E. coli; FAD analysis, NADPH titration and thioredoxin assays. limitations: Includes Sec498Cys, Sec498Ser and terminal truncation; engineered proteins, not nutrient-depleted animals. exposure: Purified-enzyme assay cross_nutrient: Distinct B2-cofactor and selenium-site functions cannot substitute for one another. evidence_location: Abstract [zhong2000] Essential role of selenium in the catalytic activities of mammalian thioredoxin reductase revealed by characterization of recombinant enzymes with selenocysteine mutations. (2000). https://pubmed.ncbi.nlm.nih.gov/10849437/ DOI: 10.1074/jbc.m000690200

evidence_access

Primary abstract

experimental_model

Rat liver microsomes with inducer/inhibitor profiling.

limitations

CYP2E1 assignment is supported by convergent microsomal tests rather than exclusive purified-enzyme proof.

nutrient_topic

Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan

plain_language

A gut-derived indole can enter a liver oxidation route.

primary_references

Hepatic microsomal metabolism of indole to indoxyl, a precursor of indoxyl sulfate. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11808865/ · DOI 10.1007/BF03226377

Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 586–592

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Rat liver microsomes with inducer/inhibitor profiling. · source_derived_draft · unverified_draft

## tryptophan-indole-oxidation A gut-derived indole can enter a liver oxidation route. Rat liver microsomal induction/inhibition experiments implicated CYP2E1 as the major enzyme oxidizing indole to indoxyl with NADPH support. Model: Rat liver microsomes with inducer/inhibitor profiling. Limitations: CYP2E1 assignment is supported by convergent microsomal tests rather than exclusive purified-enzyme proof. Evidence access: Primary abstract Hepatic microsomal metabolism of indole to indoxyl, a precursor of indoxyl sulfate. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11808865/ · DOI 10.1007/BF03226377

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

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experimental_model

Human erythrocytes, one G6PD-deficient donor and purified-enzyme assays

exposure

Lipoic acid with glucose/2-deoxyglucose and G6PD inhibition

limitations

The deficient-donor finding is small and mechanistic; it is not a clinical safety or efficacy trial in G6PD deficiency.

nutrient_topic

Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. · Lipoic acid

organism

Human

plain_language

Providing the oxidized molecule did not overcome the missing reducing capacity.

primary_references

[ala-p7632170] Reduction and transport of lipoic acid by human erythrocytes. (1995). https://pubmed.ncbi.nlm.nih.gov/7632170/ DOI: 10.1016/0006-2952(95)00084-d

tissue_or_cell_type

Erythrocytes and glutathione reductase

trigger_kind

machinery_impairment Imported condition classification; unverified.

Alpha-lipoic acid: cofactor assembly, redox signaling and nutrient interactions (2026-09-17) · lines 728–739

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human erythrocytes, one G6PD-deficient donor and purified-enzyme assays · source_derived_draft · unverified_draft

### ala-g6pd-reduction-failure Erythrocytes from a G6PD-deficient person failed to reduce lipoic acid in the assay; pharmacological G6PD inhibition also prevented reduction. Condition category: machinery_impairment nutrient_topic: Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Providing the oxidized molecule did not overcome the missing reducing capacity. organism: Human tissue_or_cell_type: Erythrocytes and glutathione reductase experimental_model: Human erythrocytes, one G6PD-deficient donor and purified-enzyme assays limitations: The deficient-donor finding is small and mechanistic; it is not a clinical safety or efficacy trial in G6PD deficiency. exposure: Lipoic acid with glucose/2-deoxyglucose and G6PD inhibition evidence_span: {"source_cache": "artifacts/ala-research/7632170.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2ebbc851e5279e646bc7c892645c931a3fd2993830c3f4405379839cbbd6e707", "start_char": 0, "end_char": 1863, "text_sha256": "2ebbc851e5279e646bc7c892645c931a3fd2993830c3f4405379839cbbd6e707"} [ala-p7632170] Reduction and transport of lipoic acid by human erythrocytes. (1995). https://pubmed.ncbi.nlm.nih.gov/7632170/ DOI: 10.1016/0006-2952(95)00084-d

evidence_span

{"source_cache": "artifacts/ala-research/7632170.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2ebbc851e5279e646bc7c892645c931a3fd2993830c3f4405379839cbbd6e707", "start_char": 0, "end_char": 1863, "text_sha256": "2ebbc851e5279e646bc7c892645c931a3fd2993830c3f4405379839cbbd6e707"}

experimental_model

Human erythrocytes, one G6PD-deficient donor and purified-enzyme assays

exposure

Lipoic acid with glucose/2-deoxyglucose and G6PD inhibition

limitations

The deficient-donor finding is small and mechanistic; it is not a clinical safety or efficacy trial in G6PD deficiency.

nutrient_topic

Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. · Lipoic acid

organism

Human

plain_language

An enzyme associated with glutathione recycling can also reduce free lipoic acid.

primary_references

[ala-p7632170] Reduction and transport of lipoic acid by human erythrocytes. (1995). https://pubmed.ncbi.nlm.nih.gov/7632170/ DOI: 10.1016/0006-2952(95)00084-d

tissue_or_cell_type

Erythrocytes and glutathione reductase

Alpha-lipoic acid: cofactor assembly, redox signaling and nutrient interactions (2026-09-17) · lines 741–752

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human erythrocytes, one G6PD-deficient donor and purified-enzyme assays · source_derived_draft · unverified_draft

### ala-gsr-free-lipoate Purified human glutathione reductase reduced free lipoic acid to DHLA in vitro. Condition category: normal nutrient_topic: Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: An enzyme associated with glutathione recycling can also reduce free lipoic acid. organism: Human tissue_or_cell_type: Erythrocytes and glutathione reductase experimental_model: Human erythrocytes, one G6PD-deficient donor and purified-enzyme assays limitations: The deficient-donor finding is small and mechanistic; it is not a clinical safety or efficacy trial in G6PD deficiency. exposure: Lipoic acid with glucose/2-deoxyglucose and G6PD inhibition evidence_span: {"source_cache": "artifacts/ala-research/7632170.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2ebbc851e5279e646bc7c892645c931a3fd2993830c3f4405379839cbbd6e707", "start_char": 0, "end_char": 1863, "text_sha256": "2ebbc851e5279e646bc7c892645c931a3fd2993830c3f4405379839cbbd6e707"} [ala-p7632170] Reduction and transport of lipoic acid by human erythrocytes. (1995). https://pubmed.ncbi.nlm.nih.gov/7632170/ DOI: 10.1016/0006-2952(95)00084-d

evidence_span

{"source_cache": "artifacts/ala-research/7632170.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2ebbc851e5279e646bc7c892645c931a3fd2993830c3f4405379839cbbd6e707", "start_char": 0, "end_char": 1863, "text_sha256": "2ebbc851e5279e646bc7c892645c931a3fd2993830c3f4405379839cbbd6e707"}

experimental_model

Human erythrocytes, one G6PD-deficient donor and purified-enzyme assays

exposure

Lipoic acid with glucose/2-deoxyglucose and G6PD inhibition

limitations

The deficient-donor finding is small and mechanistic; it is not a clinical safety or efficacy trial in G6PD deficiency.

nutrient_topic

Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. · Lipoic acid

organism

Human

plain_language

The cell must supply reducing power to make DHLA.

primary_references

[ala-p7632170] Reduction and transport of lipoic acid by human erythrocytes. (1995). https://pubmed.ncbi.nlm.nih.gov/7632170/ DOI: 10.1016/0006-2952(95)00084-d

tissue_or_cell_type

Erythrocytes and glutathione reductase

Alpha-lipoic acid: cofactor assembly, redox signaling and nutrient interactions (2026-09-17) · lines 715–726

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human erythrocytes, one G6PD-deficient donor and purified-enzyme assays · source_derived_draft · unverified_draft

### ala-rbc-glucose-reduction Human erythrocytes reduced lipoic acid to DHLA with glucose but not with 2-deoxyglucose, supporting NADPH dependence. Condition category: normal nutrient_topic: Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The cell must supply reducing power to make DHLA. organism: Human tissue_or_cell_type: Erythrocytes and glutathione reductase experimental_model: Human erythrocytes, one G6PD-deficient donor and purified-enzyme assays limitations: The deficient-donor finding is small and mechanistic; it is not a clinical safety or efficacy trial in G6PD deficiency. exposure: Lipoic acid with glucose/2-deoxyglucose and G6PD inhibition evidence_span: {"source_cache": "artifacts/ala-research/7632170.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2ebbc851e5279e646bc7c892645c931a3fd2993830c3f4405379839cbbd6e707", "start_char": 0, "end_char": 1863, "text_sha256": "2ebbc851e5279e646bc7c892645c931a3fd2993830c3f4405379839cbbd6e707"} [ala-p7632170] Reduction and transport of lipoic acid by human erythrocytes. (1995). https://pubmed.ncbi.nlm.nih.gov/7632170/ DOI: 10.1016/0006-2952(95)00084-d

evidence_span

{"source_cache": "artifacts/ala-research/8769129.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9ba6524ef04fdc03c0a6d108325b8a96fe7ad0748be4d7056e694b5afa2a8499", "start_char": 0, "end_char": 1307, "text_sha256": "9ba6524ef04fdc03c0a6d108325b8a96fe7ad0748be4d7056e694b5afa2a8499"}

experimental_model

Purified mammalian thioredoxin reductase assays

exposure

NADPH-dependent lipoate/lipoamide reduction

limitations

Isoform identity was not resolved as a specific human TXNRD gene in the indexed abstract; assay rate comparisons are not tissue-wide flux rankings.

nutrient_topic

Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. · Lipoic acid

organism

Human placenta, calf tissues and rat liver

plain_language

The thioredoxin system provides another route to DHLA.

primary_references

[ala-p8769129] Efficient reduction of lipoamide and lipoic acid by mammalian thioredoxin reductase. (1996). https://pubmed.ncbi.nlm.nih.gov/8769129/ DOI: 10.1006/bbrc.1996.1165

tissue_or_cell_type

Purified thioredoxin reductases

Alpha-lipoic acid: cofactor assembly, redox signaling and nutrient interactions (2026-09-17) · lines 754–765

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

### ala-thioredoxin-reductase-dhla Purified mammalian thioredoxin reductases, including enzyme from human placenta, catalyzed NADPH-dependent lipoic-acid reduction. Condition category: normal nutrient_topic: Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The thioredoxin system provides another route to DHLA. organism: Human placenta, calf tissues and rat liver tissue_or_cell_type: Purified thioredoxin reductases experimental_model: Purified mammalian thioredoxin reductase assays limitations: Isoform identity was not resolved as a specific human TXNRD gene in the indexed abstract; assay rate comparisons are not tissue-wide flux rankings. exposure: NADPH-dependent lipoate/lipoamide reduction evidence_span: {"source_cache": "artifacts/ala-research/8769129.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9ba6524ef04fdc03c0a6d108325b8a96fe7ad0748be4d7056e694b5afa2a8499", "start_char": 0, "end_char": 1307, "text_sha256": "9ba6524ef04fdc03c0a6d108325b8a96fe7ad0748be4d7056e694b5afa2a8499"} [ala-p8769129] Efficient reduction of lipoamide and lipoic acid by mammalian thioredoxin reductase. (1996). https://pubmed.ncbi.nlm.nih.gov/8769129/ DOI: 10.1006/bbrc.1996.1165

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Mammalian NADK2-deletion cell models; primary abstract.

limitations

Detailed model and exposure differences remain distinct; the two publications are not duplicate evidence records from one experiment.

nutrient_topic

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

plain_language

A second research group found the same synthesis vulnerability.

primary_references

Mitochondrial NADP+ is essential for proline biosynthesis during cell growth. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33833463/ · DOI 10.1038/s42255-021-00374-y

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 78–84

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mammalian NADK2-deletion cell models; primary abstract. · source_derived_draft · unverified_draft

## l-proline-nadk2-independent-study A second research group found the same synthesis vulnerability. A separate study found NADK2 loss depleted mitochondrial NADPH, limited P5C generation and made tested mammalian cells dependent on exogenous proline for growth. Model: Mammalian NADK2-deletion cell models; primary abstract. Limitations: Detailed model and exposure differences remain distinct; the two publications are not duplicate evidence records from one experiment. Evidence access: Primary abstract Mitochondrial NADP+ is essential for proline biosynthesis during cell growth. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33833463/ · DOI 10.1038/s42255-021-00374-y

