NAD+

evidence_span

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experimental_model

Purified enzymes, liver microsomes and genotyping

exposure

MK-4 oxidation and common enzyme variants

limitations

Catabolism assay; no assumption that all long-chain menaquinones have identical kinetics.

nutrient_topic

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

organism

Human CYP4F2/CYP4F11 and human liver microsomes

plain_language

Niacin-derived NAD participates in an alternative route through the breakdown sequence.

primary_references

[k2-p24138531] Cytochrome P450-dependent catabolism of vitamin K: ω-hydroxylation catalyzed by human CYP4F2 and CYP4F11. (2013). https://pubmed.ncbi.nlm.nih.gov/24138531/ DOI: 10.1021/bi401208m

tissue_or_cell_type

MK-4 catabolism

Vitamin K2: menaquinone forms, carboxylation, recycling and nutrient interactions (2026-09-17) · lines 357–368

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

### k2-mk4-nad-catabolism Microsomal NAD-dependent alcohol and aldehyde dehydrogenase activities converted the MK-4 omega-alcohol to its acid. Condition category: normal nutrient_topic: Vitamin K2 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Niacin-derived NAD participates in an alternative route through the breakdown sequence. organism: Human CYP4F2/CYP4F11 and human liver microsomes tissue_or_cell_type: MK-4 catabolism experimental_model: Purified enzymes, liver microsomes and genotyping limitations: Catabolism assay; no assumption that all long-chain menaquinones have identical kinetics. exposure: MK-4 oxidation and common enzyme variants evidence_span: {"source_cache": "artifacts/k2-research/24138531.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "bcb3784026ddabfeb55257cddc84ffd1001d6eb4fb04ba2e9daf8ade8de770fb", "start_char": 0, "end_char": 1608, "text_sha256": "bcb3784026ddabfeb55257cddc84ffd1001d6eb4fb04ba2e9daf8ade8de770fb"} [k2-p24138531] Cytochrome P450-dependent catabolism of vitamin K: ω-hydroxylation catalyzed by human CYP4F2 and CYP4F11. (2013). https://pubmed.ncbi.nlm.nih.gov/24138531/ DOI: 10.1021/bi401208m

evidence_span

{"source_cache": "artifacts/boron-research/11420139.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0792ce09223d7cf23f0d3fda6b793e6e3b9904abe2c1f934b96d50e3a0e8b703", "start_char": 0, "end_char": 1650, "text_sha256": "0792ce09223d7cf23f0d3fda6b793e6e3b9904abe2c1f934b96d50e3a0e8b703"}

experimental_model

Capillary electrophoresis of purified metabolites

exposure

Boron complexation under the reported assay conditions

limitations

Chemical affinity is not a demonstrated metabolic function or in-vivo occupancy. Rankings depend on assay and solution conditions.

nutrient_topic

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

organism

Cell-free chemistry

plain_language

The arrangement of neighboring hydroxyl groups helps determine which nucleotide molecules can bind boron.

primary_references

[boron-p11420139] Diadenosine phosphates and S-adenosylmethionine: novel boron binding biomolecules detected by capillary electrophoresis. (2001). https://pubmed.ncbi.nlm.nih.gov/11420139/ DOI: 10.1016/s0304-4165(01)00130-1

tissue_or_cell_type

Aqueous assay; no tissue

Boron: chemistry, nutrient interactions, low-intake studies and mechanistic uncertainties (2026-09-17) · lines 105–116

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Capillary electrophoresis of purified metabolites · source_derived_draft · unverified_draft

### boron-cis-diol-binding Boron binding in the tested nucleotide series depended on suitable cis-diol groups, and NAD+ bound more strongly than NADH in the capillary-electrophoresis assay. Condition category: normal nutrient_topic: Boron research collection; topical membership is not evidence of a direct dietary effect. plain_language: The arrangement of neighboring hydroxyl groups helps determine which nucleotide molecules can bind boron. organism: Cell-free chemistry tissue_or_cell_type: Aqueous assay; no tissue experimental_model: Capillary electrophoresis of purified metabolites limitations: Chemical affinity is not a demonstrated metabolic function or in-vivo occupancy. Rankings depend on assay and solution conditions. exposure: Boron complexation under the reported assay conditions evidence_span: {"source_cache": "artifacts/boron-research/11420139.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0792ce09223d7cf23f0d3fda6b793e6e3b9904abe2c1f934b96d50e3a0e8b703", "start_char": 0, "end_char": 1650, "text_sha256": "0792ce09223d7cf23f0d3fda6b793e6e3b9904abe2c1f934b96d50e3a0e8b703"} [boron-p11420139] Diadenosine phosphates and S-adenosylmethionine: novel boron binding biomolecules detected by capillary electrophoresis. (2001). https://pubmed.ncbi.nlm.nih.gov/11420139/ DOI: 10.1016/s0304-4165(01)00130-1

evidence_span

{"source_cache": "artifacts/boron-research/12827632.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a7c91724a5710f61e1907669a1137b421e1e13117ae707e567bd16ca0eea9ed6", "start_char": 0, "end_char": 1255, "text_sha256": "a7c91724a5710f61e1907669a1137b421e1e13117ae707e567bd16ca0eea9ed6"}

experimental_model

Electrospray mass spectrometry and boron-11 NMR

exposure

NAD+/NADH with boric acid or borate across pH conditions; complexes detected at 50 µM each at pH 7

limitations

Chemical structure experiments do not establish cellular concentrations or physiological consequences.

nutrient_topic

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

organism

Cell-free chemistry

plain_language

Boron attaches to the sugar portion of NAD+ in these experiments.

primary_references

[boron-p12827632] Esterification of borate with NAD+ and NADH as studied by electrospray ionization mass spectrometry and 11B NMR spectroscopy. (2003). https://pubmed.ncbi.nlm.nih.gov/12827632/ DOI: 10.1002/jms.476

tissue_or_cell_type

Purified nucleotide solutions

Boron: chemistry, nutrient interactions, low-intake studies and mechanistic uncertainties (2026-09-17) · lines 118–129

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Electrospray mass spectrometry and boron-11 NMR · source_derived_draft · unverified_draft

### boron-nad-adduct-structure NAD+ formed monoester, diester and diborate adducts through ribose cis-2,3-diol groups rather than phosphate hydroxyls; the 1:1 monoester localized to the adenosine ribose. Condition category: normal nutrient_topic: Boron research collection; topical membership is not evidence of a direct dietary effect. plain_language: Boron attaches to the sugar portion of NAD+ in these experiments. organism: Cell-free chemistry tissue_or_cell_type: Purified nucleotide solutions experimental_model: Electrospray mass spectrometry and boron-11 NMR limitations: Chemical structure experiments do not establish cellular concentrations or physiological consequences. exposure: NAD+/NADH with boric acid or borate across pH conditions; complexes detected at 50 µM each at pH 7 evidence_span: {"source_cache": "artifacts/boron-research/12827632.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a7c91724a5710f61e1907669a1137b421e1e13117ae707e567bd16ca0eea9ed6", "start_char": 0, "end_char": 1255, "text_sha256": "a7c91724a5710f61e1907669a1137b421e1e13117ae707e567bd16ca0eea9ed6"} [boron-p12827632] Esterification of borate with NAD+ and NADH as studied by electrospray ionization mass spectrometry and 11B NMR spectroscopy. (2003). https://pubmed.ncbi.nlm.nih.gov/12827632/ DOI: 10.1002/jms.476

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

evidence_access

Primary full text

experimental_model

Purified human DHPS crystallography and single-turnover assays.

limitations

NAD is regenerated during the reaction; this does not measure NAD depletion or establish niacin supplementation benefit.

nutrient_topic

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

plain_language

A niacin-derived coenzyme participates in using spermidine.

primary_references

Half Way to Hypusine-Structural Basis for Substrate Recognition by Human Deoxyhypusine Synthase. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32235505/ · DOI 10.3390/biom10040522

Spermidine: biosynthesis, hypusination, transport 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 DHPS crystallography and single-turnover assays. · source_derived_draft · unverified_draft

## spermidine-dhps-nad A niacin-derived coenzyme participates in using spermidine. Human DHPS binds NAD and spermidine; NAD-dependent chemistry initiates aminobutyl transfer. Model: Purified human DHPS crystallography and single-turnover assays. Limitations: NAD is regenerated during the reaction; this does not measure NAD depletion or establish niacin supplementation benefit. Evidence access: Primary full text Half Way to Hypusine-Structural Basis for Substrate Recognition by Human Deoxyhypusine Synthase. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32235505/ · DOI 10.3390/biom10040522

evidence_access

Primary full text

experimental_model

Genetically encoded biosensor with permeabilization calibration in human HEK293T cells.

limitations

These are cell-line estimates with calibration assumptions, not normal human blood ranges or dietary deficiency thresholds.

nutrient_topic

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

plain_language

Different compartments contain different amounts of freely available NAD+.

primary_references

Biosensor reveals multiple sources for mitochondrial NAD⁺. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27313049/ · DOI 10.1126/science.aad5168

NAD+: compartmental supply, consumption and cross-nutrient mechanisms (2026-09-19) · lines 12–18

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Genetically encoded biosensor with permeabilization calibration in human HEK293T cells. · source_derived_draft · unverified_draft

## nad-plus-free-pools Different compartments contain different amounts of freely available NAD+. A compartment-targeted biosensor estimated free NAD+ in HEK293T cells at 106 micromolar in cytoplasm, 109 micromolar in nucleus and 230 micromolar in mitochondria. Model: Genetically encoded biosensor with permeabilization calibration in human HEK293T cells. Limitations: These are cell-line estimates with calibration assumptions, not normal human blood ranges or dietary deficiency thresholds. Evidence access: Primary full text Biosensor reveals multiple sources for mitochondrial NAD⁺. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27313049/ · DOI 10.1126/science.aad5168

evidence_access

Primary full text

experimental_model

Human MCF-7 cells with NAMPT inhibition, CD73 comparison and serum-containing medium; NMN/NR XRCC1 rescue is reported as data not shown.

limitations

Rescue depended on medium and incubation time; serum-free and heat-inactivated-serum conditions did not give the same early rescue. No proof of intact cellular NAD uptake or clinical benefit.

nutrient_topic

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

plain_language

Supplying precursor material restored part of a repair response in this model.

primary_references

Extracellular NAD+ enhances PARP-dependent DNA repair capacity independently of CD73 activity. · 2020 · https://pubmed.ncbi.nlm.nih.gov/31959836/ · DOI 10.1038/s41598-020-57506-9