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human DLD1 cells; immunopurified mitochondrial fractions and enzyme-cycling assays.

limitations

A compartment-specific genetic manipulation is not equivalent to dietary niacin deficiency.

nutrient_topic

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

plain_language

The cofactor pool inside mitochondria can fail even when a whole-cell measurement looks adequate.

primary_references

Mitochondrial NADP(H) generation is essential for proline biosynthesis. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33888598/ · DOI 10.1126/science.abd5491

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 54–60

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human DLD1 cells; immunopurified mitochondrial fractions and enzyme-cycling assays. · source_derived_draft · unverified_draft

## l-proline-nadk2-pool The cofactor pool inside mitochondria can fail even when a whole-cell measurement looks adequate. CRISPR deletion of NADK2 in human DLD1 cells reduced mitochondrial NADP(H) by more than 80% while whole-cell NADP(H) was not similarly depleted. Model: Human DLD1 cells; immunopurified mitochondrial fractions and enzyme-cycling assays. Limitations: A compartment-specific genetic manipulation is not equivalent to dietary niacin deficiency. Evidence access: Primary full text Mitochondrial NADP(H) generation is essential for proline biosynthesis. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33888598/ · DOI 10.1126/science.abd5491

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human cell deletion, isotope tracing and rescue experiments.

limitations

The limiting step was cofactor-dependent synthesis, not a demonstrated lack of glutamine in the diet.

nutrient_topic

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

plain_language

Proline production needs reducing power in the right compartment.

primary_references

Mitochondrial NADP(H) generation is essential for proline biosynthesis. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33888598/ · DOI 10.1126/science.abd5491

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 62–68

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human cell deletion, isotope tracing and rescue experiments. · source_derived_draft · unverified_draft

## l-proline-nadk2-proline Proline production needs reducing power in the right compartment. NADK2 deletion reduced glutamine-derived proline synthesis; mitochondrial NADP(H) was needed for the P5CS step reducing glutamate toward P5C. Model: Human cell deletion, isotope tracing and rescue experiments. Limitations: The limiting step was cofactor-dependent synthesis, not a demonstrated lack of glutamine in the diet. Evidence access: Primary full text Mitochondrial NADP(H) generation is essential for proline biosynthesis. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33888598/ · DOI 10.1126/science.abd5491

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human cell models; ROS probes, targeted redox sensors and serine isotope tracing.

limitations

The authors do not exclude effects during other physiological stresses; this is not a universal claim that mitochondrial NADPH is irrelevant to antioxidant defense.

nutrient_topic

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

plain_language

Losing this cofactor pool did not shut down every pathway that might be connected to it.

primary_references

Mitochondrial NADP(H) generation is essential for proline biosynthesis. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33888598/ · DOI 10.1126/science.abd5491

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 86–92

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human cell models; ROS probes, targeted redox sensors and serine isotope tracing. · source_derived_draft · unverified_draft

## l-proline-nadk2-redox-boundary Losing this cofactor pool did not shut down every pathway that might be connected to it. Under the tested culture conditions, NADK2 deletion did not increase measured mitochondrial oxidative stress or disrupt mitochondrial folate pathway activity despite reduced proline synthesis. Model: Human cell models; ROS probes, targeted redox sensors and serine isotope tracing. Limitations: The authors do not exclude effects during other physiological stresses; this is not a universal claim that mitochondrial NADPH is irrelevant to antioxidant defense. Evidence access: Primary full text Mitochondrial NADP(H) generation is essential for proline biosynthesis. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33888598/ · DOI 10.1126/science.abd5491

evidence_access

Primary full text

experimental_model

Purified human enzyme; comparison with 0.1 mM P5C and 0.1 mM reduced cofactor, 37 degrees C.

limitations

Cofactor preference depends on assay conditions and does not make the alternative cofactor unusable.

nutrient_topic

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

plain_language

One mitochondrial enzyme finishes the synthesis of proline.

primary_references

Functional specialization in proline biosynthesis of melanoma. · 2012 · https://pubmed.ncbi.nlm.nih.gov/23024808/ · DOI 10.1371/journal.pone.0045190

L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 14–20

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Purified human enzyme; comparison with 0.1 mM P5C and 0.1 mM reduced cofactor, 37 degrees C. · source_derived_draft · unverified_draft

## l-proline-pycr1-reduction One mitochondrial enzyme finishes the synthesis of proline. Recombinant human PYCR1 reduced P5C to proline with NADH or NADPH; in the tested conditions its specific activity was higher with NADH. Model: Purified human enzyme; comparison with 0.1 mM P5C and 0.1 mM reduced cofactor, 37 degrees C. Limitations: Cofactor preference depends on assay conditions and does not make the alternative cofactor unusable. Evidence access: Primary full text Functional specialization in proline biosynthesis of melanoma. · 2012 · https://pubmed.ncbi.nlm.nih.gov/23024808/ · DOI 10.1371/journal.pone.0045190

evidence_access

Primary full text

experimental_model

Purified human PYCR2 and human melanoma-cell localization experiments.

limitations

PYCR2 has its own identity and disease associations; it is not interchangeable with PYCR1.

nutrient_topic

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

plain_language

A second mitochondrial enzyme performs the final reduction.

primary_references

Functional specialization in proline biosynthesis of melanoma. · 2012 · https://pubmed.ncbi.nlm.nih.gov/23024808/ · DOI 10.1371/journal.pone.0045190

L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 22–28

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Purified human PYCR2 and human melanoma-cell localization experiments. · source_derived_draft · unverified_draft

## l-proline-pycr2-reduction A second mitochondrial enzyme performs the final reduction. Recombinant human PYCR2 reduced P5C to proline and favored NADH over NADPH under the reported comparison conditions. Model: Purified human PYCR2 and human melanoma-cell localization experiments. Limitations: PYCR2 has its own identity and disease associations; it is not interchangeable with PYCR1. Evidence access: Primary full text Functional specialization in proline biosynthesis of melanoma. · 2012 · https://pubmed.ncbi.nlm.nih.gov/23024808/ · DOI 10.1371/journal.pone.0045190

evidence_access

Primary full text

experimental_model

Lu1205 cell fractionation and recombinant human PYCRL kinetics.

limitations

The melanoma routing pattern is not asserted to apply identically in every human tissue.

nutrient_topic

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

plain_language

The cytosolic version has different preferences from the mitochondrial enzymes.

primary_references

Functional specialization in proline biosynthesis of melanoma. · 2012 · https://pubmed.ncbi.nlm.nih.gov/23024808/ · DOI 10.1371/journal.pone.0045190

L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 30–36

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Lu1205 cell fractionation and recombinant human PYCRL kinetics. · source_derived_draft · unverified_draft

## l-proline-pycr3-reduction The cytosolic version has different preferences from the mitochondrial enzymes. Human PYCRL/PYCR3 localized predominantly to the cytosol in the tested melanoma cells and was more efficient with NADPH in the biochemical comparison. Model: Lu1205 cell fractionation and recombinant human PYCRL kinetics. Limitations: The melanoma routing pattern is not asserted to apply identically in every human tissue. Evidence access: Primary full text Functional specialization in proline biosynthesis of melanoma. · 2012 · https://pubmed.ncbi.nlm.nih.gov/23024808/ · DOI 10.1371/journal.pone.0045190

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

dose

Tartrazine among tested substrates; exact substrate/cofactor concentrations unavailable in abstract

duration

Assay interval unavailable in primary abstract

evidence_access

Primary PubMed abstract; unrecovered method details explicitly retained.

evidence_scope

literature_reviewed; source-specific experimental curation

experimental_model

Purified Escherichia coli K12 azoreductases I and II

limitations

Both NADH and NADPH served as electron donors in enzyme characterization. This does not prove that niacin intake controls dye metabolism in humans. Protein genes and tartrazine-specific kinetic constants are unresolved.

nutrient_topic

Tartrazine food-colorant chapter; nutrient, drug and peptide interactions retain their models and limits. · Tartrazine

organism

Purified Escherichia coli K12 azoreductases I and II

plain_language

Purified E. coli K12 azoreductase I used tartrazine as a substrate.

primary_references

Purification of two azoreductases from Escherichia coli K12. (1993). https://pubmed.ncbi.nlm.nih.gov/8112774/

route

In vitro enzyme/substrate incubation

tissue

Cell-free azo-reduction assays

Tartrazine: mechanisms, molecular forms and cross-actor connections (2026-09-20) · lines 17–26

Original AI-assisted curation of eighteen primary studies. Study-specific citations, negative findings and limitations retained. Not publisher full text. · supports · Purified Escherichia coli K12 azoreductases I and II · source_derived_draft · unverified_draft

## tartrazine-azoreductase-i Purified E. coli K12 azoreductase I used tartrazine as a substrate. Model/species: Purified Escherichia coli K12 azoreductases I and II Tissue: Cell-free azo-reduction assays Exposure: Tartrazine among tested substrates; exact substrate/cofactor concentrations unavailable in abstract Route: In vitro enzyme/substrate incubation Duration: Assay interval unavailable in primary abstract Limits: Both NADH and NADPH served as electron donors in enzyme characterization. This does not prove that niacin intake controls dye metabolism in humans. Protein genes and tartrazine-specific kinetic constants are unresolved. Primary reference: Purification of two azoreductases from Escherichia coli K12. (1993). https://pubmed.ncbi.nlm.nih.gov/8112774/ Access: Primary PubMed abstract; unrecovered method details explicitly retained.

dose

Tartrazine among tested substrates; exact substrate/cofactor concentrations unavailable in abstract

duration

Assay interval unavailable in primary abstract

evidence_access

Primary PubMed abstract; unrecovered method details explicitly retained.

evidence_scope

literature_reviewed; source-specific experimental curation

experimental_model

Purified Escherichia coli K12 azoreductases I and II

limitations

Both NADH and NADPH served as electron donors in enzyme characterization. This does not prove that niacin intake controls dye metabolism in humans. Protein genes and tartrazine-specific kinetic constants are unresolved.

nutrient_topic

Tartrazine food-colorant chapter; nutrient, drug and peptide interactions retain their models and limits. · Tartrazine

organism

Purified Escherichia coli K12 azoreductases I and II

plain_language

Purified E. coli K12 azoreductase II used tartrazine less efficiently than azoreductase I.

primary_references

Purification of two azoreductases from Escherichia coli K12. (1993). https://pubmed.ncbi.nlm.nih.gov/8112774/

route

In vitro enzyme/substrate incubation

tissue

Cell-free azo-reduction assays

Tartrazine: mechanisms, molecular forms and cross-actor connections (2026-09-20) · lines 28–37

Original AI-assisted curation of eighteen primary studies. Study-specific citations, negative findings and limitations retained. Not publisher full text. · supports · Purified Escherichia coli K12 azoreductases I and II · source_derived_draft · unverified_draft

## tartrazine-azoreductase-ii Purified E. coli K12 azoreductase II used tartrazine less efficiently than azoreductase I. Model/species: Purified Escherichia coli K12 azoreductases I and II Tissue: Cell-free azo-reduction assays Exposure: Tartrazine among tested substrates; exact substrate/cofactor concentrations unavailable in abstract Route: In vitro enzyme/substrate incubation Duration: Assay interval unavailable in primary abstract Limits: Both NADH and NADPH served as electron donors in enzyme characterization. This does not prove that niacin intake controls dye metabolism in humans. Protein genes and tartrazine-specific kinetic constants are unresolved. Primary reference: Purification of two azoreductases from Escherichia coli K12. (1993). https://pubmed.ncbi.nlm.nih.gov/8112774/ Access: Primary PubMed abstract; unrecovered method details explicitly retained.

evidence_span

{"source_cache": "artifacts/boron-research/15282753.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9385dca91d3dc7bb5a3d2a9c71a8e4c4ec0af136a15de2ea9536365a048d8057", "start_char": 0, "end_char": 1378, "text_sha256": "9385dca91d3dc7bb5a3d2a9c71a8e4c4ec0af136a15de2ea9536365a048d8057"}

experimental_model

Electrospray mass spectrometry comparing nucleotide binding

exposure

100 µM nucleotide and 500 µM boric acid in WAT solvent at pH 10.3; separate pH 7.4 ammonium bicarbonate condition

limitations

Relative ion signals and assay-specific rankings cannot be treated as universal binding constants or in-vivo metabolic effects.

nutrient_topic

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

organism

Cell-free chemistry

plain_language

Added phosphate groups and the test solution change the observed binding pattern.

primary_references

[boron-p15282753] Borate-nucleotide complex formation depends on charge and phosphorylation state. (2004). https://pubmed.ncbi.nlm.nih.gov/15282753/ DOI: 10.1002/jms.645

tissue_or_cell_type

Purified nucleotide solutions

Boron: chemistry, nutrient interactions, low-intake studies and mechanistic uncertainties (2026-09-17) · lines 144–155

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Electrospray mass spectrometry comparing nucleotide binding · source_derived_draft · unverified_draft

### boron-nad-phosphate-context The reported boron-binding order was NAD+ > NADH > NADP+ > NADPH at pH 10.3; only the NAD+ complex was observed in the separate pH 7.4 ammonium-bicarbonate condition. Condition category: normal nutrient_topic: Boron research collection; topical membership is not evidence of a direct dietary effect. plain_language: Added phosphate groups and the test solution change the observed binding pattern. organism: Cell-free chemistry tissue_or_cell_type: Purified nucleotide solutions experimental_model: Electrospray mass spectrometry comparing nucleotide binding limitations: Relative ion signals and assay-specific rankings cannot be treated as universal binding constants or in-vivo metabolic effects. exposure: 100 µM nucleotide and 500 µM boric acid in WAT solvent at pH 10.3; separate pH 7.4 ammonium bicarbonate condition evidence_span: {"source_cache": "artifacts/boron-research/15282753.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9385dca91d3dc7bb5a3d2a9c71a8e4c4ec0af136a15de2ea9536365a048d8057", "start_char": 0, "end_char": 1378, "text_sha256": "9385dca91d3dc7bb5a3d2a9c71a8e4c4ec0af136a15de2ea9536365a048d8057"} [boron-p15282753] Borate-nucleotide complex formation depends on charge and phosphorylation state. (2004). https://pubmed.ncbi.nlm.nih.gov/15282753/ DOI: 10.1002/jms.645

cross_nutrient

true

evidence_location

Results: Figure 4; Materials and Methods: Decyanation of CNCbl

experimental_model

Purified human MMACHC with human flavoprotein donor

exposure

Anaerobic CNCbl/MMACHC, NADPH and MTRR or NDOR1

limitations

Reconstituted biochemical system; establishes reaction capability rather than the quantitatively dominant pathway in living humans.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Processing removes the cyano group and leaves a reduced B12 intermediate.

primary_references

[kim-2008-decyanation] Decyanation of vitamin B12 by a trafficking chaperone (2008). https://pubmed.ncbi.nlm.nih.gov/18779575/ DOI: 10.1073/pnas.0805989105

tissue_or_cell_type

Cell-free assay

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 669–681

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human MMACHC with human flavoprotein donor · source_derived_draft · unverified_draft

### b12-mmachc-decyanation Human MMACHC converted bound cyanocobalamin to cob(II)alamin during NADPH-supported reductive decyanation; EPR identified the product in a base-off coordination state. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Processing removes the cyano group and leaves a reduced B12 intermediate. organism: Homo sapiens tissue_or_cell_type: Cell-free assay experimental_model: Purified human MMACHC with human flavoprotein donor limitations: Reconstituted biochemical system; establishes reaction capability rather than the quantitatively dominant pathway in living humans. exposure: Anaerobic CNCbl/MMACHC, NADPH and MTRR or NDOR1 cross_nutrient: true evidence_location: Results: Figure 4; Materials and Methods: Decyanation of CNCbl [kim-2008-decyanation] Decyanation of vitamin B12 by a trafficking chaperone (2008). https://pubmed.ncbi.nlm.nih.gov/18779575/ DOI: 10.1073/pnas.0805989105

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

true

evidence_location

Experimental procedures and Results: CblC Has a Flavin Reductase Fold; Figure 1c

experimental_model

Recombinant human MMACHC deltaC38 biochemical assay

exposure

30–40 micromolar FMN/FAD with 200 micromolar NADPH, or photoreduced FMN

limitations

Engineered truncation and reconstitution; does not establish that riboflavin supplementation rescues MMACHC defects.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

A truncated B12-processing protein could use supplied flavins to carry out this reaction.

primary_references

[koutmos-2011-flavin] Structural Basis of Multifunctionality in a Vitamin B12-processing Enzyme (2011). https://pubmed.ncbi.nlm.nih.gov/21697092/ DOI: 10.1074/jbc.M111.261370

tissue_or_cell_type

Cell-free assay

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 753–765

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human MMACHC deltaC38 biochemical assay · source_derived_draft · unverified_draft

### b12-mmachc-free-flavin-decyanation Human MMACHC residues 1–244 supported cyanocobalamin decyanation with FMN or FAD plus NADPH, without a separately supplied flavoprotein reductase; reduced FMN also supported the reaction. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: A truncated B12-processing protein could use supplied flavins to carry out this reaction. organism: Homo sapiens tissue_or_cell_type: Cell-free assay experimental_model: Recombinant human MMACHC deltaC38 biochemical assay limitations: Engineered truncation and reconstitution; does not establish that riboflavin supplementation rescues MMACHC defects. exposure: 30–40 micromolar FMN/FAD with 200 micromolar NADPH, or photoreduced FMN cross_nutrient: true evidence_location: Experimental procedures and Results: CblC Has a Flavin Reductase Fold; Figure 1c [koutmos-2011-flavin] Structural Basis of Multifunctionality in a Vitamin B12-processing Enzyme (2011). https://pubmed.ncbi.nlm.nih.gov/21697092/ DOI: 10.1074/jbc.M111.261370

cross_nutrient

true

evidence_location

Results: Figure 4; Materials and Methods: Decyanation of CNCbl

experimental_model

Human purified-protein anaerobic reconstitution

exposure

4 micromolar reductase, 20 micromolar MMACHC/CNCbl, 200 micromolar NADPH

limitations

Reconstituted biochemical system; establishes reaction capability rather than the quantitatively dominant pathway in living humans.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

This flavoprotein can pass reducing power into B12 processing.

primary_references

[kim-2008-decyanation] Decyanation of vitamin B12 by a trafficking chaperone (2008). https://pubmed.ncbi.nlm.nih.gov/18779575/ DOI: 10.1073/pnas.0805989105

tissue_or_cell_type

Cell-free assay

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 683–695

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human purified-protein anaerobic reconstitution · source_derived_draft · unverified_draft

### b12-mtrr-mmachc-electrons Recombinant human MTRR with NADPH supported MMACHC-bound cyanocobalamin conversion to cob(II)alamin; free cyanocobalamin was not detectably reduced without MMACHC. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: This flavoprotein can pass reducing power into B12 processing. organism: Homo sapiens tissue_or_cell_type: Cell-free assay experimental_model: Human purified-protein anaerobic reconstitution limitations: Reconstituted biochemical system; establishes reaction capability rather than the quantitatively dominant pathway in living humans. exposure: 4 micromolar reductase, 20 micromolar MMACHC/CNCbl, 200 micromolar NADPH cross_nutrient: true evidence_location: Results: Figure 4; Materials and Methods: Decyanation of CNCbl [kim-2008-decyanation] Decyanation of vitamin B12 by a trafficking chaperone (2008). https://pubmed.ncbi.nlm.nih.gov/18779575/ DOI: 10.1073/pnas.0805989105

cross_nutrient

true

evidence_location

Results: Figure 4; Materials and Methods: Decyanation of CNCbl

experimental_model

Human purified-protein anaerobic reconstitution

exposure

4 micromolar reductase, 20 micromolar MMACHC/CNCbl, 200 micromolar NADPH

limitations

Reconstituted biochemical system; establishes reaction capability rather than the quantitatively dominant pathway in living humans.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

This flavoprotein can pass reducing power into B12 processing.

primary_references

[kim-2008-decyanation] Decyanation of vitamin B12 by a trafficking chaperone (2008). https://pubmed.ncbi.nlm.nih.gov/18779575/ DOI: 10.1073/pnas.0805989105

tissue_or_cell_type

Cell-free assay

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 697–709

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human purified-protein anaerobic reconstitution · source_derived_draft · unverified_draft

### b12-ndor1-mmachc-electrons Recombinant human NDOR1/NR1 with NADPH supported MMACHC-bound cyanocobalamin conversion to cob(II)alamin; free cyanocobalamin was not detectably reduced without MMACHC. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: This flavoprotein can pass reducing power into B12 processing. organism: Homo sapiens tissue_or_cell_type: Cell-free assay experimental_model: Human purified-protein anaerobic reconstitution limitations: Reconstituted biochemical system; establishes reaction capability rather than the quantitatively dominant pathway in living humans. exposure: 4 micromolar reductase, 20 micromolar MMACHC/CNCbl, 200 micromolar NADPH cross_nutrient: true evidence_location: Results: Figure 4; Materials and Methods: Decyanation of CNCbl [kim-2008-decyanation] Decyanation of vitamin B12 by a trafficking chaperone (2008). https://pubmed.ncbi.nlm.nih.gov/18779575/ DOI: 10.1073/pnas.0805989105

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

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

true

evidence_location

Abstract and indexed primary Results, Figure 3

experimental_model

Purified human MMAB R186Q

exposure

R186Q variant; FDX1/FDXR/NADPH versus titanium(III)citrate

limitations

Detection-limited in-vitro activity; not proof of zero activity in every tissue.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

This MMAB variant failed in the ferredoxin assay; the result depended on the electron donor.

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

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1019–1031

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human MMAB R186Q · source_derived_draft · unverified_draft

### mmab-r186q-fdx-system-fails R186Q human MMAB showed no detectable adenosylcobalamin synthesis with FDX1/FDXR/NADPH, although a strong chemical reductant supported activity. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: This MMAB variant failed in the ferredoxin assay; the result depended on the electron donor. organism: Homo sapiens tissue_or_cell_type: Purified protein assay experimental_model: Purified human MMAB R186Q limitations: Detection-limited in-vitro activity; not proof of zero activity in every tissue. exposure: R186Q variant; FDX1/FDXR/NADPH versus titanium(III)citrate 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

true

evidence_location

Indexed primary abstract

experimental_model

Purified human proteins

exposure

Purified MTRR plus MMAB and reductants

limitations

MTRR coupling in vitro does not identify the physiological mitochondrial electron donor.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Human MTRR supported B12 activation in a test-tube system; this does not establish its mitochondrial role.