NAD+: compartmental supply, consumption 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 · Human MCF-7 cells with NAMPT inhibition, CD73 comparison and serum-containing medium; NMN/NR XRCC1 rescue is reported as data not shown. · source_derived_draft · unverified_draft

## nad-plus-repair-precursor-rescue Supplying precursor material restored part of a repair response in this model. Extracellular NAD+ or NMN restored intracellular NAD availability, PAR-dependent signaling and XRCC1 recruitment in the tested NAD-depleted human cells independently of CD73 status. Model: Human MCF-7 cells with NAMPT inhibition, CD73 comparison and serum-containing medium; NMN/NR XRCC1 rescue is reported as data not shown. Limitations: Rescue depended on medium and incubation time; serum-free and heat-inactivated-serum conditions did not give the same early rescue. No proof of intact cellular NAD uptake or clinical benefit. Evidence access: Primary full text Extracellular NAD+ enhances PARP-dependent DNA repair capacity independently of CD73 activity. · 2020 · https://pubmed.ncbi.nlm.nih.gov/31959836/ · DOI 10.1038/s41598-020-57506-9

evidence_access

Primary full text

experimental_model

Drosophila-domain ITC and NMR competition.

limitations

Species/domain-specific affinity; separate from catalytic-site kinetics.

nutrient_topic

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

plain_language

NAD can help restrain the switch at a regulatory site while also being its substrate.

primary_references

SARM1 is a metabolic sensor activated by an increased NMN/NAD+ ratio to trigger axon degeneration. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33657413/ · DOI 10.1016/j.neuron.2021.02.009

NAD+: compartmental supply, consumption and cross-nutrient mechanisms (2026-09-19) · lines 92–98

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Drosophila-domain ITC and NMR competition. · source_derived_draft · unverified_draft

## nad-plus-sarm-nad-binding NAD can help restrain the switch at a regulatory site while also being its substrate. NAD+ bound the same Drosophila SARM1 ARM-domain regulatory site with approximately 54.2 micromolar dissociation constant; competition assays supported opposing occupancy by NAD+ and NMN. Model: Drosophila-domain ITC and NMR competition. Limitations: Species/domain-specific affinity; separate from catalytic-site kinetics. Evidence access: Primary full text SARM1 is a metabolic sensor activated by an increased NMN/NAD+ ratio to trigger axon degeneration. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33657413/ · DOI 10.1016/j.neuron.2021.02.009

evidence_span

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experimental_model

Recombinant ferret enzyme and tissue-fraction metabolism

exposure

5-cis, 13-cis and all-trans lycopene; iron; NAD+ or NADH

limitations

Ferret experiments do not quantify human cleavage flux or predict supplement response.

nutrient_topic

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

organism

Ferret

plain_language

The oxidized niacin-derived cofactor helped steer the aldehyde toward an acid.

primary_references

[lycopene-p16672231] The biochemical characterization of ferret carotene-9',10'-monooxygenase catalyzing cleavage of carotenoids in vitro and in vivo. (2006). https://pubmed.ncbi.nlm.nih.gov/16672231/ DOI: 10.1074/jbc.m512095200

tissue_or_cell_type

BCO2 enzyme; hepatic fractions and lung

Lycopene: absorption, metabolism, nutrient connections and human outcomes (2026-09-17) · lines 338–349

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

### lycopene-apo-nad NAD+ supported conversion of apo-10-prime-lycopenal to apo-10-prime-lycopenoic acid in ferret hepatic fractions. Condition category: normal nutrient_topic: Lycopene research collection; topical membership is not evidence of a direct dietary effect. plain_language: The oxidized niacin-derived cofactor helped steer the aldehyde toward an acid. organism: Ferret tissue_or_cell_type: BCO2 enzyme; hepatic fractions and lung experimental_model: Recombinant ferret enzyme and tissue-fraction metabolism limitations: Ferret experiments do not quantify human cleavage flux or predict supplement response. exposure: 5-cis, 13-cis and all-trans lycopene; iron; NAD+ or NADH evidence_span: {"source_cache": "artifacts/lycopene-research/16672231.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "135695c9d3106469d8d64ec0806ba5bf048f0f1df6f3e3cd53e838e50b960445", "start_char": 0, "end_char": 1967, "text_sha256": "135695c9d3106469d8d64ec0806ba5bf048f0f1df6f3e3cd53e838e50b960445"} [lycopene-p16672231] The biochemical characterization of ferret carotene-9',10'-monooxygenase catalyzing cleavage of carotenoids in vitro and in vivo. (2006). https://pubmed.ncbi.nlm.nih.gov/16672231/ DOI: 10.1074/jbc.m512095200

evidence_span

{"source_cache": "artifacts/inositol-research/15024000.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5ab3a8eda77989c3e4a681b4a971fb7e969c285d3e5c8e41bc31713a7f88c9ac", "start_char": 0, "end_char": 1427, "text_sha256": "5ab3a8eda77989c3e4a681b4a971fb7e969c285d3e5c8e41bc31713a7f88c9ac"}

experimental_model

Recombinant human enzyme and complementation of yeast ino1 deletion

exposure

Substrate, NAD+, cation and valproate experiments

limitations

Purified-enzyme and yeast results do not establish supplement effects or a human dietary deficiency threshold.

nutrient_topic

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

organism

Human protein expressed in bacteria and yeast

plain_language

The synthesis enzyme depends on NAD+, connecting inositol chemistry to the niacin-derived cofactor network.

primary_references

[ino-p15024000] Human 1-D-myo-inositol-3-phosphate synthase is functional in yeast. (2004). https://pubmed.ncbi.nlm.nih.gov/15024000/ DOI: 10.1074/jbc.m312078200

tissue_or_cell_type

Purified enzyme; yeast cultures

Inositol: synthesis, signaling, mineral interactions and conditional deficiency (2026-09-17) · lines 184–195

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human enzyme and complementation of yeast ino1 deletion · source_derived_draft · unverified_draft

### ino-isyna-nad Human ISYNA1 used NAD+ in its catalytic assay, with a reported apparent Km of 8 micromolar. Condition category: normal nutrient_topic: Inositol research collection; topical membership is not evidence of a direct dietary effect. plain_language: The synthesis enzyme depends on NAD+, connecting inositol chemistry to the niacin-derived cofactor network. organism: Human protein expressed in bacteria and yeast tissue_or_cell_type: Purified enzyme; yeast cultures experimental_model: Recombinant human enzyme and complementation of yeast ino1 deletion limitations: Purified-enzyme and yeast results do not establish supplement effects or a human dietary deficiency threshold. exposure: Substrate, NAD+, cation and valproate experiments evidence_span: {"source_cache": "artifacts/inositol-research/15024000.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5ab3a8eda77989c3e4a681b4a971fb7e969c285d3e5c8e41bc31713a7f88c9ac", "start_char": 0, "end_char": 1427, "text_sha256": "5ab3a8eda77989c3e4a681b4a971fb7e969c285d3e5c8e41bc31713a7f88c9ac"} [ino-p15024000] Human 1-D-myo-inositol-3-phosphate synthase is functional in yeast. (2004). https://pubmed.ncbi.nlm.nih.gov/15024000/ DOI: 10.1074/jbc.m312078200

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

Bounds the B2-KMO-niacin link: a cofactor-dependent pathway step is not proof that total NAD pools must fall.

evidence_location

Results: liver Fig 4 and brain Fig 7; matching abstract conclusion

experimental_model

Constitutive Kmo knockout and wild-type mice, approximately two months old; liver and brain metabolite assays.

exposure

Constitutive Kmo deletion

limitations

Steady-state pools do not measure de novo synthesis flux; diet and salvage can affect the result.

nutrient_topic

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

organism

Mus musculus

plain_language

Losing the KMO branch did not collapse the measured NAD+ pools.

primary_references

[giorgini2013] Targeted deletion of kynurenine 3-monooxygenase in mice: a new tool for studying kynurenine pathway metabolism in periphery and brain. (2013). https://pubmed.ncbi.nlm.nih.gov/24189070/ DOI: 10.1074/jbc.m113.503813

tissue_or_cell_type

Liver and brain

trigger_kind

machinery_impairment Imported condition classification; unverified.

Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1262–1274

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Constitutive Kmo knockout and wild-type mice, approximately two months old; liver and brain metabolite assays. · source_derived_draft · unverified_draft

### b2-kmo-loss-nad-preserved Measured liver and brain NAD+ contents were not significantly different between Kmo-knockout and wild-type mice. Condition category: machinery_impairment nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Losing the KMO branch did not collapse the measured NAD+ pools. organism: Mus musculus tissue_or_cell_type: Liver and brain experimental_model: Constitutive Kmo knockout and wild-type mice, approximately two months old; liver and brain metabolite assays. limitations: Steady-state pools do not measure de novo synthesis flux; diet and salvage can affect the result. exposure: Constitutive Kmo deletion cross_nutrient: Bounds the B2-KMO-niacin link: a cofactor-dependent pathway step is not proof that total NAD pools must fall. evidence_location: Results: liver Fig 4 and brain Fig 7; matching abstract conclusion [giorgini2013] Targeted deletion of kynurenine 3-monooxygenase in mice: a new tool for studying kynurenine pathway metabolism in periphery and brain. (2013). https://pubmed.ncbi.nlm.nih.gov/24189070/ DOI: 10.1074/jbc.m113.503813

evidence_access

Primary abstract

experimental_model

Mouse genetic/pharmacological work within a study also using C. elegans.

limitations

Not a human longevity outcome or evidence for tryptophan megadoses.

nutrient_topic

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

plain_language

Restricting one exit route increased flow toward NAD in a preclinical model.

primary_references

De novo NAD+ synthesis enhances mitochondrial function and improves health. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30356218/ · DOI 10.1038/s41586-018-0645-6

Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 234–240

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mouse genetic/pharmacological work within a study also using C. elegans. · source_derived_draft · unverified_draft

## tryptophan-acmsd-inhibition-nad Restricting one exit route increased flow toward NAD in a preclinical model. ACMSD inhibition increased de novo NAD synthesis and SIRT1-related mitochondrial function in the mouse experiments. Model: Mouse genetic/pharmacological work within a study also using C. elegans. Limitations: Not a human longevity outcome or evidence for tryptophan megadoses. Evidence access: Primary abstract De novo NAD+ synthesis enhances mitochondrial function and improves health. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30356218/ · DOI 10.1038/s41586-018-0645-6

evidence_access

Primary full text

experimental_model

Human cancer-cell nutrient manipulation and NAD+/NADH measurements.