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 991–1003

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

### mtrr-supports-mmab-in-vitro Purified human MTRR coupled cob(II)alamin reduction to MMAB-dependent adenosylcobalamin synthesis in vitro. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Human MTRR supported B12 activation in a test-tube system; this does not establish its mitochondrial role. organism: Homo sapiens tissue_or_cell_type: Purified protein assay experimental_model: Purified human proteins limitations: MTRR coupling in vitro does not identify the physiological mitochondrial electron donor. exposure: Purified MTRR plus MMAB and reductants cross_nutrient: true 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

evidence_access

Primary abstract and publisher methods/results

experimental_model

Rat TrxR biochemical experiments.

limitations

Semiquinone mediation was proposed; do not treat the precise intermediate as directly proven.

nutrient_topic

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

plain_language

The enzyme’s chemical state affects vulnerability.

primary_references

Inhibition of Mammalian thioredoxin reductase by some flavonoids: implications for myricetin and quercetin anticancer activity. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16618767/ · DOI 10.1158/0008-5472.CAN-05-3310

Myricetin: metabolism, immune signaling, redox chemistry and cross-nutrient mechanisms (2026-09-19) · lines 260–266

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

## myricetin-txnrd-active-site The enzyme’s chemical state affects vulnerability. Myricetin inhibition was time- and NADPH-dependent and involved the reduced C-terminal Cys-Sec-Gly active site. Model: Rat TrxR biochemical experiments. Limitations: Semiquinone mediation was proposed; do not treat the precise intermediate as directly proven. Evidence access: Primary abstract and publisher methods/results Inhibition of Mammalian thioredoxin reductase by some flavonoids: implications for myricetin and quercetin anticancer activity. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16618767/ · DOI 10.1158/0008-5472.CAN-05-3310

evidence_access

Primary abstract and publisher methods/results

experimental_model

Recombinant rat TrxR; one-hour preincubation and DTNB assay.

limitations

Enzyme potency differs from cellular exposure; not human dietary selenium depletion.

nutrient_topic

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

plain_language

A selenium-containing defense enzyme can be inhibited.

primary_references

Inhibition of Mammalian thioredoxin reductase by some flavonoids: implications for myricetin and quercetin anticancer activity. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16618767/ · DOI 10.1158/0008-5472.CAN-05-3310

Myricetin: metabolism, immune signaling, redox chemistry and cross-nutrient mechanisms (2026-09-19) · lines 252–258

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Recombinant rat TrxR; one-hour preincubation and DTNB assay. · source_derived_draft · unverified_draft

## myricetin-txnrd-inhibition A selenium-containing defense enzyme can be inhibited. Myricetin inhibited NADPH-reduced recombinant rat TrxR1, IC50 0.62 micromolar after the reported preincubation. Model: Recombinant rat TrxR; one-hour preincubation and DTNB assay. Limitations: Enzyme potency differs from cellular exposure; not human dietary selenium depletion. Evidence access: Primary abstract and publisher methods/results Inhibition of Mammalian thioredoxin reductase by some flavonoids: implications for myricetin and quercetin anticancer activity. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16618767/ · DOI 10.1158/0008-5472.CAN-05-3310

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human cancer-cell transporter manipulation, glucose withdrawal and metabolic assays.

limitations

Complete glucose withdrawal in culture is not ordinary fasting or dietary carbohydrate restriction.

nutrient_topic

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

plain_language

Importing more oxidized nutrient also creates more work for the reducing system.

primary_references

Cystine transporter regulation of pentose phosphate pathway dependency and disulfide stress exposes a targetable metabolic vulnerability in cancer. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32231310/ · DOI 10.1038/s41556-020-0496-x

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Cysteine: sulfur allocation, redox supply and cross-nutrient mechanisms (2026-09-19) · lines 236–242

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human cancer-cell transporter manipulation, glucose withdrawal and metabolic assays. · source_derived_draft · unverified_draft

## l-cysteine-cystine-nadph-demand Importing more oxidized nutrient also creates more work for the reducing system. High SLC7A11-mediated cystine uptake increased reliance on glucose and the pentose phosphate pathway; glucose deprivation depleted NADPH and promoted intracellular disulfide accumulation. Model: Human cancer-cell transporter manipulation, glucose withdrawal and metabolic assays. Limitations: Complete glucose withdrawal in culture is not ordinary fasting or dietary carbohydrate restriction. Evidence access: Primary full text Cystine transporter regulation of pentose phosphate pathway dependency and disulfide stress exposes a targetable metabolic vulnerability in cancer. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32231310/ · DOI 10.1038/s41556-020-0496-x

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human cancer-cell glucose/cystine manipulation.

limitations

This is distinct from cystine-withdrawal ferroptosis under other conditions; no universal benefit of removing cystine is implied.

nutrient_topic

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

plain_language

Reducing the incoming load helped when the cell could not process it.

primary_references

Cystine transporter regulation of pentose phosphate pathway dependency and disulfide stress exposes a targetable metabolic vulnerability in cancer. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32231310/ · DOI 10.1038/s41556-020-0496-x

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Cysteine: sulfur allocation, redox supply and cross-nutrient mechanisms (2026-09-19) · lines 244–250

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human cancer-cell glucose/cystine manipulation. · source_derived_draft · unverified_draft

## l-cysteine-cystine-reduction-rescue Reducing the incoming load helped when the cell could not process it. Preventing cystine uptake or removing cystine relieved the disulfide stress associated with glucose deprivation in SLC7A11-high cells. Model: Human cancer-cell glucose/cystine manipulation. Limitations: This is distinct from cystine-withdrawal ferroptosis under other conditions; no universal benefit of removing cystine is implied. Evidence access: Primary full text Cystine transporter regulation of pentose phosphate pathway dependency and disulfide stress exposes a targetable metabolic vulnerability in cancer. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32231310/ · DOI 10.1038/s41556-020-0496-x

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary abstract and primary publisher figure descriptions

experimental_model

Human cancer cultures, chemical proteomics and cell-biological assays.

limitations

Experimental deprivation; do not infer this occurs whenever blood glucose falls modestly.

nutrient_topic

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

plain_language

The damage involved cross-linked structural proteins rather than the same lipid-peroxide pathway.

primary_references

Actin cytoskeleton vulnerability to disulfide stress mediates disulfidptosis. · 2023 · https://pubmed.ncbi.nlm.nih.gov/36747082/ · DOI 10.1038/s41556-023-01091-2

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Cysteine: sulfur allocation, redox supply and cross-nutrient mechanisms (2026-09-19) · lines 252–258

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human cancer cultures, chemical proteomics and cell-biological assays. · source_derived_draft · unverified_draft

## l-cysteine-disulfidptosis-actin The damage involved cross-linked structural proteins rather than the same lipid-peroxide pathway. Glucose starvation of SLC7A11-high human cancer cells induced abnormal disulfide bonding in actin-cytoskeleton proteins, F-actin collapse and disulfidptosis, distinct from apoptosis and ferroptosis. Model: Human cancer cultures, chemical proteomics and cell-biological assays. Limitations: Experimental deprivation; do not infer this occurs whenever blood glucose falls modestly. Evidence access: Primary abstract and primary publisher figure descriptions Actin cytoskeleton vulnerability to disulfide stress mediates disulfidptosis. · 2023 · https://pubmed.ncbi.nlm.nih.gov/36747082/ · DOI 10.1038/s41556-023-01091-2

evidence_access

Primary full text

experimental_model

Recombinant human Prx2; cysteinylation and hydrogen-peroxide reduction assays.

limitations

TRP14 repairs this modification; it is not being assigned the ordinary catalytic peroxide-reduction cycle of thioredoxin.

nutrient_topic

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

plain_language

A cysteine modification can temporarily obstruct another antioxidant enzyme.

primary_references

TRP14 is the rate-limiting enzyme for intracellular cystine reduction and regulates proteome cysteinylation. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38811853/ · DOI 10.1038/s44318-024-00117-1

L-Cysteine: sulfur allocation, redox supply and cross-nutrient mechanisms (2026-09-19) · lines 84–90

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Recombinant human Prx2; cysteinylation and hydrogen-peroxide reduction assays. · source_derived_draft · unverified_draft

## l-cysteine-protein-decysteinylation A cysteine modification can temporarily obstruct another antioxidant enzyme. TRP14 removed cysteinyl mixed-disulfide modifications from human peroxiredoxin 2 and restored its peroxide-reducing activity in vitro. Model: Recombinant human Prx2; cysteinylation and hydrogen-peroxide reduction assays. Limitations: TRP14 repairs this modification; it is not being assigned the ordinary catalytic peroxide-reduction cycle of thioredoxin. Evidence access: Primary full text TRP14 is the rate-limiting enzyme for intracellular cystine reduction and regulates proteome cysteinylation. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38811853/ · DOI 10.1038/s44318-024-00117-1

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human HEK293 knockout/rescue; fluorescent cystine-reduction assays.

limitations

The paper identifies a major rate-limiting route in tested systems, not the only possible reductase in every tissue.

nutrient_topic

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

plain_language

Importing oxidized cysteine is not enough: the cell must reduce it to use it.

primary_references

TRP14 is the rate-limiting enzyme for intracellular cystine reduction and regulates proteome cysteinylation. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38811853/ · DOI 10.1038/s44318-024-00117-1

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Cysteine: sulfur allocation, redox supply 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 HEK293 knockout/rescue; fluorescent cystine-reduction assays. · source_derived_draft · unverified_draft

## l-cysteine-trp14-cystine-reduction Importing oxidized cysteine is not enough: the cell must reduce it to use it. TXNDC17 knockout in human HEK293 cells markedly reduced intracellular cystine reduction; wild-type TRP14 re-expression restored activity whereas its active-site mutant did not. Model: Human HEK293 knockout/rescue; fluorescent cystine-reduction assays. Limitations: The paper identifies a major rate-limiting route in tested systems, not the only possible reductase in every tissue. Evidence access: Primary full text TRP14 is the rate-limiting enzyme for intracellular cystine reduction and regulates proteome cysteinylation. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38811853/ · DOI 10.1038/s44318-024-00117-1

evidence_access

Primary full text

experimental_model

Purified enzyme systems, including human peroxiredoxin-2 decysteinylation.

limitations

This establishes a biochemical dependency; selenium or niacin depletion/repletion was not tested in this study.

nutrient_topic

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

plain_language

The sulfur-supply step depends on an electron supply and another enzyme.

primary_references

TRP14 is the rate-limiting enzyme for intracellular cystine reduction and regulates proteome cysteinylation. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38811853/ · DOI 10.1038/s44318-024-00117-1

L-Cysteine: sulfur allocation, redox supply 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 · Purified enzyme systems, including human peroxiredoxin-2 decysteinylation. · source_derived_draft · unverified_draft

## l-cysteine-trp14-electron-supply The sulfur-supply step depends on an electron supply and another enzyme. The reconstituted TRP14 system used thioredoxin reductase 1 and NADPH to drive disulfide-reduction reactions. Model: Purified enzyme systems, including human peroxiredoxin-2 decysteinylation. Limitations: This establishes a biochemical dependency; selenium or niacin depletion/repletion was not tested in this study. Evidence access: Primary full text TRP14 is the rate-limiting enzyme for intracellular cystine reduction and regulates proteome cysteinylation. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38811853/ · DOI 10.1038/s44318-024-00117-1

evidence_span

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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

evidence_span

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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

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/niacin-redox-sources/nadk2-patient-2014.abstract.txt", "locator": "Indexed abstract, enzyme assay", "start_char": 706, "end_char": 1462, "file_sha256": "0e8ce719f0454f41ce98a5c35f75c88a21f5219f0d9b574cf8a793697f39db5a", "text_sha256": "3e8d0b720e24732ab8f9603138f761f1dc2974876c1f81919cf5ecdae2f71eeb"}

experimental_model

Patient fibroblast lysate enzyme assay

exposure

Inherited NADK2 alteration

limitations

Abstract-backed genetic association plus rescue experiment; not proof that niacin supplementation restores enzyme activity.

nutrient_topic

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

organism

Homo sapiens

plain_language

The impaired cofactor machinery was accompanied by loss of a dependent fatty-acid enzyme activity.

primary_references

[nadk2-patient-2014] Mitochondrial NADP(H) deficiency due to a mutation in NADK2 causes dienoyl-CoA reductase deficiency with hyperlysinemia. (2014). https://pubmed.ncbi.nlm.nih.gov/24847004/ DOI: 10.1093/hmg/ddu218

tissue_or_cell_type

Fibroblasts

trigger_kind

machinery_impairment Imported condition classification; unverified.

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 977–988

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

### b3-redox-nadk2-patient-decr Dienoyl-CoA reductase activity was deficient in lysates from the NADK2 patient fibroblasts. Condition category: machinery_impairment nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The impaired cofactor machinery was accompanied by loss of a dependent fatty-acid enzyme activity. organism: Homo sapiens tissue_or_cell_type: Fibroblasts experimental_model: Patient fibroblast lysate enzyme assay limitations: Abstract-backed genetic association plus rescue experiment; not proof that niacin supplementation restores enzyme activity. exposure: Inherited NADK2 alteration evidence_span: {"source_cache": "artifacts/niacin-redox-sources/nadk2-patient-2014.abstract.txt", "locator": "Indexed abstract, enzyme assay", "start_char": 706, "end_char": 1462, "file_sha256": "0e8ce719f0454f41ce98a5c35f75c88a21f5219f0d9b574cf8a793697f39db5a", "text_sha256": "3e8d0b720e24732ab8f9603138f761f1dc2974876c1f81919cf5ecdae2f71eeb"} [nadk2-patient-2014] Mitochondrial NADP(H) deficiency due to a mutation in NADK2 causes dienoyl-CoA reductase deficiency with hyperlysinemia. (2014). https://pubmed.ncbi.nlm.nih.gov/24847004/ DOI: 10.1093/hmg/ddu218

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/niacin-redox-sources/nadk2-patient-2014.abstract.txt", "locator": "Indexed abstract, rescue experiment", "start_char": 706, "end_char": 1462, "file_sha256": "0e8ce719f0454f41ce98a5c35f75c88a21f5219f0d9b574cf8a793697f39db5a", "text_sha256": "3e8d0b720e24732ab8f9603138f761f1dc2974876c1f81919cf5ecdae2f71eeb"}

experimental_model

Functional NADK2 transfection of patient fibroblasts

exposure

Genetic complementation

limitations

Cellular gene rescue; neither dietary niacin nor NADPH dosing was shown to reproduce it.

nutrient_topic

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

organism

Homo sapiens

plain_language

Replacing the defective kinase restored the enzyme readout in cells.

primary_references

[nadk2-patient-2014] Mitochondrial NADP(H) deficiency due to a mutation in NADK2 causes dienoyl-CoA reductase deficiency with hyperlysinemia. (2014). https://pubmed.ncbi.nlm.nih.gov/24847004/ DOI: 10.1093/hmg/ddu218

tissue_or_cell_type

Fibroblasts

trigger_kind

machinery_impairment Imported condition classification; unverified.

Niacin: NAD metabolism, deficiency and nutrient interactions (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 · Functional NADK2 transfection of patient fibroblasts · source_derived_draft · unverified_draft

### b3-redox-nadk2-patient-decr-rescue Transfection with functional NADK2 rescued deficient DECR activity in the patient-cell experiments. Condition category: machinery_impairment nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Replacing the defective kinase restored the enzyme readout in cells. organism: Homo sapiens tissue_or_cell_type: Fibroblasts experimental_model: Functional NADK2 transfection of patient fibroblasts limitations: Cellular gene rescue; neither dietary niacin nor NADPH dosing was shown to reproduce it. exposure: Genetic complementation evidence_span: {"source_cache": "artifacts/niacin-redox-sources/nadk2-patient-2014.abstract.txt", "locator": "Indexed abstract, rescue experiment", "start_char": 706, "end_char": 1462, "file_sha256": "0e8ce719f0454f41ce98a5c35f75c88a21f5219f0d9b574cf8a793697f39db5a", "text_sha256": "3e8d0b720e24732ab8f9603138f761f1dc2974876c1f81919cf5ecdae2f71eeb"} [nadk2-patient-2014] Mitochondrial NADP(H) deficiency due to a mutation in NADK2 causes dienoyl-CoA reductase deficiency with hyperlysinemia. (2014). https://pubmed.ncbi.nlm.nih.gov/24847004/ DOI: 10.1093/hmg/ddu218

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/niacin-redox-sources/nadk2-patient-2014.abstract.txt", "locator": "Indexed abstract, genetic and fibroblast results", "start_char": 357, "end_char": 1462, "file_sha256": "0e8ce719f0454f41ce98a5c35f75c88a21f5219f0d9b574cf8a793697f39db5a", "text_sha256": "e468b1beee1be208d337cdf94488aca05296b2dd3fcbba587ca323b8db6d2c96"}

experimental_model

Patient-derived fibroblasts

exposure

Inherited NADK2 alteration

limitations

Single described patient context; mitochondrial NADP(H) shortage arose from kinase machinery impairment, not demonstrated dietary niacin shortage.

nutrient_topic

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

organism

Homo sapiens

plain_language

The genetic defect impaired the mitochondrial phosphorylated cofactor pool.

primary_references

[nadk2-patient-2014] Mitochondrial NADP(H) deficiency due to a mutation in NADK2 causes dienoyl-CoA reductase deficiency with hyperlysinemia. (2014). https://pubmed.ncbi.nlm.nih.gov/24847004/ DOI: 10.1093/hmg/ddu218

tissue_or_cell_type

Fibroblasts

trigger_kind

machinery_impairment Imported condition classification; unverified.

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 964–975

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

### b3-redox-nadk2-patient-pool Patient fibroblasts bearing a pathogenic NADK2 alteration had reduced mitochondrial NADP(H). Condition category: machinery_impairment nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The genetic defect impaired the mitochondrial phosphorylated cofactor pool. organism: Homo sapiens tissue_or_cell_type: Fibroblasts experimental_model: Patient-derived fibroblasts limitations: Single described patient context; mitochondrial NADP(H) shortage arose from kinase machinery impairment, not demonstrated dietary niacin shortage. exposure: Inherited NADK2 alteration evidence_span: {"source_cache": "artifacts/niacin-redox-sources/nadk2-patient-2014.abstract.txt", "locator": "Indexed abstract, genetic and fibroblast results", "start_char": 357, "end_char": 1462, "file_sha256": "0e8ce719f0454f41ce98a5c35f75c88a21f5219f0d9b574cf8a793697f39db5a", "text_sha256": "e468b1beee1be208d337cdf94488aca05296b2dd3fcbba587ca323b8db6d2c96"} [nadk2-patient-2014] Mitochondrial NADP(H) deficiency due to a mutation in NADK2 causes dienoyl-CoA reductase deficiency with hyperlysinemia. (2014). https://pubmed.ncbi.nlm.nih.gov/24847004/ DOI: 10.1093/hmg/ddu218

experimental_model

Recombinant human AASS and isolated reductase domain

limitations

Reaction reversibility in vitro does not imply appreciable human lysine biosynthesis.

organism

Homo sapiens

plain_language

AASS starts the main lysine breakdown route.

primary_references

[leandro2022] Characterization and structure of the human lysine-2-oxoglutarate reductase domain, a novel therapeutic target for treatment of glutaric aciduria type 1 (2022). https://pmc.ncbi.nlm.nih.gov/articles/PMC9490328/ DOI: 10.1098/rsob.220179

tissue_or_cell_type

Mitochondrial matrix

L-Lysine: mechanism-first literature curation (2026-09-17) · lines 74–82

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human AASS and isolated reductase domain · source_derived_draft · unverified_draft

### aass-reductase The AASS reductase domain condenses lysine with 2-oxoglutarate using NADPH to form saccharopine. Plain language: AASS starts the main lysine breakdown route. Condition category: normal organism: Homo sapiens tissue_or_cell_type: Mitochondrial matrix experimental_model: Recombinant human AASS and isolated reductase domain limitations: Reaction reversibility in vitro does not imply appreciable human lysine biosynthesis. [leandro2022] Characterization and structure of the human lysine-2-oxoglutarate reductase domain, a novel therapeutic target for treatment of glutaric aciduria type 1 (2022). https://pmc.ncbi.nlm.nih.gov/articles/PMC9490328/ DOI: 10.1098/rsob.220179

experimental_model

Recombinant human CRYM and mammalian enzyme substrate assays

limitations

Catalytic capacity does not determine the route's quantitative contribution to human brain lysine clearance.

organism

Homo sapiens enzyme; ovine enzyme used for initial purification

plain_language

A ring-shaped intermediate can be reduced to pipecolate.

primary_references

[hallen2011] Mammalian forebrain ketimine reductase identified as mu-crystallin; potential regulation by thyroid hormones. (2011). https://pubmed.ncbi.nlm.nih.gov/21332720/ DOI: 10.1111/j.1471-4159.2011.07220.x [hallen2015] Insights into Enzyme Catalysis and Thyroid Hormone Regulation of Cerebral Ketimine Reductase/mu-Crystallin Under Physiological Conditions. (2015). https://pubmed.ncbi.nlm.nih.gov/25931162/ DOI: 10.1007/s11064-015-1590-5

tissue_or_cell_type

Cytosolic enzyme; forebrain biochemical context

L-Lysine: mechanism-first literature curation (2026-09-17) · lines 336–345

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human CRYM and mammalian enzyme substrate assays · source_derived_draft · unverified_draft

### crym-p2c-reduction CRYM ketimine reductase reduces P2C to L-pipecolate using reduced nicotinamide cofactors. Plain language: A ring-shaped intermediate can be reduced to pipecolate. Condition category: normal organism: Homo sapiens enzyme; ovine enzyme used for initial purification tissue_or_cell_type: Cytosolic enzyme; forebrain biochemical context experimental_model: Recombinant human CRYM and mammalian enzyme substrate assays limitations: Catalytic capacity does not determine the route's quantitative contribution to human brain lysine clearance. [hallen2011] Mammalian forebrain ketimine reductase identified as mu-crystallin; potential regulation by thyroid hormones. (2011). https://pubmed.ncbi.nlm.nih.gov/21332720/ DOI: 10.1111/j.1471-4159.2011.07220.x [hallen2015] Insights into Enzyme Catalysis and Thyroid Hormone Regulation of Cerebral Ketimine Reductase/mu-Crystallin Under Physiological Conditions. (2015). https://pubmed.ncbi.nlm.nih.gov/25931162/ DOI: 10.1007/s11064-015-1590-5

cross_nutrient

true

experimental_model

Human volunteer erythrocytes ex vivo

exposure

DHA challenge with or without 5 mM glucose

limitations

Metabolic support and transporter competition are different processes; this does not imply dietary sugar supplementation is needed.

nutrient_topic

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

organism

Homo sapiens

plain_language

Glucose metabolism helped sustain the reducing resources used to recycle vitamin C.

primary_references

[may2001] Mechanisms of ascorbic acid recycling in human erythrocytes. (2001). https://pubmed.ncbi.nlm.nih.gov/11687303/ DOI: 10.1016/s0304-4165(01)00188-x

tissue_or_cell_type

Erythrocytes

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 325–336

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human volunteer erythrocytes ex vivo · source_derived_draft · unverified_draft

### vc-transport-rbc-glucose-support During DHA reduction by human erythrocytes, 5 mM D-glucose maintained GSH and NADH concentrations whereas NADPH still declined; without glucose all three fell. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Glucose metabolism helped sustain the reducing resources used to recycle vitamin C. organism: Homo sapiens tissue_or_cell_type: Erythrocytes experimental_model: Human volunteer erythrocytes ex vivo limitations: Metabolic support and transporter competition are different processes; this does not imply dietary sugar supplementation is needed. exposure: DHA challenge with or without 5 mM glucose cross_nutrient: true [may2001] Mechanisms of ascorbic acid recycling in human erythrocytes. (2001). https://pubmed.ncbi.nlm.nih.gov/11687303/ DOI: 10.1016/s0304-4165(01)00188-x

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

true

experimental_model

Purified rat liver enzyme, dialyzed cytosol and microsomes from control/selenium-deficient rats

exposure

Dietary selenium depletion; isolated dialyzed cytosol

limitations

Activity assignment also used inhibitor sensitivity; this is a fraction assay, not a direct human outcome.

nutrient_topic

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

organism

Rattus norvegicus

plain_language

Selenium deficiency impaired radical recycling in the rat liver’s soluble fraction.

primary_references

[may1998] Reduction of the ascorbyl free radical to ascorbate by thioredoxin reductase. (1998). https://pubmed.ncbi.nlm.nih.gov/9722529/ DOI: 10.1074/jbc.273.36.23039

tissue_or_cell_type

Liver cytosol

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 429–440

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified rat liver enzyme, dialyzed cytosol and microsomes from control/selenium-deficient rats · source_derived_draft · unverified_draft

### vc-transport-selenium-cytosolic-radical Dialyzed liver cytosol from selenium-deficient rats lost NADPH-dependent ascorbyl-radical reducing activity attributed to thioredoxin reductase. Condition category: nutrient_deficiency nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Selenium deficiency impaired radical recycling in the rat liver’s soluble fraction. organism: Rattus norvegicus tissue_or_cell_type: Liver cytosol experimental_model: Purified rat liver enzyme, dialyzed cytosol and microsomes from control/selenium-deficient rats limitations: Activity assignment also used inhibitor sensitivity; this is a fraction assay, not a direct human outcome. exposure: Dietary selenium depletion; isolated dialyzed cytosol cross_nutrient: true [may1998] Reduction of the ascorbyl free radical to ascorbate by thioredoxin reductase. (1998). https://pubmed.ncbi.nlm.nih.gov/9722529/ DOI: 10.1074/jbc.273.36.23039

cross_nutrient

true

experimental_model

Purified rat liver thioredoxin reductase/thioredoxin and selenium-deficient rat liver

exposure

2.8 µM thioredoxin added to NADPH/thioredoxin-reductase assay

limitations

Apparent kinetic effect is not proof of a faster whole-body recycling rate.