limitations

Reaction-level LDH activity is recorded without assigning an untested isoform.

nutrient_topic

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

plain_language

An electron acceptor can restore NAD without making new NAD molecules.

primary_references

Environment Dictates Dependence on Mitochondrial Complex I for NAD+ and Aspartate Production and Determines Cancer Cell Sensitivity to Metformin. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27746050/ · DOI 10.1016/j.cmet.2016.09.006

NAD+: compartmental supply, consumption and cross-nutrient mechanisms (2026-09-19) · lines 348–354

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

## nad-plus-ldh-redox An electron acceptor can restore NAD without making new NAD molecules. In the tested human A549 and HeLa cancer cells, net pyruvate-to-lactate conversion provided an alternative route to regenerate NAD+ from NADH during complex-I inhibition. Model: Human cancer-cell nutrient manipulation and NAD+/NADH measurements. Limitations: Reaction-level LDH activity is recorded without assigning an untested isoform. Evidence access: Primary full text Environment Dictates Dependence on Mitochondrial Complex I for NAD+ and Aspartate Production and Determines Cancer Cell Sensitivity to Metformin. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27746050/ · DOI 10.1016/j.cmet.2016.09.006

cross_nutrient

false

evidence_span

{"source_cache": "artifacts/niacin-consumption-sources/cd381998.abstract.txt", "locator": "Indexed abstract", "start_char": 0, "end_char": 1755, "file_sha256": "39f90bb382ddfee34e808fc93c5a1afafc1d9638a9dc73f2770e815827b4f2ad", "text_sha256": "39f90bb382ddfee34e808fc93c5a1afafc1d9638a9dc73f2770e815827b4f2ad"}

experimental_model

Biochemical characterization of human CD38

exposure

NAD+ as substrate

limitations

Primary human enzyme study; source abstract used. Product proportions are assay-specific and do not establish tissue flux or supplementation outcomes.

nutrient_topic

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

organism

Human

plain_language

CD38 can break NAD into ADP-ribose and nicotinamide.

primary_references

[b3-cons-cd381998] Human CD38 is an authentic NAD(P)+ glycohydrolase. (1998). https://pubmed.ncbi.nlm.nih.gov/9494110/ DOI: 10.1042/bj3301383

tissue_or_cell_type

Cell-free enzyme preparation

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 565–577

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Biochemical characterization of human CD38 · source_derived_draft · unverified_draft

### b3-cons-cd38-hydrolysis Human CD38 hydrolyzes NAD+ to free ADP-ribose and nicotinamide. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: CD38 can break NAD into ADP-ribose and nicotinamide. organism: Human tissue_or_cell_type: Cell-free enzyme preparation experimental_model: Biochemical characterization of human CD38 limitations: Primary human enzyme study; source abstract used. Product proportions are assay-specific and do not establish tissue flux or supplementation outcomes. exposure: NAD+ as substrate cross_nutrient: false evidence_span: {"source_cache": "artifacts/niacin-consumption-sources/cd381998.abstract.txt", "locator": "Indexed abstract", "start_char": 0, "end_char": 1755, "file_sha256": "39f90bb382ddfee34e808fc93c5a1afafc1d9638a9dc73f2770e815827b4f2ad", "text_sha256": "39f90bb382ddfee34e808fc93c5a1afafc1d9638a9dc73f2770e815827b4f2ad"} [b3-cons-cd381998] Human CD38 is an authentic NAD(P)+ glycohydrolase. (1998). https://pubmed.ncbi.nlm.nih.gov/9494110/ DOI: 10.1042/bj3301383

cross_nutrient

false

evidence_span

{"source_cache": "artifacts/niacin-consumption-sources/sarm2017.txt", "locator": "Full text, normalized paragraph 24", "start_char": 15550, "end_char": 16946, "file_sha256": "fc30de231911f5c30425173d684495e62c725ba27c78d44592e6bc68433ef545", "text_sha256": "9a9b91a772186c34d8b6305a04bbcf6d3acc40b0448e6f478811527c5174981e"}

experimental_model

Purified human SARM1 TIR domain; HPLC and LC-MS/MS

exposure

NAD+ incubation

limitations

Purified engineered TIR fragment rather than basal activity of intact full-length SARM1; no dietary dose inference.

nutrient_topic

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

organism

Human

plain_language

SARM1 contains a catalytic domain that breaks NAD.

primary_references

[b3-cons-sarm2017] The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD+ Cleavage Activity that Promotes Pathological Axonal Degeneration. (2017). https://pubmed.ncbi.nlm.nih.gov/28334607/ DOI: 10.1016/j.neuron.2017.02.022

tissue_or_cell_type

Cell-free preparation

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 677–689

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human SARM1 TIR domain; HPLC and LC-MS/MS · source_derived_draft · unverified_draft

### b3-cons-sarm-adpr-nam Purified human SARM1 TIR domain cleaved NAD+, producing ADP-ribose and nicotinamide as major products. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: SARM1 contains a catalytic domain that breaks NAD. organism: Human tissue_or_cell_type: Cell-free preparation experimental_model: Purified human SARM1 TIR domain; HPLC and LC-MS/MS limitations: Purified engineered TIR fragment rather than basal activity of intact full-length SARM1; no dietary dose inference. exposure: NAD+ incubation cross_nutrient: false evidence_span: {"source_cache": "artifacts/niacin-consumption-sources/sarm2017.txt", "locator": "Full text, normalized paragraph 24", "start_char": 15550, "end_char": 16946, "file_sha256": "fc30de231911f5c30425173d684495e62c725ba27c78d44592e6bc68433ef545", "text_sha256": "9a9b91a772186c34d8b6305a04bbcf6d3acc40b0448e6f478811527c5174981e"} [b3-cons-sarm2017] The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD+ Cleavage Activity that Promotes Pathological Axonal Degeneration. (2017). https://pubmed.ncbi.nlm.nih.gov/28334607/ DOI: 10.1016/j.neuron.2017.02.022

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

evidence_span

{"source_cache": "artifacts/niacin-consumption-sources/sarm2017.txt", "locator": "Full text, normalized paragraph 27", "start_char": 18354, "end_char": 20343, "file_sha256": "fc30de231911f5c30425173d684495e62c725ba27c78d44592e6bc68433ef545", "text_sha256": "eda6dc283d30b48f68dc8626f2ea00ffb36d08cf8597eb6e7b1ce7e091fd0cb3"}

experimental_model

Cell-free translation, purification and NADase assay

exposure

E642A compared with wild-type TIR

limitations

Purified engineered TIR fragment rather than basal activity of intact full-length SARM1; no dietary dose inference.

nutrient_topic

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

organism

Human

plain_language

Changing a catalytic glutamate disabled NAD cleavage in the assay.

primary_references

[b3-cons-sarm2017] The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD+ Cleavage Activity that Promotes Pathological Axonal Degeneration. (2017). https://pubmed.ncbi.nlm.nih.gov/28334607/ DOI: 10.1016/j.neuron.2017.02.022

tissue_or_cell_type

Purified human mutant domain

trigger_kind

machinery_impairment Imported condition classification; unverified.

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 719–731

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cell-free translation, purification and NADase assay · source_derived_draft · unverified_draft

### b3-cons-sarm-e642a-loss The human SARM1 TIR E642A mutant failed to cleave NAD+ in the cell-free NADase assay. Condition category: machinery_impairment nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Changing a catalytic glutamate disabled NAD cleavage in the assay. organism: Human tissue_or_cell_type: Purified human mutant domain experimental_model: Cell-free translation, purification and NADase assay limitations: Purified engineered TIR fragment rather than basal activity of intact full-length SARM1; no dietary dose inference. exposure: E642A compared with wild-type TIR cross_nutrient: false evidence_span: {"source_cache": "artifacts/niacin-consumption-sources/sarm2017.txt", "locator": "Full text, normalized paragraph 27", "start_char": 18354, "end_char": 20343, "file_sha256": "fc30de231911f5c30425173d684495e62c725ba27c78d44592e6bc68433ef545", "text_sha256": "eda6dc283d30b48f68dc8626f2ea00ffb36d08cf8597eb6e7b1ce7e091fd0cb3"} [b3-cons-sarm2017] The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD+ Cleavage Activity that Promotes Pathological Axonal Degeneration. (2017). https://pubmed.ncbi.nlm.nih.gov/28334607/ DOI: 10.1016/j.neuron.2017.02.022

evidence_span

{"source_cache": "artifacts/niacin-precursors-sources/nmrk2016.paragraphs.txt", "locator": "Normalized full-text paragraphs 12–12 (0-based)", "start_char": 12567, "end_char": 14130, "file_sha256": "fcbd5465aff51c9870d65fc9812edbad2cdf2af8bb16b6afb3170d7f0503178a", "text_sha256": "69b7b09a26aadc957c5bcb7c3f38cd4a426b94162ce4ff5424e98fe679c4e47c"}

experimental_model

Murine NRK gain/loss of function in fibroblasts and primary hepatocytes; separate human HepG2 stable-isotope experiments

exposure

10 micromolar oxygen-18-labelled NR; 24-hour tracing

limitations

HepG2 is a transformed cell line in specialized culture medium; does not describe oral bioavailability or every tissue.

nutrient_topic

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

organism

Homo sapiens

plain_language

These cultured human liver-derived cells used intact NR as a NAD precursor.

primary_references

[b3-pre-nmrk2016] NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells. (2016). https://pubmed.ncbi.nlm.nih.gov/27725675/ DOI: 10.1038/ncomms13103

supporting_evidence_spans

[{"source_cache": "artifacts/niacin-precursors-sources/nmrk2016.paragraphs.txt", "locator": "Normalized full-text paragraphs 38–38 (0-based)", "start_char": 39692, "end_char": 41308, "file_sha256": "fcbd5465aff51c9870d65fc9812edbad2cdf2af8bb16b6afb3170d7f0503178a", "text_sha256": "06af8996de76dd8a158899f05c337e45aa341ac5bd340a12cd041c89bc4c2d13"}]

tissue_or_cell_type

HepG2 cells

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 451–463

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Murine NRK gain/loss of function in fibroblasts and primary hepatocytes; separate human HepG2 stable-isotope experiments · source_derived_draft · unverified_draft