nutrient_topic

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

organism

Rattus norvegicus

plain_language

Thioredoxin improved the system’s apparent affinity for oxidized vitamin C in this assay.

primary_references

[may1997] Reduction of dehydroascorbate to ascorbate by the selenoenzyme thioredoxin reductase. (1997). https://pubmed.ncbi.nlm.nih.gov/9278416/ DOI: 10.1074/jbc.272.36.22607

tissue_or_cell_type

Purified liver enzymes

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 390–401

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified rat liver thioredoxin reductase/thioredoxin and selenium-deficient rat liver · source_derived_draft · unverified_draft

### vc-transport-thioredoxin-dha-affinity Adding 2.8 µM rat liver thioredoxin lowered apparent DHA Km of the thioredoxin-reductase system from 2.5 to 0.7 mM without materially increasing turnover. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Thioredoxin improved the system’s apparent affinity for oxidized vitamin C in this assay. organism: Rattus norvegicus tissue_or_cell_type: Purified liver enzymes experimental_model: Purified rat liver thioredoxin reductase/thioredoxin and selenium-deficient rat liver limitations: Apparent kinetic effect is not proof of a faster whole-body recycling rate. exposure: 2.8 µM thioredoxin added to NADPH/thioredoxin-reductase assay cross_nutrient: true [may1997] Reduction of dehydroascorbate to ascorbate by the selenoenzyme thioredoxin reductase. (1997). https://pubmed.ncbi.nlm.nih.gov/9278416/ DOI: 10.1074/jbc.272.36.22607

cross_nutrient

true

experimental_model

Purified rat liver thioredoxin reductase/thioredoxin and selenium-deficient rat liver

exposure

Purified enzyme plus NADPH and DHA

limitations

Biochemical capacity; not the same as cellular rate at low DHA concentration.

nutrient_topic

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

organism

Rattus norvegicus

plain_language

Thioredoxin reductase provides another route for recovering reduced vitamin C.

primary_references

[may1997] Reduction of dehydroascorbate to ascorbate by the selenoenzyme thioredoxin reductase. (1997). https://pubmed.ncbi.nlm.nih.gov/9278416/ DOI: 10.1074/jbc.272.36.22607

tissue_or_cell_type

Purified liver enzyme

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 377–388

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified rat liver thioredoxin reductase/thioredoxin and selenium-deficient rat liver · source_derived_draft · unverified_draft

### vc-transport-txnrd-dha Purified rat liver thioredoxin reductase reduced DHA using NADPH, with apparent DHA Km 2.5 mM and turnover 90 min−1. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Thioredoxin reductase provides another route for recovering reduced vitamin C. organism: Rattus norvegicus tissue_or_cell_type: Purified liver enzyme experimental_model: Purified rat liver thioredoxin reductase/thioredoxin and selenium-deficient rat liver limitations: Biochemical capacity; not the same as cellular rate at low DHA concentration. exposure: Purified enzyme plus NADPH and DHA cross_nutrient: true [may1997] Reduction of dehydroascorbate to ascorbate by the selenoenzyme thioredoxin reductase. (1997). https://pubmed.ncbi.nlm.nih.gov/9278416/ DOI: 10.1074/jbc.272.36.22607

cross_nutrient

true

experimental_model

Purified rat liver enzyme, dialyzed cytosol and microsomes from control/selenium-deficient rats

exposure

Low-micromolar ascorbyl radical generated by ascorbate oxidase

limitations

Purified assay; radical and DHA reduction are distinct reactions.

nutrient_topic

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

organism

Rattus norvegicus

plain_language

The reductase can also recycle the one-electron vitamin C radical.

primary_references

[may1998] Reduction of the ascorbyl free radical to ascorbate by thioredoxin reductase. (1998). https://pubmed.ncbi.nlm.nih.gov/9722529/ DOI: 10.1074/jbc.273.36.23039

tissue_or_cell_type

Purified liver enzyme

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 416–427

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified rat liver enzyme, dialyzed cytosol and microsomes from control/selenium-deficient rats · source_derived_draft · unverified_draft

### vc-transport-txnrd-radical Purified rat liver thioredoxin reductase decreased ascorbyl radical measured by electron paramagnetic resonance while consuming NADPH; DHA controls could not explain the signal. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: The reductase can also recycle the one-electron vitamin C radical. organism: Rattus norvegicus tissue_or_cell_type: Purified liver enzyme experimental_model: Purified rat liver enzyme, dialyzed cytosol and microsomes from control/selenium-deficient rats limitations: Purified assay; radical and DHA reduction are distinct reactions. exposure: Low-micromolar ascorbyl radical generated by ascorbate oxidase cross_nutrient: true [may1998] Reduction of the ascorbyl free radical to ascorbate by thioredoxin reductase. (1998). https://pubmed.ncbi.nlm.nih.gov/9722529/ DOI: 10.1074/jbc.273.36.23039

cross_nutrient

NADPH and heme-containing P450 machinery support retinoid oxidation; nutritional deficiency was not tested.

evidence_location

Abstract

experimental_model

Human CYP26A1/CYP26B1 expressed in insect cells; purified/reconstituted metabolism and tissue assays.

exposure

All-trans-retinoic-acid concentration series with P450 reductase and NADPH.

limitations

Assay kinetics are not whole-body clearance; hydroxylated products are not assumed biologically inert.

nutrient_topic

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

organism

Homo sapiens recombinant protein in insect cells

outcome

Recombinant human CYP26A1 hydroxylated all-trans-retinoic acid to 4-hydroxy-retinoic acid.

plain_language

This P450 begins oxidative removal of the signaling retinoid.

primary_references

[va-topletz-2012] Comparison of the function and expression of CYP26A1 and CYP26B1, the two retinoic acid hydroxylases (2012). https://pubmed.ncbi.nlm.nih.gov/22020119/ DOI: 10.1016/j.bcp.2011.10.007

tissue_or_cell_type

Reconstituted enzyme/microsomes

Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 601–614

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human CYP26A1/CYP26B1 expressed in insect cells; purified/reconstituted metabolism and tissue assays. · source_derived_draft · unverified_draft

### va-cyp26a1-primary-hydroxylation Recombinant human CYP26A1 hydroxylated all-trans-retinoic acid to 4-hydroxy-retinoic acid. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: This P450 begins oxidative removal of the signaling retinoid. organism: Homo sapiens recombinant protein in insect cells tissue_or_cell_type: Reconstituted enzyme/microsomes experimental_model: Human CYP26A1/CYP26B1 expressed in insect cells; purified/reconstituted metabolism and tissue assays. limitations: Assay kinetics are not whole-body clearance; hydroxylated products are not assumed biologically inert. exposure: All-trans-retinoic-acid concentration series with P450 reductase and NADPH. outcome: Recombinant human CYP26A1 hydroxylated all-trans-retinoic acid to 4-hydroxy-retinoic acid. evidence_location: Abstract cross_nutrient: NADPH and heme-containing P450 machinery support retinoid oxidation; nutritional deficiency was not tested. [va-topletz-2012] Comparison of the function and expression of CYP26A1 and CYP26B1, the two retinoic acid hydroxylases (2012). https://pubmed.ncbi.nlm.nih.gov/22020119/ DOI: 10.1016/j.bcp.2011.10.007

evidence_location

Abstract

experimental_model

Human CYP26A1/CYP26B1 expressed in insect cells; purified/reconstituted metabolism and tissue assays.

exposure

Substrate series with NADPH and P450 reductase.

limitations

Lower in vitro turnover than CYP26A1 does not mean lower importance in every tissue.

nutrient_topic

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

organism

Homo sapiens recombinant protein in insect cells

outcome

Recombinant human CYP26B1 formed 4-hydroxy-retinoic acid from all-trans-retinoic acid.

plain_language

A second independent P450 enzyme also removes the signaling precursor.

primary_references

[va-topletz-2012] Comparison of the function and expression of CYP26A1 and CYP26B1, the two retinoic acid hydroxylases (2012). https://pubmed.ncbi.nlm.nih.gov/22020119/ DOI: 10.1016/j.bcp.2011.10.007

tissue_or_cell_type

Reconstituted enzyme/microsomes

Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 616–628

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human CYP26A1/CYP26B1 expressed in insect cells; purified/reconstituted metabolism and tissue assays. · source_derived_draft · unverified_draft

### va-cyp26b1-primary-hydroxylation Recombinant human CYP26B1 formed 4-hydroxy-retinoic acid from all-trans-retinoic acid. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: A second independent P450 enzyme also removes the signaling precursor. organism: Homo sapiens recombinant protein in insect cells tissue_or_cell_type: Reconstituted enzyme/microsomes experimental_model: Human CYP26A1/CYP26B1 expressed in insect cells; purified/reconstituted metabolism and tissue assays. limitations: Lower in vitro turnover than CYP26A1 does not mean lower importance in every tissue. exposure: Substrate series with NADPH and P450 reductase. outcome: Recombinant human CYP26B1 formed 4-hydroxy-retinoic acid from all-trans-retinoic acid. evidence_location: Abstract [va-topletz-2012] Comparison of the function and expression of CYP26A1 and CYP26B1, the two retinoic acid hydroxylases (2012). https://pubmed.ncbi.nlm.nih.gov/22020119/ DOI: 10.1016/j.bcp.2011.10.007

cross_nutrient

NADPH supports a retinoid buffering reaction.

evidence_location

Figure 5 and Table 1

experimental_model

Human RDH10/DHRS3 coexpression in HEK293 and Sf9 cells, plus Dhrs3-null embryos.

exposure

DHRS3 coexpressed with RDH10; retinal plus NADPH.

limitations

Cofactor dependency is not a dietary niacin intervention.

nutrient_topic

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

organism

Homo sapiens proteins in Sf9 and HEK293 systems

outcome

RDH10-activated DHRS3 reduced all-trans-retinal to retinol preferentially using NADPH.

plain_language

This reverse step restrains retinal available for acid production.

primary_references

[va-adams-2014] The retinaldehyde reductase activity of DHRS3 is reciprocally activated by retinol dehydrogenase 10 to control retinoid homeostasis (2014). https://pmc.ncbi.nlm.nih.gov/articles/PMC4031538/ DOI: 10.1074/jbc.M114.552257

tissue_or_cell_type

Microsomal/cellular retinoid system

Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 516–529

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human RDH10/DHRS3 coexpression in HEK293 and Sf9 cells, plus Dhrs3-null embryos. · source_derived_draft · unverified_draft

### va-dhrs3-retinal-reduction RDH10-activated DHRS3 reduced all-trans-retinal to retinol preferentially using NADPH. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: This reverse step restrains retinal available for acid production. organism: Homo sapiens proteins in Sf9 and HEK293 systems tissue_or_cell_type: Microsomal/cellular retinoid system experimental_model: Human RDH10/DHRS3 coexpression in HEK293 and Sf9 cells, plus Dhrs3-null embryos. limitations: Cofactor dependency is not a dietary niacin intervention. exposure: DHRS3 coexpressed with RDH10; retinal plus NADPH. outcome: RDH10-activated DHRS3 reduced all-trans-retinal to retinol preferentially using NADPH. evidence_location: Figure 5 and Table 1 cross_nutrient: NADPH supports a retinoid buffering reaction. [va-adams-2014] The retinaldehyde reductase activity of DHRS3 is reciprocally activated by retinol dehydrogenase 10 to control retinoid homeostasis (2014). https://pmc.ncbi.nlm.nih.gov/articles/PMC4031538/ DOI: 10.1074/jbc.M114.552257

cross_nutrient

false

experimental_model

Recombinant human P450 enzyme comparison

exposure

alpha-Tocopherol substrate with NADPH; quantitative incubation details not assigned here.