### b3-pre-hepg2-nr-tracer In serum- and nicotinamide-free HepG2 cultures, oxygen-18-labelled NR entered intracellular NR, NMN and NAD+ pools without detectable labelled NMN or nicotinamide appearing in the medium over 24 hours. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: These cultured human liver-derived cells used intact NR as a NAD precursor. organism: Homo sapiens tissue_or_cell_type: HepG2 cells experimental_model: Murine NRK gain/loss of function in fibroblasts and primary hepatocytes; separate human HepG2 stable-isotope experiments limitations: HepG2 is a transformed cell line in specialized culture medium; does not describe oral bioavailability or every tissue. exposure: 10 micromolar oxygen-18-labelled NR; 24-hour tracing evidence_span: {"source_cache": "artifacts/niacin-precursors-sources/nmrk2016.paragraphs.txt", "locator": "Normalized full-text paragraphs 12–12 (0-based)", "start_char": 12567, "end_char": 14130, "file_sha256": "fcbd5465aff51c9870d65fc9812edbad2cdf2af8bb16b6afb3170d7f0503178a", "text_sha256": "69b7b09a26aadc957c5bcb7c3f38cd4a426b94162ce4ff5424e98fe679c4e47c"} supporting_evidence_spans: [{"source_cache": "artifacts/niacin-precursors-sources/nmrk2016.paragraphs.txt", "locator": "Normalized full-text paragraphs 38–38 (0-based)", "start_char": 39692, "end_char": 41308, "file_sha256": "fcbd5465aff51c9870d65fc9812edbad2cdf2af8bb16b6afb3170d7f0503178a", "text_sha256": "06af8996de76dd8a158899f05c337e45aa341ac5bd340a12cd041c89bc4c2d13"}] [b3-pre-nmrk2016] NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells. (2016). https://pubmed.ncbi.nlm.nih.gov/27725675/ DOI: 10.1038/ncomms13103

evidence_span

{"source_cache": "artifacts/niacin-precursors-sources/nmrk2016.paragraphs.txt", "locator": "Normalized full-text paragraphs 7–7 (0-based)", "start_char": 5559, "end_char": 7104, "file_sha256": "fcbd5465aff51c9870d65fc9812edbad2cdf2af8bb16b6afb3170d7f0503178a", "text_sha256": "ffb453285526cec1670cc565f0b57f3893b48aba7e5014f693f09ea75079348f"}

experimental_model

Murine NRK gain/loss of function in fibroblasts and primary hepatocytes; separate human HepG2 stable-isotope experiments

exposure

Transient kinase overexpression with 4 micrograms plasmid; NR 0.5 mM for 6 h under the stated default protocol; mutant comparator NRK1-D36A or NRK2-D35A.

limitations

Forced expression in mouse fibroblasts; not a human supplementation study. Basal NAD was unchanged by active kinase overexpression without NR.

nutrient_topic

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

organism

Mus musculus

plain_language

NR utilization depended on active riboside kinase in this cell model.

primary_references

[b3-pre-nmrk2016] NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells. (2016). https://pubmed.ncbi.nlm.nih.gov/27725675/ DOI: 10.1038/ncomms13103

supporting_evidence_spans

[{"source_cache": "artifacts/niacin-precursors-sources/nmrk2016.paragraphs.txt", "locator": "Normalized full-text paragraphs 30–30 (0-based)", "start_char": 33613, "end_char": 35106, "file_sha256": "fcbd5465aff51c9870d65fc9812edbad2cdf2af8bb16b6afb3170d7f0503178a", "text_sha256": "e43865f05c251c7fbb357b31c7968056ae1b58fb1d0f4e61216e5013cb928a41"}, {"source_cache": "artifacts/niacin-precursors-sources/nmrk2016.paragraphs.txt", "locator": "Normalized full-text paragraphs 48–48 (0-based)", "start_char": 46035, "end_char": 46419, "file_sha256": "fcbd5465aff51c9870d65fc9812edbad2cdf2af8bb16b6afb3170d7f0503178a", "text_sha256": "4261a1ca6a50f8b37fd569171c8a9111b9a5ee53b2504811a46cfb40badcb90c"}]

tissue_or_cell_type

NIH/3T3 fibroblasts

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 395–407

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Murine NRK gain/loss of function in fibroblasts and primary hepatocytes; separate human HepG2 stable-isotope experiments · source_derived_draft · unverified_draft

### b3-pre-mouse-nrk1-nr Transient overexpression of active mouse NRK1 made NIH/3T3 fibroblasts responsive to nicotinamide riboside with increased cellular NAD+; the tested catalytically inactive kinase failed to support the response. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: NR utilization depended on active riboside kinase in this cell model. organism: Mus musculus tissue_or_cell_type: NIH/3T3 fibroblasts experimental_model: Murine NRK gain/loss of function in fibroblasts and primary hepatocytes; separate human HepG2 stable-isotope experiments limitations: Forced expression in mouse fibroblasts; not a human supplementation study. Basal NAD was unchanged by active kinase overexpression without NR. exposure: Transient kinase overexpression with 4 micrograms plasmid; NR 0.5 mM for 6 h under the stated default protocol; mutant comparator NRK1-D36A or NRK2-D35A. evidence_span: {"source_cache": "artifacts/niacin-precursors-sources/nmrk2016.paragraphs.txt", "locator": "Normalized full-text paragraphs 7–7 (0-based)", "start_char": 5559, "end_char": 7104, "file_sha256": "fcbd5465aff51c9870d65fc9812edbad2cdf2af8bb16b6afb3170d7f0503178a", "text_sha256": "ffb453285526cec1670cc565f0b57f3893b48aba7e5014f693f09ea75079348f"} supporting_evidence_spans: [{"source_cache": "artifacts/niacin-precursors-sources/nmrk2016.paragraphs.txt", "locator": "Normalized full-text paragraphs 30–30 (0-based)", "start_char": 33613, "end_char": 35106, "file_sha256": "fcbd5465aff51c9870d65fc9812edbad2cdf2af8bb16b6afb3170d7f0503178a", "text_sha256": "e43865f05c251c7fbb357b31c7968056ae1b58fb1d0f4e61216e5013cb928a41"}, {"source_cache": "artifacts/niacin-precursors-sources/nmrk2016.paragraphs.txt", "locator": "Normalized full-text paragraphs 48–48 (0-based)", "start_char": 46035, "end_char": 46419, "file_sha256": "fcbd5465aff51c9870d65fc9812edbad2cdf2af8bb16b6afb3170d7f0503178a", "text_sha256": "4261a1ca6a50f8b37fd569171c8a9111b9a5ee53b2504811a46cfb40badcb90c"}] [b3-pre-nmrk2016] NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells. (2016). https://pubmed.ncbi.nlm.nih.gov/27725675/ DOI: 10.1038/ncomms13103

evidence_span

{"source_cache": "artifacts/niacin-precursors-sources/nmrk2016.paragraphs.txt", "locator": "Normalized full-text paragraphs 7–7 (0-based)", "start_char": 5559, "end_char": 7104, "file_sha256": "fcbd5465aff51c9870d65fc9812edbad2cdf2af8bb16b6afb3170d7f0503178a", "text_sha256": "ffb453285526cec1670cc565f0b57f3893b48aba7e5014f693f09ea75079348f"}

experimental_model

Murine NRK gain/loss of function in fibroblasts and primary hepatocytes; separate human HepG2 stable-isotope experiments

exposure

Transient kinase overexpression with 4 micrograms plasmid; NR 0.5 mM for 6 h under the stated default protocol; mutant comparator NRK1-D36A or NRK2-D35A.

limitations

Forced expression in mouse fibroblasts; not a human supplementation study. Basal NAD was unchanged by active kinase overexpression without NR.

nutrient_topic

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

organism

Mus musculus

plain_language

NR utilization depended on active riboside kinase in this cell model.

primary_references

[b3-pre-nmrk2016] NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells. (2016). https://pubmed.ncbi.nlm.nih.gov/27725675/ DOI: 10.1038/ncomms13103

supporting_evidence_spans

[{"source_cache": "artifacts/niacin-precursors-sources/nmrk2016.paragraphs.txt", "locator": "Normalized full-text paragraphs 30–30 (0-based)", "start_char": 33613, "end_char": 35106, "file_sha256": "fcbd5465aff51c9870d65fc9812edbad2cdf2af8bb16b6afb3170d7f0503178a", "text_sha256": "e43865f05c251c7fbb357b31c7968056ae1b58fb1d0f4e61216e5013cb928a41"}, {"source_cache": "artifacts/niacin-precursors-sources/nmrk2016.paragraphs.txt", "locator": "Normalized full-text paragraphs 48–48 (0-based)", "start_char": 46035, "end_char": 46419, "file_sha256": "fcbd5465aff51c9870d65fc9812edbad2cdf2af8bb16b6afb3170d7f0503178a", "text_sha256": "4261a1ca6a50f8b37fd569171c8a9111b9a5ee53b2504811a46cfb40badcb90c"}]

tissue_or_cell_type

NIH/3T3 fibroblasts

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 409–421

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Murine NRK gain/loss of function in fibroblasts and primary hepatocytes; separate human HepG2 stable-isotope experiments · source_derived_draft · unverified_draft

### b3-pre-mouse-nrk2-nr Transient overexpression of active mouse NRK2 made NIH/3T3 fibroblasts responsive to nicotinamide riboside with increased cellular NAD+; the tested catalytically inactive kinase failed to support the response. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: NR utilization depended on active riboside kinase in this cell model. organism: Mus musculus tissue_or_cell_type: NIH/3T3 fibroblasts experimental_model: Murine NRK gain/loss of function in fibroblasts and primary hepatocytes; separate human HepG2 stable-isotope experiments limitations: Forced expression in mouse fibroblasts; not a human supplementation study. Basal NAD was unchanged by active kinase overexpression without NR. exposure: Transient kinase overexpression with 4 micrograms plasmid; NR 0.5 mM for 6 h under the stated default protocol; mutant comparator NRK1-D36A or NRK2-D35A. evidence_span: {"source_cache": "artifacts/niacin-precursors-sources/nmrk2016.paragraphs.txt", "locator": "Normalized full-text paragraphs 7–7 (0-based)", "start_char": 5559, "end_char": 7104, "file_sha256": "fcbd5465aff51c9870d65fc9812edbad2cdf2af8bb16b6afb3170d7f0503178a", "text_sha256": "ffb453285526cec1670cc565f0b57f3893b48aba7e5014f693f09ea75079348f"} supporting_evidence_spans: [{"source_cache": "artifacts/niacin-precursors-sources/nmrk2016.paragraphs.txt", "locator": "Normalized full-text paragraphs 30–30 (0-based)", "start_char": 33613, "end_char": 35106, "file_sha256": "fcbd5465aff51c9870d65fc9812edbad2cdf2af8bb16b6afb3170d7f0503178a", "text_sha256": "e43865f05c251c7fbb357b31c7968056ae1b58fb1d0f4e61216e5013cb928a41"}, {"source_cache": "artifacts/niacin-precursors-sources/nmrk2016.paragraphs.txt", "locator": "Normalized full-text paragraphs 48–48 (0-based)", "start_char": 46035, "end_char": 46419, "file_sha256": "fcbd5465aff51c9870d65fc9812edbad2cdf2af8bb16b6afb3170d7f0503178a", "text_sha256": "4261a1ca6a50f8b37fd569171c8a9111b9a5ee53b2504811a46cfb40badcb90c"}] [b3-pre-nmrk2016] NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells. (2016). https://pubmed.ncbi.nlm.nih.gov/27725675/ DOI: 10.1038/ncomms13103

cross_nutrient

Glutamine supplies nitrogen for the final amidation of the nicotinic-acid/de novo NAD pathway.

evidence_span

{"source_cache": "artifacts/niacin-precursors-sources/nadsyn2019.paragraphs.txt", "locator": "Normalized full-text paragraphs 8–8 (0-based)", "start_char": 7090, "end_char": 8684, "file_sha256": "36ad82ce734c8e0c44d01c7dc813b1641708738319b53a926e429155b1a602f4", "text_sha256": "90cb4d2ce3001f2ecf18f1d751db36047726b71a75be94b073474f6f518c96cd"}

experimental_model

Recombinant human NADSYN1 steady-state kinetic assays and crystallography; bacterial comparison kept separate

exposure

Biochemical or structural assay; no dietary intervention

limitations

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

nutrient_topic

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

organism

Homo sapiens

plain_language

The deamidated route finishes by making NAD+ through NADSYN1.

primary_references

[b3-pre-nadsyn2019] Different ways to transport ammonia in human and Mycobacterium tuberculosis NAD+ synthetases. (2020). https://pubmed.ncbi.nlm.nih.gov/31911602/ DOI: 10.1038/s41467-019-13845-4

tissue_or_cell_type

Purified recombinant protein; no intact tissue

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 328–340

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human NADSYN1 steady-state kinetic assays and crystallography; bacterial comparison kept separate · source_derived_draft · unverified_draft

### b3-pre-nadsyn-amidation Purified human NADSYN1 catalyzed ATP-dependent NAD+ production from nicotinic acid adenine dinucleotide in glutamine-supported assays. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The deamidated route finishes by making NAD+ through NADSYN1. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Recombinant human NADSYN1 steady-state kinetic assays and crystallography; bacterial comparison kept separate limitations: Purified-enzyme evidence does not establish dietary intake requirements or clinical outcomes. exposure: Biochemical or structural assay; no dietary intervention cross_nutrient: Glutamine supplies nitrogen for the final amidation of the nicotinic-acid/de novo NAD pathway. evidence_span: {"source_cache": "artifacts/niacin-precursors-sources/nadsyn2019.paragraphs.txt", "locator": "Normalized full-text paragraphs 8–8 (0-based)", "start_char": 7090, "end_char": 8684, "file_sha256": "36ad82ce734c8e0c44d01c7dc813b1641708738319b53a926e429155b1a602f4", "text_sha256": "90cb4d2ce3001f2ecf18f1d751db36047726b71a75be94b073474f6f518c96cd"} [b3-pre-nadsyn2019] Different ways to transport ammonia in human and Mycobacterium tuberculosis NAD+ synthetases. (2020). https://pubmed.ncbi.nlm.nih.gov/31911602/ DOI: 10.1038/s41467-019-13845-4

evidence_span

{"source_cache": "artifacts/niacin-precursors-sources/nadsyn2019.paragraphs.txt", "locator": "Normalized full-text paragraphs 8–8 (0-based)", "start_char": 7090, "end_char": 8684, "file_sha256": "36ad82ce734c8e0c44d01c7dc813b1641708738319b53a926e429155b1a602f4", "text_sha256": "90cb4d2ce3001f2ecf18f1d751db36047726b71a75be94b073474f6f518c96cd"}

experimental_model

Recombinant human NADSYN1 steady-state kinetic assays and crystallography; bacterial comparison kept separate

exposure

Biochemical or structural assay; no dietary intervention

limitations

Assay substrate efficiency does not show that free ammonia replaces glutamine physiologically or justify ammonia exposure.

nutrient_topic

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

organism

Homo sapiens

plain_language

Human NADSYN1 can use either tested nitrogen source in vitro.

primary_references

[b3-pre-nadsyn2019] Different ways to transport ammonia in human and Mycobacterium tuberculosis NAD+ synthetases. (2020). https://pubmed.ncbi.nlm.nih.gov/31911602/ DOI: 10.1038/s41467-019-13845-4

tissue_or_cell_type

Purified recombinant protein; no intact tissue

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 356–367

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human NADSYN1 steady-state kinetic assays and crystallography; bacterial comparison kept separate · source_derived_draft · unverified_draft

### b3-pre-nadsyn-ammonia Purified human NADSYN1 also supported NAD+ formation with free ammonia; its reported catalytic efficiencies for glutamine and ammonia were similar, 0.45 and 0.49 per second per millimolar. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Human NADSYN1 can use either tested nitrogen source in vitro. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Recombinant human NADSYN1 steady-state kinetic assays and crystallography; bacterial comparison kept separate limitations: Assay substrate efficiency does not show that free ammonia replaces glutamine physiologically or justify ammonia exposure. exposure: Biochemical or structural assay; no dietary intervention evidence_span: {"source_cache": "artifacts/niacin-precursors-sources/nadsyn2019.paragraphs.txt", "locator": "Normalized full-text paragraphs 8–8 (0-based)", "start_char": 7090, "end_char": 8684, "file_sha256": "36ad82ce734c8e0c44d01c7dc813b1641708738319b53a926e429155b1a602f4", "text_sha256": "90cb4d2ce3001f2ecf18f1d751db36047726b71a75be94b073474f6f518c96cd"} [b3-pre-nadsyn2019] Different ways to transport ammonia in human and Mycobacterium tuberculosis NAD+ synthetases. (2020). https://pubmed.ncbi.nlm.nih.gov/31911602/ DOI: 10.1038/s41467-019-13845-4

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/niacin-precursors-sources/hara2007.abstract.txt", "locator": "Indexed primary abstract", "start_char": 0, "end_char": 1634, "file_sha256": "4a605e0551bc9453dec63e8aa1e0fcd78985ae7dfca8d4b785039de0e0382547", "text_sha256": "4a605e0551bc9453dec63e8aa1e0fcd78985ae7dfca8d4b785039de0e0382547"}

experimental_model

Cultured human cells with endogenous NAPRT and experimental NAPRT knockdown; separate mouse expression measurements

exposure

NAPRT knockdown plus nicotinic acid; concentration and duration not independently available in indexed abstract

limitations

The abstract does not specify the cell line or dosing details; no inference to oral intake or patient response.

nutrient_topic

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

organism

Homo sapiens

plain_language

Nicotinic acid could not produce the same NAD rise after its entry enzyme was suppressed.

primary_references

[b3-pre-hara2007] Elevation of cellular NAD levels by nicotinic acid and involvement of nicotinic acid phosphoribosyltransferase in human cells. (2007). https://pubmed.ncbi.nlm.nih.gov/17604275/ DOI: 10.1074/jbc.m610357200

tissue_or_cell_type

Cultured human cells expressing endogenous NAPRT

trigger_kind

machinery_impairment Imported condition classification; unverified.

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 289–300

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cultured human cells with endogenous NAPRT and experimental NAPRT knockdown; separate mouse expression measurements · source_derived_draft · unverified_draft

### b3-pre-naprt-knockdown-na NAPRT knockdown reversed the rise in cellular NAD caused by nicotinic acid in the cultured human cells studied. Condition category: machinery_impairment nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Nicotinic acid could not produce the same NAD rise after its entry enzyme was suppressed. organism: Homo sapiens tissue_or_cell_type: Cultured human cells expressing endogenous NAPRT experimental_model: Cultured human cells with endogenous NAPRT and experimental NAPRT knockdown; separate mouse expression measurements limitations: The abstract does not specify the cell line or dosing details; no inference to oral intake or patient response. exposure: NAPRT knockdown plus nicotinic acid; concentration and duration not independently available in indexed abstract evidence_span: {"source_cache": "artifacts/niacin-precursors-sources/hara2007.abstract.txt", "locator": "Indexed primary abstract", "start_char": 0, "end_char": 1634, "file_sha256": "4a605e0551bc9453dec63e8aa1e0fcd78985ae7dfca8d4b785039de0e0382547", "text_sha256": "4a605e0551bc9453dec63e8aa1e0fcd78985ae7dfca8d4b785039de0e0382547"} [b3-pre-hara2007] Elevation of cellular NAD levels by nicotinic acid and involvement of nicotinic acid phosphoribosyltransferase in human cells. (2007). https://pubmed.ncbi.nlm.nih.gov/17604275/ DOI: 10.1074/jbc.m610357200

evidence_span

{"source_cache": "artifacts/niacin-precursors-sources/nmnat2002.abstract.txt", "locator": "Indexed primary abstract", "start_char": 0, "end_char": 826, "file_sha256": "5064cc6a7b31875eeaea8def5544c3cce75a971f73aa74f332d89e06c3c54477", "text_sha256": "5064cc6a7b31875eeaea8def5544c3cce75a971f73aa74f332d89e06c3c54477"}

experimental_model

Cloned, expressed and purified recombinant human NMNAT2

exposure

Biochemical or structural assay; no dietary intervention

limitations

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

nutrient_topic

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

organism

Homo sapiens

plain_language

The same human isozyme processes either the amidated or deamidated mononucleotide.

primary_references

[b3-pre-nmnat2002] Identification of a novel human nicotinamide mononucleotide adenylyltransferase. (2002). https://pubmed.ncbi.nlm.nih.gov/12359228/ DOI: 10.1016/s0006-291x(02)02285-4

tissue_or_cell_type

Purified recombinant protein; no intact tissue

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 302–313

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cloned, expressed and purified recombinant human NMNAT2 · source_derived_draft · unverified_draft