limitations

Initial oxidation only; other enzymes perform subsequent side-chain shortening.

nutrient_topic

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

organism

Human protein in recombinant microsomes

plain_language

CYP4F2 begins breakdown of this tocopherol form.

primary_references

[sontag2002] Cytochrome P450 omega-hydroxylase pathway of tocopherol catabolism. Novel mechanism of regulation of vitamin E status. (2002). https://pubmed.ncbi.nlm.nih.gov/11997390/ DOI: 10.1074/jbc.m201466200

tissue_or_cell_type

Microsomal enzyme preparation

Vitamin E: transport, membrane protection and nutrient interactions (2026-09-17) · lines 402–413

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human P450 enzyme comparison · source_derived_draft · unverified_draft

### ve-transport-cyp4f2-alpha-hydroxylation Recombinant human CYP4F2 catalyzed terminal side-chain hydroxylation of alpha-tocopherol to its 13′-hydroxy product. Condition category: normal nutrient_topic: Vitamin E research collection; topical membership is not evidence of a direct dietary effect. plain_language: CYP4F2 begins breakdown of this tocopherol form. organism: Human protein in recombinant microsomes tissue_or_cell_type: Microsomal enzyme preparation experimental_model: Recombinant human P450 enzyme comparison limitations: Initial oxidation only; other enzymes perform subsequent side-chain shortening. exposure: alpha-Tocopherol substrate with NADPH; quantitative incubation details not assigned here. cross_nutrient: false [sontag2002] Cytochrome P450 omega-hydroxylase pathway of tocopherol catabolism. Novel mechanism of regulation of vitamin E status. (2002). https://pubmed.ncbi.nlm.nih.gov/11997390/ DOI: 10.1074/jbc.m201466200

cross_nutrient

false

experimental_model

Recombinant human P450 enzyme comparison

exposure

gamma-Tocopherol substrate with NADPH; quantitative incubation details not assigned here.

limitations

Initial oxidation only; other enzymes perform subsequent side-chain shortening.

nutrient_topic

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

organism

Human protein in recombinant microsomes

plain_language

CYP4F2 begins breakdown of this tocopherol form.

primary_references

[sontag2002] Cytochrome P450 omega-hydroxylase pathway of tocopherol catabolism. Novel mechanism of regulation of vitamin E status. (2002). https://pubmed.ncbi.nlm.nih.gov/11997390/ DOI: 10.1074/jbc.m201466200

tissue_or_cell_type

Microsomal enzyme preparation

Vitamin E: transport, membrane protection and nutrient interactions (2026-09-17) · lines 415–426

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human P450 enzyme comparison · source_derived_draft · unverified_draft

### ve-transport-cyp4f2-gamma-hydroxylation Recombinant human CYP4F2 catalyzed terminal side-chain hydroxylation of gamma-tocopherol to its 13′-hydroxy product. Condition category: normal nutrient_topic: Vitamin E research collection; topical membership is not evidence of a direct dietary effect. plain_language: CYP4F2 begins breakdown of this tocopherol form. organism: Human protein in recombinant microsomes tissue_or_cell_type: Microsomal enzyme preparation experimental_model: Recombinant human P450 enzyme comparison limitations: Initial oxidation only; other enzymes perform subsequent side-chain shortening. exposure: gamma-Tocopherol substrate with NADPH; quantitative incubation details not assigned here. cross_nutrient: false [sontag2002] Cytochrome P450 omega-hydroxylase pathway of tocopherol catabolism. Novel mechanism of regulation of vitamin E status. (2002). https://pubmed.ncbi.nlm.nih.gov/11997390/ DOI: 10.1074/jbc.m201466200

cross_nutrient

true

experimental_model

Recombinant CYP4F2 kinetic assay

exposure

25 pmol CYP4F2; labeled phylloquinone 1–100 µM; 1 mM NADPH; 30 min at 37 °C.

limitations

Shared substrate use alone does not imply vitamin E accelerates vitamin K depletion.

nutrient_topic

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

organism

Human protein in insect microsomes

plain_language

Vitamins E and K1 share an initial catabolic enzyme.

primary_references

[farley2013] ω-Hydroxylation of phylloquinone by CYP4F2 is not increased by α-tocopherol. (2013). https://pubmed.ncbi.nlm.nih.gov/23650179/ DOI: 10.1002/mnfr.201200797

tissue_or_cell_type

Microsomal enzyme preparation

Vitamin E: transport, membrane protection and nutrient interactions (2026-09-17) · lines 454–465

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant CYP4F2 kinetic assay · source_derived_draft · unverified_draft

### ve-transport-cyp4f2-k1-hydroxylation Human CYP4F2-expressing microsomes hydroxylated phylloquinone, demonstrating substrate overlap with tocopherol catabolism. Condition category: normal nutrient_topic: Vitamin E research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamins E and K1 share an initial catabolic enzyme. organism: Human protein in insect microsomes tissue_or_cell_type: Microsomal enzyme preparation experimental_model: Recombinant CYP4F2 kinetic assay limitations: Shared substrate use alone does not imply vitamin E accelerates vitamin K depletion. exposure: 25 pmol CYP4F2; labeled phylloquinone 1–100 µM; 1 mM NADPH; 30 min at 37 °C. cross_nutrient: true [farley2013] ω-Hydroxylation of phylloquinone by CYP4F2 is not increased by α-tocopherol. (2013). https://pubmed.ncbi.nlm.nih.gov/23650179/ DOI: 10.1002/mnfr.201200797

evidence_span

{"source_cache": "artifacts/inositol-research/12051772.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "28ae1225b489898738997d2376ab09857f017314086979032d3ad907299a1154", "start_char": 0, "end_char": 2218, "text_sha256": "28ae1225b489898738997d2376ab09857f017314086979032d3ad907299a1154"}

experimental_model

Radiotracer conversion and cytosolic enzyme assays

exposure

Diabetic rat versus controls; reduced pyridine-nucleotide cofactors

limitations

The molecular identity of the activity was not established here. A later mouse stable-isotope study found no myo-to-D-chiro conversion; the research disagreement is recorded separately. Do not invent a human epimerase gene or infer a universal supplement ratio.

nutrient_topic

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

organism

Goto-Kakizaki and Wistar rats

plain_language

Reduced niacin-derived cofactors supported the observed conversion.

primary_references

[ino-p12051772] Both myo-inositol to chiro-inositol epimerase activities and chiro-inositol to myo-inositol ratios are decreased in tissues of GK type 2 diabetic rats compared to Wistar controls. (2002). https://pubmed.ncbi.nlm.nih.gov/12051772/ DOI: 10.1016/s0006-291x(02)00313-3

tissue_or_cell_type

Liver, muscle, kidney and adipose preparations

Inositol: synthesis, signaling, mineral interactions and conditional deficiency (2026-09-17) · lines 1185–1196

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

### ino-epimerase-nadh The rat cytosolic epimerase assay required NADH and NADPH for full activity. Condition category: normal nutrient_topic: Inositol research collection; topical membership is not evidence of a direct dietary effect. plain_language: Reduced niacin-derived cofactors supported the observed conversion. organism: Goto-Kakizaki and Wistar rats tissue_or_cell_type: Liver, muscle, kidney and adipose preparations experimental_model: Radiotracer conversion and cytosolic enzyme assays limitations: The molecular identity of the activity was not established here. A later mouse stable-isotope study found no myo-to-D-chiro conversion; the research disagreement is recorded separately. Do not invent a human epimerase gene or infer a universal supplement ratio. exposure: Diabetic rat versus controls; reduced pyridine-nucleotide cofactors evidence_span: {"source_cache": "artifacts/inositol-research/12051772.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "28ae1225b489898738997d2376ab09857f017314086979032d3ad907299a1154", "start_char": 0, "end_char": 2218, "text_sha256": "28ae1225b489898738997d2376ab09857f017314086979032d3ad907299a1154"} [ino-p12051772] Both myo-inositol to chiro-inositol epimerase activities and chiro-inositol to myo-inositol ratios are decreased in tissues of GK type 2 diabetic rats compared to Wistar controls. (2002). https://pubmed.ncbi.nlm.nih.gov/12051772/ DOI: 10.1016/s0006-291x(02)00313-3

cross_nutrient

CoA maturation enables the folate-to-NADPH reaction.

experimental_model

Recombinant enzyme activation assay

exposure

Assay conditions described in the linked primary study.

limitations

Figure 5 used stable dideazafolate analogue rather than physiological folate.

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

The installed arm enables oxidation of folate-bound carbon.

primary_references

[strickland-2011] Enzymatic properties of ALDH1L2, a mitochondrial 10-formyltetrahydrofolate dehydrogenase (2011). https://pubmed.ncbi.nlm.nih.gov/21238436/ DOI: 10.1016/j.cbi.2011.01.008

tissue_or_cell_type

Cell-free

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1059–1070

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

### aldh1l2-activation-folate-oxidation Phosphopantetheinylation restored recombinant ALDH1L2 folate dehydrogenase activity with NADPH formation. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The installed arm enables oxidation of folate-bound carbon. organism: Homo sapiens tissue_or_cell_type: Cell-free experimental_model: Recombinant enzyme activation assay limitations: Figure 5 used stable dideazafolate analogue rather than physiological folate. exposure: Assay conditions described in the linked primary study. cross_nutrient: CoA maturation enables the folate-to-NADPH reaction. [strickland-2011] Enzymatic properties of ALDH1L2, a mitochondrial 10-formyltetrahydrofolate dehydrogenase (2011). https://pubmed.ncbi.nlm.nih.gov/21238436/ DOI: 10.1016/j.cbi.2011.01.008

experimental_model

Fresh human liver extracts from six donors and rat comparison

exposure

DHF substrate; THF quantified by HPLC

limitations

Assay chemistry, not an outcome study.

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

DHFR regenerates reduced folate from DHF.

primary_references

[bailey2009] The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake (2009). https://pubmed.ncbi.nlm.nih.gov/19706381/ DOI: 10.1073/pnas.0902072106

tissue_or_cell_type

Liver extracts

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 363–373

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Fresh human liver extracts from six donors and rat comparison · source_derived_draft · unverified_draft

### folate-dhfr-dhf-recycling Human liver DHFR converted 7,8-dihydrofolate to tetrahydrofolate in NADPH-containing assays. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: DHFR regenerates reduced folate from DHF. organism: Homo sapiens tissue_or_cell_type: Liver extracts experimental_model: Fresh human liver extracts from six donors and rat comparison limitations: Assay chemistry, not an outcome study. exposure: DHF substrate; THF quantified by HPLC [bailey2009] The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake (2009). https://pubmed.ncbi.nlm.nih.gov/19706381/ DOI: 10.1073/pnas.0902072106

experimental_model

Fresh human liver extracts from six donors and rat comparison

exposure

Folic acid substrate with NADPH

limitations

Reaction identity; liver rates cannot define a universal intake ceiling.

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

Folic acid needs a reduction step before it becomes usable folate.

primary_references

[bailey2009] The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake (2009). https://pubmed.ncbi.nlm.nih.gov/19706381/ DOI: 10.1073/pnas.0902072106

tissue_or_cell_type

Liver enzyme preparations

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 351–361

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Fresh human liver extracts from six donors and rat comparison · source_derived_draft · unverified_draft

### folate-dhfr-folic-acid-first-reduction DHFR reduces folic acid to dihydrofolate before further reduction to tetrahydrofolate. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Folic acid needs a reduction step before it becomes usable folate. organism: Homo sapiens tissue_or_cell_type: Liver enzyme preparations experimental_model: Fresh human liver extracts from six donors and rat comparison limitations: Reaction identity; liver rates cannot define a universal intake ceiling. exposure: Folic acid substrate with NADPH [bailey2009] The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake (2009). https://pubmed.ncbi.nlm.nih.gov/19706381/ DOI: 10.1073/pnas.0902072106

cross_nutrient

Flavin-dependent MTRR supports B12-enzyme assembly.

experimental_model

Human MTR/MTRR expressed in insect cells; purified enzymes and extracts.

limitations

In-vitro assembly.