### b3-pre-nmnat2-nmn Purified recombinant human NMNAT2 has adenylyltransferase activity toward NMN, supporting NAD+ formation. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The same human isozyme processes either the amidated or deamidated mononucleotide. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Cloned, expressed and purified recombinant human NMNAT2 limitations: Purified-enzyme evidence does not establish dietary intake requirements or clinical outcomes. exposure: Biochemical or structural assay; no dietary intervention evidence_span: {"source_cache": "artifacts/niacin-precursors-sources/nmnat2002.abstract.txt", "locator": "Indexed primary abstract", "start_char": 0, "end_char": 826, "file_sha256": "5064cc6a7b31875eeaea8def5544c3cce75a971f73aa74f332d89e06c3c54477", "text_sha256": "5064cc6a7b31875eeaea8def5544c3cce75a971f73aa74f332d89e06c3c54477"} [b3-pre-nmnat2002] Identification of a novel human nicotinamide mononucleotide adenylyltransferase. (2002). https://pubmed.ncbi.nlm.nih.gov/12359228/ DOI: 10.1016/s0006-291x(02)02285-4

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/niacin-precursors-sources/nmrk2016.paragraphs.txt", "locator": "Normalized full-text paragraphs 14–14 (0-based)", "start_char": 14813, "end_char": 16096, "file_sha256": "fcbd5465aff51c9870d65fc9812edbad2cdf2af8bb16b6afb3170d7f0503178a", "text_sha256": "fcfc45b2ce45c05afffe5608ea3be48fe50bd17083c12f5b0993f3bc183da63f"}

experimental_model

Murine NRK gain/loss of function in fibroblasts and primary hepatocytes; separate human HepG2 stable-isotope experiments

exposure

0.5 mM NMN for 6 h (Fig. 5e)

limitations

Isolated hepatocytes. Whole-animal liver retained substantial response after injected NR/NMN; the claim is not universal direct-uptake exclusion.

nutrient_topic

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

organism

Mus musculus

plain_language

The precursor response required NRK1 in these isolated liver cells.

primary_references

[b3-pre-nmrk2016] NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells. (2016). https://pubmed.ncbi.nlm.nih.gov/27725675/ DOI: 10.1038/ncomms13103

supporting_evidence_spans

[{"source_cache": "artifacts/niacin-precursors-sources/nmrk2016.paragraphs.txt", "locator": "Normalized full-text paragraphs 52–52 (0-based)", "start_char": 47696, "end_char": 48288, "file_sha256": "fcbd5465aff51c9870d65fc9812edbad2cdf2af8bb16b6afb3170d7f0503178a", "text_sha256": "541856eddb8e5c1162040cb1e010a6d556de92ee36f223d0da751b4c53b06104"}]

tissue_or_cell_type

Primary hepatocytes from male mice aged 10–15 weeks

trigger_kind

machinery_impairment Imported condition classification; unverified.

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 437–449

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Murine NRK gain/loss of function in fibroblasts and primary hepatocytes; separate human HepG2 stable-isotope experiments · source_derived_draft · unverified_draft

### b3-pre-nrk1ko-nmn Primary hepatocytes from Nmrk1-knockout mice failed to increase NAD+ after NMN treatment, whereas wild-type hepatocytes responded. Condition category: machinery_impairment nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The precursor response required NRK1 in these isolated liver cells. organism: Mus musculus tissue_or_cell_type: Primary hepatocytes from male mice aged 10–15 weeks experimental_model: Murine NRK gain/loss of function in fibroblasts and primary hepatocytes; separate human HepG2 stable-isotope experiments limitations: Isolated hepatocytes. Whole-animal liver retained substantial response after injected NR/NMN; the claim is not universal direct-uptake exclusion. exposure: 0.5 mM NMN for 6 h (Fig. 5e) evidence_span: {"source_cache": "artifacts/niacin-precursors-sources/nmrk2016.paragraphs.txt", "locator": "Normalized full-text paragraphs 14–14 (0-based)", "start_char": 14813, "end_char": 16096, "file_sha256": "fcbd5465aff51c9870d65fc9812edbad2cdf2af8bb16b6afb3170d7f0503178a", "text_sha256": "fcfc45b2ce45c05afffe5608ea3be48fe50bd17083c12f5b0993f3bc183da63f"} supporting_evidence_spans: [{"source_cache": "artifacts/niacin-precursors-sources/nmrk2016.paragraphs.txt", "locator": "Normalized full-text paragraphs 52–52 (0-based)", "start_char": 47696, "end_char": 48288, "file_sha256": "fcbd5465aff51c9870d65fc9812edbad2cdf2af8bb16b6afb3170d7f0503178a", "text_sha256": "541856eddb8e5c1162040cb1e010a6d556de92ee36f223d0da751b4c53b06104"}] [b3-pre-nmrk2016] NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells. (2016). https://pubmed.ncbi.nlm.nih.gov/27725675/ DOI: 10.1038/ncomms13103

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/niacin-precursors-sources/nmrk2016.paragraphs.txt", "locator": "Normalized full-text paragraphs 14–14 (0-based)", "start_char": 14813, "end_char": 16096, "file_sha256": "fcbd5465aff51c9870d65fc9812edbad2cdf2af8bb16b6afb3170d7f0503178a", "text_sha256": "fcfc45b2ce45c05afffe5608ea3be48fe50bd17083c12f5b0993f3bc183da63f"}

experimental_model

Murine NRK gain/loss of function in fibroblasts and primary hepatocytes; separate human HepG2 stable-isotope experiments

exposure

0.5 mM NR for 6 h (Fig. 5e)

limitations

Isolated hepatocytes. Whole-animal liver retained substantial response after injected NR/NMN; the claim is not universal direct-uptake exclusion.

nutrient_topic

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

organism

Mus musculus

plain_language

The precursor response required NRK1 in these isolated liver cells.

primary_references

[b3-pre-nmrk2016] NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells. (2016). https://pubmed.ncbi.nlm.nih.gov/27725675/ DOI: 10.1038/ncomms13103

supporting_evidence_spans

[{"source_cache": "artifacts/niacin-precursors-sources/nmrk2016.paragraphs.txt", "locator": "Normalized full-text paragraphs 52–52 (0-based)", "start_char": 47696, "end_char": 48288, "file_sha256": "fcbd5465aff51c9870d65fc9812edbad2cdf2af8bb16b6afb3170d7f0503178a", "text_sha256": "541856eddb8e5c1162040cb1e010a6d556de92ee36f223d0da751b4c53b06104"}]

tissue_or_cell_type

Primary hepatocytes from male mice aged 10–15 weeks

trigger_kind

machinery_impairment Imported condition classification; unverified.

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 423–435

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Murine NRK gain/loss of function in fibroblasts and primary hepatocytes; separate human HepG2 stable-isotope experiments · source_derived_draft · unverified_draft

### b3-pre-nrk1ko-nr Primary hepatocytes from Nmrk1-knockout mice failed to increase NAD+ after NR treatment, whereas wild-type hepatocytes responded. Condition category: machinery_impairment nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The precursor response required NRK1 in these isolated liver cells. organism: Mus musculus tissue_or_cell_type: Primary hepatocytes from male mice aged 10–15 weeks experimental_model: Murine NRK gain/loss of function in fibroblasts and primary hepatocytes; separate human HepG2 stable-isotope experiments limitations: Isolated hepatocytes. Whole-animal liver retained substantial response after injected NR/NMN; the claim is not universal direct-uptake exclusion. exposure: 0.5 mM NR for 6 h (Fig. 5e) evidence_span: {"source_cache": "artifacts/niacin-precursors-sources/nmrk2016.paragraphs.txt", "locator": "Normalized full-text paragraphs 14–14 (0-based)", "start_char": 14813, "end_char": 16096, "file_sha256": "fcbd5465aff51c9870d65fc9812edbad2cdf2af8bb16b6afb3170d7f0503178a", "text_sha256": "fcfc45b2ce45c05afffe5608ea3be48fe50bd17083c12f5b0993f3bc183da63f"} supporting_evidence_spans: [{"source_cache": "artifacts/niacin-precursors-sources/nmrk2016.paragraphs.txt", "locator": "Normalized full-text paragraphs 52–52 (0-based)", "start_char": 47696, "end_char": 48288, "file_sha256": "fcbd5465aff51c9870d65fc9812edbad2cdf2af8bb16b6afb3170d7f0503178a", "text_sha256": "541856eddb8e5c1162040cb1e010a6d556de92ee36f223d0da751b4c53b06104"}] [b3-pre-nmrk2016] NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells. (2016). https://pubmed.ncbi.nlm.nih.gov/27725675/ DOI: 10.1038/ncomms13103

evidence_span

{"source_cache": "artifacts/molybdenum-research/37713777.fulltext.txt", "locator": "Exact primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a8092b2aa7328b59f0275dd8a37d2a2dbb5abb2a32236d0cab5fffcc1ddc671d", "start_char": 0, "end_char": 1579, "text_sha256": "18325172be489f8f4beae16c04dbc4f49f94c87186321e32aede61f27089c7c4"}

experimental_model

Recombinant human XDH variants with urate, superoxide and NO assays

exposure

Xanthine, oxygen and inorganic nitrite assays

limitations

Canonical electron-transfer mechanism stated in this primary article; not an experiment on dietary B2 or niacin depletion.

nutrient_topic

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

organism

Homo sapiens protein

plain_language

Riboflavin-derived FAD, iron-sulfur centers and niacin-derived NAD work alongside molybdenum.

primary_references

[mo-p37713777] Natural mutations of human XDH promote the nitrite (NO2-)-reductase capacity of xanthine oxidoreductase: A novel mechanism to promote redox health? (2023). https://pubmed.ncbi.nlm.nih.gov/37713777/ DOI: 10.1016/j.redox.2023.102864

tissue_or_cell_type

Purified human enzyme

Molybdenum: cofactor assembly, sulfur metabolism and nutrient interactions (2026-09-17) · lines 768–779

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human XDH variants with urate, superoxide and NO assays · source_derived_draft · unverified_draft

### mo-xdh-nad The XDH form transfers purine-derived electrons through its iron-sulfur centers and FAD to NAD+, producing NADH. Condition category: normal nutrient_topic: Molybdenum research collection; topical membership is not evidence of a direct dietary effect. plain_language: Riboflavin-derived FAD, iron-sulfur centers and niacin-derived NAD work alongside molybdenum. organism: Homo sapiens protein tissue_or_cell_type: Purified human enzyme experimental_model: Recombinant human XDH variants with urate, superoxide and NO assays limitations: Canonical electron-transfer mechanism stated in this primary article; not an experiment on dietary B2 or niacin depletion. exposure: Xanthine, oxygen and inorganic nitrite assays evidence_span: {"source_cache": "artifacts/molybdenum-research/37713777.fulltext.txt", "locator": "Exact primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a8092b2aa7328b59f0275dd8a37d2a2dbb5abb2a32236d0cab5fffcc1ddc671d", "start_char": 0, "end_char": 1579, "text_sha256": "18325172be489f8f4beae16c04dbc4f49f94c87186321e32aede61f27089c7c4"} [mo-p37713777] Natural mutations of human XDH promote the nitrite (NO2-)-reductase capacity of xanthine oxidoreductase: A novel mechanism to promote redox health? (2023). https://pubmed.ncbi.nlm.nih.gov/37713777/ DOI: 10.1016/j.redox.2023.102864

cell_type

experimental cells

experimental_model

Biochemical and cellular assays

limitations

Recent 2026 finding; no dietary-dose inference.

organism

mammalian

Selenium: literature corrections and mechanism additions · lines 438–448

Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Biochemical and cellular assays · secondary_verified · secondary_verified

## selenoo-hydrolyzes-nad SELENOO can split NAD into two smaller molecules. SELENOO catalyzes NAD+ hydrolysis to NMN and AMP. Organism: mammalian Cell type: experimental cells Experimental model: Biochemical and cellular assays Limitations: Recent 2026 finding; no dietary-dose inference. Primary reference: [NAD+ hydrolysis catalyzed by SelO is required for mitochondrial homeostasis](https://pubmed.ncbi.nlm.nih.gov/41806834/)

evidence_access

Primary full text, pathway background

experimental_model

Established pathway shown in a human ECHS1 disease/biochemistry study; not a new BCKDH assay in that paper.

limitations

Cofactor and catalytic evidence is separately linked from existing ThDP/DLD records.

nutrient_topic

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

plain_language

A shared BCAA enzyme commits the carbon skeleton to further breakdown.

primary_references

Clinical and biochemical characterization of four patients with mutations in ECHS1. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26081110/ · DOI 10.1186/s13023-015-0290-1

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 170–176

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Established pathway shown in a human ECHS1 disease/biochemistry study; not a new BCKDH assay in that paper. · source_derived_draft · unverified_draft

## isoleucine-bckdh-carbon-step A shared BCAA enzyme commits the carbon skeleton to further breakdown. The isoleucine pathway in the primary biochemical study places BCKDH-mediated oxidative decarboxylation of the branched ketoacid upstream of 2-methylbutyryl-CoA. Model: Established pathway shown in a human ECHS1 disease/biochemistry study; not a new BCKDH assay in that paper. Limitations: Cofactor and catalytic evidence is separately linked from existing ThDP/DLD records. Evidence access: Primary full text, pathway background Clinical and biochemical characterization of four patients with mutations in ECHS1. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26081110/ · DOI 10.1186/s13023-015-0290-1

evidence_access

Primary abstract

experimental_model

Established biochemical function in a primary loss-of-function/rescue study.

limitations

The protein also has essential functions beyond this reaction; metabolic activity alone does not explain its disease phenotype.

nutrient_topic

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

plain_language

Another enzyme changes the intermediate before the final carbon split.

primary_references

A non-enzymatic function of 17beta-hydroxysteroid dehydrogenase type 10 is required for mitochondrial integrity and cell survival. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20077426/ · DOI 10.1002/emmm.200900055

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 210–216

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Established biochemical function in a primary loss-of-function/rescue study. · source_derived_draft · unverified_draft

## isoleucine-hsd10-reaction Another enzyme changes the intermediate before the final carbon split. HSD17B10 encodes the 2-methyl-3-hydroxybutyryl-CoA dehydrogenase step of isoleucine metabolism. Model: Established biochemical function in a primary loss-of-function/rescue study. Limitations: The protein also has essential functions beyond this reaction; metabolic activity alone does not explain its disease phenotype. Evidence access: Primary abstract A non-enzymatic function of 17beta-hydroxysteroid dehydrogenase type 10 is required for mitochondrial integrity and cell survival. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20077426/ · DOI 10.1002/emmm.200900055

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

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

limitations

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

nutrient_topic

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

plain_language

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

primary_references

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

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

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

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

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

cross_nutrient

NAD links niacin-derived redox chemistry to B6 catabolism in this rat assay.

evidence_location

Indexed abstract: partially purified rat enzyme and urinary metabolites

experimental_model

Rat tissue enzyme fractions and aldehyde-oxidase activity variants.

exposure

Partially purified activity; kinetic assays at pH 9.6.

limitations

Molecular isoenzyme and quantitative contribution in humans not established.

nutrient_topic

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

organism

Rattus norvegicus

plain_language

Rat B6 breakdown had an alternative to aldehyde oxidase.

primary_references

[stanulovic1976] New pathway of conversion of pyridoxal to 4-pyridoxic acid. (1976). https://pubmed.ncbi.nlm.nih.gov/939227/ DOI: 10.1159/000458879

tissue_or_cell_type

Rat tissue enzyme fractions and urine

Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 491–503

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat tissue enzyme fractions and aldehyde-oxidase activity variants. · source_derived_draft · unverified_draft

### b6-transport-rat-pl-catabolism Partially purified rat tissue NAD-dependent aldehyde-dehydrogenase activity oxidized PL to 4-pyridoxic acid; oxidase-null rats still excreted the acid. Condition category: normal nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Rat B6 breakdown had an alternative to aldehyde oxidase. organism: Rattus norvegicus tissue_or_cell_type: Rat tissue enzyme fractions and urine experimental_model: Rat tissue enzyme fractions and aldehyde-oxidase activity variants. limitations: Molecular isoenzyme and quantitative contribution in humans not established. exposure: Partially purified activity; kinetic assays at pH 9.6. evidence_location: Indexed abstract: partially purified rat enzyme and urinary metabolites cross_nutrient: NAD links niacin-derived redox chemistry to B6 catabolism in this rat assay. [stanulovic1976] New pathway of conversion of pyridoxal to 4-pyridoxic acid. (1976). https://pubmed.ncbi.nlm.nih.gov/939227/ DOI: 10.1159/000458879

evidence_access

Primary abstract

experimental_model

Human CD38 enzyme assay with docking.

limitations

Docking does not prove a binding pose; no human NAD increase or longevity effect established.

nutrient_topic

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

plain_language

One experimentally inhibited target consumes NAD-related substrates.

primary_references

Flavonoids as inhibitors of human CD38. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21641214/ · DOI 10.1016/j.bmcl.2011.05.022

Luteolin: metabolism, immune signaling, redox chemistry and cross-nutrient mechanisms (2026-09-19) · lines 276–282

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human CD38 enzyme assay with docking. · source_derived_draft · unverified_draft

## luteolin-cd38-inhibition One experimentally inhibited target consumes NAD-related substrates. Luteolin inhibited human CD38 at an IC50 below 10 micromolar in vitro. Model: Human CD38 enzyme assay with docking. Limitations: Docking does not prove a binding pose; no human NAD increase or longevity effect established. Evidence access: Primary abstract Flavonoids as inhibitors of human CD38. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21641214/ · DOI 10.1016/j.bmcl.2011.05.022

cross_nutrient

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

evidence

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

experimental_model

Intact/permeabilized rat hepatocytes and liver preparations.

limitations

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

nutrient

Thiamine (vitamin B1) · Thiamine (vitamin B1)

nutrient_topic

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

organism

Rattus norvegicus

plain_language

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

primary_references

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

tissue_or_cell_type

Liver

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

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

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

cross_nutrient

B1-dependent lysine catabolism converges on the same lipoyl, CoA and NAD/FAD machinery used in OGDH.

evidence

[{"paper_key": "nemeria-2018-oadh", "source_bundle": "artifacts/thiamine_metabolism_sources.json", "passage_ids": ["abstract"], "locator": "Primary publication abstract", "preservation": "Exact text retained in the source bundle; full source document retained when openly retrievable."}]

experimental_model

Human recombinant component reconstitution.

limitations

Reconstituted proteins; sharing does not establish competition for limiting subunits in vivo.

nutrient

Thiamine (vitamin B1) · Thiamine (vitamin B1)

nutrient_topic

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

organism

Homo sapiens

plain_language

Lysine-related carbon disposal uses a different B1-dependent E1, while sharing the downstream E2 and E3 proteins with a TCA-cycle enzyme.

primary_references

[nemeria-2018-oadh] The mitochondrial 2-oxoadipate and 2-oxoglutarate dehydrogenase complexes share their E2 and E3 components for their function and both generate reactive oxygen species (2018). https://pubmed.ncbi.nlm.nih.gov/29191460/ DOI: 10.1016/j.freeradbiomed.2017.11.018

tissue_or_cell_type

Purified complex

Thiamine: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 869–881

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

### b1-dhtkd1-recruits-shared-dlst-dld Human DHTKD1 supported 2-oxoadipate dehydrogenase activity when combined with the DLST and DLD components also used by OGDH. Condition category: normal nutrient_topic: Thiamine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Lysine-related carbon disposal uses a different B1-dependent E1, while sharing the downstream E2 and E3 proteins with a TCA-cycle enzyme. organism: Homo sapiens tissue_or_cell_type: Purified complex experimental_model: Human recombinant component reconstitution. limitations: Reconstituted proteins; sharing does not establish competition for limiting subunits in vivo. evidence: [{"paper_key": "nemeria-2018-oadh", "source_bundle": "artifacts/thiamine_metabolism_sources.json", "passage_ids": ["abstract"], "locator": "Primary publication abstract", "preservation": "Exact text retained in the source bundle; full source document retained when openly retrievable."}] cross_nutrient: B1-dependent lysine catabolism converges on the same lipoyl, CoA and NAD/FAD machinery used in OGDH. nutrient: Thiamine (vitamin B1) [nemeria-2018-oadh] The mitochondrial 2-oxoadipate and 2-oxoglutarate dehydrogenase complexes share their E2 and E3 components for their function and both generate reactive oxygen species (2018). https://pubmed.ncbi.nlm.nih.gov/29191460/ DOI: 10.1016/j.freeradbiomed.2017.11.018

cross_nutrient

B1 performs E1 carbon chemistry; B2-derived FAD and the niacin-related NAD cofactor participate in the separate shared E3 reaction.