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

MTRR also helps MTR acquire its cofactor.

primary_references

[yamada-2006] Human methionine synthase reductase is a molecular chaperone for human methionine synthase (2006). https://pubmed.ncbi.nlm.nih.gov/16769880/ DOI: 10.1073/pnas.0603694103

tissue_or_cell_type

Human proteins expressed in insect cells

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 494–504

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human MTR/MTRR expressed in insect cells; purified enzymes and extracts. · source_derived_draft · unverified_draft

### folate-methyl-mtrr-apoenzyme Human MTRR stabilized apo-MTR and enhanced holoenzyme formation from methylcobalamin in the presence of NADPH. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: MTRR also helps MTR acquire its cofactor. organism: Homo sapiens tissue_or_cell_type: Human proteins expressed in insect cells experimental_model: Human MTR/MTRR expressed in insect cells; purified enzymes and extracts. limitations: In-vitro assembly. cross_nutrient: Flavin-dependent MTRR supports B12-enzyme assembly. [yamada-2006] Human methionine synthase reductase is a molecular chaperone for human methionine synthase (2006). https://pubmed.ncbi.nlm.nih.gov/16769880/ DOI: 10.1073/pnas.0603694103

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

cross_nutrient

Folate polyglutamylation changes nicotinamide-cofactor use.

experimental_model

Purified recombinant enzyme

exposure

Mono- versus pentaglutamate folate substrates; controlled NAD(P)+ assays.

limitations

Kinetics do not establish dominant in vivo NADPH production.

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

The folate tail affects which electron carrier the enzyme uses.

primary_references

[shin-2017] Human mitochondrial MTHFD2 is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase (2017). https://pubmed.ncbi.nlm.nih.gov/29225823/ DOI: 10.1186/s40170-017-0173-0

tissue_or_cell_type

Cell-free

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 825–836

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

### mthfd2-nadp-polyglutamate Human MTHFD2 also uses NADP+ with methylene-THF pentaglutamate; NADP-linked activity increases relative to the monoglutamate assay. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The folate tail affects which electron carrier the enzyme uses. organism: Homo sapiens tissue_or_cell_type: Cell-free experimental_model: Purified recombinant enzyme limitations: Kinetics do not establish dominant in vivo NADPH production. exposure: Mono- versus pentaglutamate folate substrates; controlled NAD(P)+ assays. cross_nutrient: Folate polyglutamylation changes nicotinamide-cofactor use. [shin-2017] Human mitochondrial MTHFD2 is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase (2017). https://pubmed.ncbi.nlm.nih.gov/29225823/ DOI: 10.1186/s40170-017-0173-0

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

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experimental_model

Random mutagenesis of recombinant human CYP2A6

exposure

Wild-type enzyme and selected activity-reducing mutants

limitations

Engineered protein dysfunction is not nutrient deficiency; no rescue by nutritional supplementation was tested.

nutrient_topic

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

organism

Human engineered protein

plain_language

Adding more partner enzyme did not fully repair this variant.

primary_references

[coumarin-p16207711] Analysis of coumarin 7-hydroxylation activity of cytochrome P450 2A6 using random mutagenesis. (2005). https://pubmed.ncbi.nlm.nih.gov/16207711/ DOI: 10.1074/jbc.m508171200

tissue_or_cell_type

Reconstituted enzyme system

trigger_kind

machinery_impairment Imported condition classification; unverified.

Coumarin: metabolism, signaling and nutrient connections (2026-09-17) · lines 618–629

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Random mutagenesis of recombinant human CYP2A6 · source_derived_draft · unverified_draft

### coumarin-k476e-hydroxylation K476E reduced NADPH oxidation and ferric-enzyme reduction; excess reductase did not restore wild-type coumarin hydroxylation. Condition category: machinery_impairment nutrient_topic: Coumarin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Adding more partner enzyme did not fully repair this variant. organism: Human engineered protein tissue_or_cell_type: Reconstituted enzyme system experimental_model: Random mutagenesis of recombinant human CYP2A6 limitations: Engineered protein dysfunction is not nutrient deficiency; no rescue by nutritional supplementation was tested. exposure: Wild-type enzyme and selected activity-reducing mutants evidence_span: {"source_cache": "artifacts/coumarin-research/16207711.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a5f0bef9ac62d55ff5725e8c5cb4eca3e76ef715c758654e76c0c596c52ceab7", "start_char": 0, "end_char": 1740, "text_sha256": "a5f0bef9ac62d55ff5725e8c5cb4eca3e76ef715c758654e76c0c596c52ceab7"} [coumarin-p16207711] Analysis of coumarin 7-hydroxylation activity of cytochrome P450 2A6 using random mutagenesis. (2005). https://pubmed.ncbi.nlm.nih.gov/16207711/ DOI: 10.1074/jbc.m508171200

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

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experimental_model

Random mutagenesis of recombinant human CYP2A6

exposure

Wild-type enzyme and selected activity-reducing mutants

limitations

Engineered protein dysfunction is not nutrient deficiency; no rescue by nutritional supplementation was tested.

nutrient_topic

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

organism

Human engineered protein

plain_language

A protein change weakened its connection to the electron donor.

primary_references

[coumarin-p16207711] Analysis of coumarin 7-hydroxylation activity of cytochrome P450 2A6 using random mutagenesis. (2005). https://pubmed.ncbi.nlm.nih.gov/16207711/ DOI: 10.1074/jbc.m508171200

tissue_or_cell_type

Reconstituted enzyme system

trigger_kind

machinery_impairment Imported condition classification; unverified.

Coumarin: metabolism, signaling and nutrient connections (2026-09-17) · lines 605–616

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Random mutagenesis of recombinant human CYP2A6 · source_derived_draft · unverified_draft

### coumarin-k476e-por CYP2A6 K476E had lower affinity for NADPH-P450 reductase, contributing to reduced catalytic activity. Condition category: machinery_impairment nutrient_topic: Coumarin research collection; topical membership is not evidence of a direct dietary effect. plain_language: A protein change weakened its connection to the electron donor. organism: Human engineered protein tissue_or_cell_type: Reconstituted enzyme system experimental_model: Random mutagenesis of recombinant human CYP2A6 limitations: Engineered protein dysfunction is not nutrient deficiency; no rescue by nutritional supplementation was tested. exposure: Wild-type enzyme and selected activity-reducing mutants evidence_span: {"source_cache": "artifacts/coumarin-research/16207711.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a5f0bef9ac62d55ff5725e8c5cb4eca3e76ef715c758654e76c0c596c52ceab7", "start_char": 0, "end_char": 1740, "text_sha256": "a5f0bef9ac62d55ff5725e8c5cb4eca3e76ef715c758654e76c0c596c52ceab7"} [coumarin-p16207711] Analysis of coumarin 7-hydroxylation activity of cytochrome P450 2A6 using random mutagenesis. (2005). https://pubmed.ncbi.nlm.nih.gov/16207711/ DOI: 10.1074/jbc.m508171200

evidence_access

Primary abstract

experimental_model

Rat cerebellar NOS preparation; separated partial reactions.

limitations

Purified preparation; residual enzyme reductant supported a limited first reaction without added NADPH. This does not imply physiological NOS is NADPH independent.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

The next reaction produces the signal and recycles the carbon skeleton.

primary_references

Characteristics of the nitric oxide synthase-catalyzed conversion of arginine to N-hydroxyarginine, the first oxygenation step in the enzymic synthesis of nitric oxide. · 1995 · https://pubmed.ncbi.nlm.nih.gov/7530247/ · DOI 10.1074/jbc.270.4.1721

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 78–84

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Rat cerebellar NOS preparation; separated partial reactions. · source_derived_draft · unverified_draft

## arg-nos-second The next reaction produces the signal and recycles the carbon skeleton. The second oxygenation yielded NO and citrulline and required added NADPH and calcium/calmodulin. Model: Rat cerebellar NOS preparation; separated partial reactions. Limitations: Purified preparation; residual enzyme reductant supported a limited first reaction without added NADPH. This does not imply physiological NOS is NADPH independent. Evidence access: Primary abstract Characteristics of the nitric oxide synthase-catalyzed conversion of arginine to N-hydroxyarginine, the first oxygenation step in the enzymic synthesis of nitric oxide. · 1995 · https://pubmed.ncbi.nlm.nih.gov/7530247/ · DOI 10.1074/jbc.270.4.1721

dose

6-Gingerol with NADPH; exact concentrations not in accessed abstract

duration

Not specified in accessed abstract

evidence_access

Primary PubMed abstract.

evidence_scope

literature_reviewed; model-specific source-derived curation, not universally established human effects

experimental_model

Rat hepatic microsomes

limitations

Metabolite assignments were tentative; neither a specific human CYP nor dietary NADPH depletion is established.

nutrient_topic

Gingerols collection; each molecular form and experimental preparation remains explicit. · Gingerols

organism

Rat hepatic microsomes

plain_language

NADPH-fortified rat hepatic microsomes converted 6-gingerol into a mixture of tentatively identified metabolites.

primary_references

Microsomal hydroxylation and glucuronidation of [6]-gingerol. (2006). https://pubmed.ncbi.nlm.nih.gov/17090120/ DOI: 10.1021/jf062235l

route

In vitro microsomal incubation

tissue

Liver microsomal preparation

Gingerols: mechanisms, molecular forms and cross-actor connections (2026-09-20) · lines 261–270

Original AI-assisted curation of thirteen primary research papers; study-specific PubMed/DOI links and limitations retained. Not publisher full text. · supports · Rat hepatic microsomes · source_derived_draft · unverified_draft

## gingerols-6-rat-metabolism NADPH-fortified rat hepatic microsomes converted 6-gingerol into a mixture of tentatively identified metabolites. Model/species: Rat hepatic microsomes Tissue: Liver microsomal preparation Exposure: 6-Gingerol with NADPH; exact concentrations not in accessed abstract Route: In vitro microsomal incubation Duration: Not specified in accessed abstract Limits: Metabolite assignments were tentative; neither a specific human CYP nor dietary NADPH depletion is established. Primary reference: Microsomal hydroxylation and glucuronidation of [6]-gingerol. (2006). https://pubmed.ncbi.nlm.nih.gov/17090120/ DOI: 10.1021/jf062235l Access: Primary PubMed abstract.

experimental_model

Purified rat liver cytosolic thioredoxin reductase and recombinant active-site variants.

limitations

This experiment-specific relationship does not establish a human dietary-deficiency threshold or supplementation benefit.

organism

Rat protein and recombinant enzyme assays

Selenium: literature corrections and mechanism additions · lines 965–974

Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Purified rat liver cytosolic thioredoxin reductase and recombinant active-site variants. · secondary_verified · secondary_verified

## txnrd1-reduces-txn1 TXNRD1 recharges thioredoxin so it can reduce other proteins. Cytosolic TXNRD1 uses NADPH-derived reducing equivalents to reduce oxidized thioredoxin through its flavin and C-terminal redox centers. Experimental model: Purified rat liver cytosolic thioredoxin reductase and recombinant active-site variants. Organism: Rat protein and recombinant enzyme assays Limitations: This experiment-specific relationship does not establish a human dietary-deficiency threshold or supplementation benefit. Primary reference: [Mammalian thioredoxin reductase: C-terminal redox center and selenium-to-sulfur substitution](https://pmc.ncbi.nlm.nih.gov/articles/PMC15961/)

cell_type

cardiac mitochondria

experimental_model

Redox perturbation and peroxide-emission assays

limitations

Functional relay; not every chemical step isolated here.

organism

mouse and guinea pig

Selenium: literature corrections and mechanism additions · lines 606–616

Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Redox perturbation and peroxide-emission assays · secondary_verified · secondary_verified

## txnrd2-reduces-txn2 A selenium enzyme restores mitochondrial thioredoxin's reducing power. TXNRD2 uses NADPH-derived reducing equivalents to regenerate reduced TXN2. Organism: mouse and guinea pig Cell type: cardiac mitochondria Experimental model: Redox perturbation and peroxide-emission assays Limitations: Functional relay; not every chemical step isolated here. Primary reference: [Thioredoxin Reductase-2 Is Essential for Keeping Low Levels of H2O2 Emission from Isolated Heart Mitochondria](https://pubmed.ncbi.nlm.nih.gov/21832082/)