evidence

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

experimental_model

Human DLD crystallography with NAD+ and NADH.

limitations

Cofactor chemistry does not establish dietary B2/B3 limitation or prove rescue of B1 deficiency.

nutrient

Thiamine (vitamin B1) · Thiamine (vitamin B1)

nutrient_topic

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

organism

Homo sapiens

plain_language

The shared E3 protein resets reduced lipoyl carriers using the B2-derived flavin and B3-related NAD system, allowing another round of B1-dependent turnover.

primary_references

[brautigam-2005-dld] Crystal structure of human dihydrolipoamide dehydrogenase: NAD+/NADH binding and the structural basis of disease-causing mutations (2005). https://pubmed.ncbi.nlm.nih.gov/15946682/ DOI: 10.1016/j.jmb.2005.05.014

tissue_or_cell_type

Purified enzyme

Thiamine: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 717–729

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human DLD crystallography with NAD+ and NADH. · source_derived_draft · unverified_draft

### b1-dld-fad-nad-lipoyl-regeneration Human DLD uses bound FAD and transiently bound NAD+ to oxidize dihydrolipoamide; NADH-bound structures place its nicotinamide ring beside FAD. Condition category: normal nutrient_topic: Thiamine research collection; topical membership is not evidence of a direct dietary effect. plain_language: The shared E3 protein resets reduced lipoyl carriers using the B2-derived flavin and B3-related NAD system, allowing another round of B1-dependent turnover. organism: Homo sapiens tissue_or_cell_type: Purified enzyme experimental_model: Human DLD crystallography with NAD+ and NADH. limitations: Cofactor chemistry does not establish dietary B2/B3 limitation or prove rescue of B1 deficiency. evidence: [{"paper_key": "brautigam-2005-dld", "source_bundle": "artifacts/thiamine_metabolism_sources.json", "passage_ids": ["abstract"], "locator": "Primary publication abstract", "preservation": "Exact text retained in the source bundle; full source document retained when openly retrievable."}] cross_nutrient: B1 performs E1 carbon chemistry; B2-derived FAD and the niacin-related NAD cofactor participate in the separate shared E3 reaction. nutrient: Thiamine (vitamin B1) [brautigam-2005-dld] Crystal structure of human dihydrolipoamide dehydrogenase: NAD+/NADH binding and the structural basis of disease-causing mutations (2005). https://pubmed.ncbi.nlm.nih.gov/15946682/ DOI: 10.1016/j.jmb.2005.05.014

cross_nutrient

B1, B5-derived CoA, B2-derived FAD and niacin-related NAD act at different steps of one complex.

evidence

[{"paper_key": "nemeria-2014-ogdh", "source_bundle": "artifacts/thiamine_metabolism_sources.json", "passage_ids": ["p-28"], "locator": "The reaction medium contained the following in 1.0 ml", "preservation": "Exact text retained in the source bundle; full source document retained when openly retrievable."}]

experimental_model

Reconstituted human multienzyme assay.

limitations

NADH assay measures overall complex turnover, not every intermediate independently.

nutrient

Thiamine (vitamin B1) · Thiamine (vitamin B1)

nutrient_topic

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

organism

Homo sapiens

plain_language

B1-dependent E1 feeds a lipoyl/CoA transfer pathway, and E3 transfers the resulting reducing equivalents to NAD.

primary_references

[nemeria-2014-ogdh] Human 2-oxoglutarate dehydrogenase complex E1 component forms a thiamin-derived radical by aerobic oxidation of the enamine intermediate (2014). https://pubmed.ncbi.nlm.nih.gov/25210035/ DOI: 10.1074/jbc.m114.591073

tissue_or_cell_type

Purified enzyme complex

Thiamine: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 855–867

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

### b1-ogdh-complex-couples-succinyl-nadh Human OGDH, lipoylated DLST and DLD assembled into an active complex coupling 2-oxoglutarate oxidation to NADH production in the CoA-containing assay. Condition category: normal nutrient_topic: Thiamine research collection; topical membership is not evidence of a direct dietary effect. plain_language: B1-dependent E1 feeds a lipoyl/CoA transfer pathway, and E3 transfers the resulting reducing equivalents to NAD. organism: Homo sapiens tissue_or_cell_type: Purified enzyme complex experimental_model: Reconstituted human multienzyme assay. limitations: NADH assay measures overall complex turnover, not every intermediate independently. evidence: [{"paper_key": "nemeria-2014-ogdh", "source_bundle": "artifacts/thiamine_metabolism_sources.json", "passage_ids": ["p-28"], "locator": "The reaction medium contained the following in 1.0 ml", "preservation": "Exact text retained in the source bundle; full source document retained when openly retrievable."}] cross_nutrient: B1, B5-derived CoA, B2-derived FAD and niacin-related NAD act at different steps of one complex. nutrient: Thiamine (vitamin B1) [nemeria-2014-ogdh] Human 2-oxoglutarate dehydrogenase complex E1 component forms a thiamin-derived radical by aerobic oxidation of the enamine intermediate (2014). https://pubmed.ncbi.nlm.nih.gov/25210035/ DOI: 10.1074/jbc.m114.591073

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Same cellular mechanism study.

limitations

NAD measurement and substrate deacetylation do not establish direct SIRT1 binding.

nutrient_topic

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

plain_language

Calcium/cAMP signaling connects to NAD-dependent regulation.

primary_references

Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22304913/ · DOI 10.1016/j.cell.2012.01.017

trigger_kind

machinery_impairment Imported condition classification; unverified.

Resveratrol: metabolites, target selectivity and cross-nutrient mechanisms (2026-09-19) · lines 246–252

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Same cellular mechanism study. · source_derived_draft · unverified_draft

## resveratrol-epac-nad-loss Calcium/cAMP signaling connects to NAD-dependent regulation. Epac1 siRNA prevented the resveratrol-induced NAD increase and PGC-1alpha deacetylation in human HeLa experiments. Model: Same cellular mechanism study. Limitations: NAD measurement and substrate deacetylation do not establish direct SIRT1 binding. Evidence access: Primary full text Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22304913/ · DOI 10.1016/j.cell.2012.01.017

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

High-fat-fed mice receiving approximately 25–30 or 215–230 mg/kg/day.

limitations

Adult knockout, tissue context and high-fat diet matter; not a human niacin-deficiency experiment.

nutrient_topic

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

plain_language

A response can require intact machinery even if upstream signals still change.

primary_references

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

trigger_kind

machinery_impairment Imported condition classification; unverified.

Resveratrol: metabolites, target selectivity and cross-nutrient mechanisms (2026-09-19) · lines 174–180

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · High-fat-fed mice receiving approximately 25–30 or 215–230 mg/kg/day. · source_derived_draft · unverified_draft

## resveratrol-mouse-sirt1-loss A response can require intact machinery even if upstream signals still change. Adult-induced Sirt1 deletion prevented resveratrol-associated improvements in mouse skeletal-muscle mitochondrial function at both tested dietary doses. Model: High-fat-fed mice receiving approximately 25–30 or 215–230 mg/kg/day. Limitations: Adult knockout, tissue context and high-fat diet matter; not a human niacin-deficiency experiment. Evidence access: Primary full text SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22560220/ · DOI 10.1016/j.cmet.2012.04.003

evidence_access

Primary full text

experimental_model

Low-dose time course; 5 micromolar used in dependency experiments.

limitations

Whole-cell NAD is not a measurement of every subcellular pool.

nutrient_topic

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

plain_language

Initial consumption and later replenishment are separate phases.

primary_references

A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25533949/ · DOI 10.1038/nature14028

Resveratrol: metabolites, target selectivity and cross-nutrient mechanisms (2026-09-19) · lines 310–316

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Low-dose time course; 5 micromolar used in dependency experiments. · source_derived_draft · unverified_draft

## resveratrol-nad-timecourse Initial consumption and later replenishment are separate phases. In human HeLa cells, resveratrol initially reduced NAD with increased nicotinamide/ADP-ribose at 15 minutes; low concentrations raised NAD by one hour. Model: Low-dose time course; 5 micromolar used in dependency experiments. Limitations: Whole-cell NAD is not a measurement of every subcellular pool. Evidence access: Primary full text A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25533949/ · DOI 10.1038/nature14028

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Pharmacological NAMPT inhibition.

limitations

This does not prove supplementation with niacin, NR or NMN improves the response.

nutrient_topic

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

plain_language

The response needs functioning NAD salvage machinery.

primary_references

A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25533949/ · DOI 10.1038/nature14028

trigger_kind

machinery_impairment Imported condition classification; unverified.

Resveratrol: metabolites, target selectivity and cross-nutrient mechanisms (2026-09-19) · lines 334–340

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

## resveratrol-nampt-block The response needs functioning NAD salvage machinery. NAD depletion with NAMPT inhibitor STF-118804 abolished resveratrol-mediated induction of BRCA1, FOXO3A, NAMPT, SESN2 and SIRT6 in human HeLa cells. Model: Pharmacological NAMPT inhibition. Limitations: This does not prove supplementation with niacin, NR or NMN improves the response. Evidence access: Primary full text A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25533949/ · DOI 10.1038/nature14028

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

siRNA experiments; 5 micromolar resveratrol.

limitations

Cell-model dependency, not a dietary resveratrol-deficiency state.

nutrient_topic

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

plain_language

Removing a signaling component prevented the rebound.

primary_references

A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25533949/ · DOI 10.1038/nature14028

trigger_kind

machinery_impairment Imported condition classification; unverified.

Resveratrol: metabolites, target selectivity and cross-nutrient mechanisms (2026-09-19) · lines 326–332

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · siRNA experiments; 5 micromolar resveratrol. · source_derived_draft · unverified_draft

## resveratrol-parp-loss Removing a signaling component prevented the rebound. Silencing PARP1 abolished the one-hour NAD increase induced by low-dose resveratrol in human HeLa cells. Model: siRNA experiments; 5 micromolar resveratrol. Limitations: Cell-model dependency, not a dietary resveratrol-deficiency state. Evidence access: Primary full text A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25533949/ · DOI 10.1038/nature14028

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

siRNA experiments; 5 micromolar resveratrol.

limitations

Cell-model dependency, not a dietary resveratrol-deficiency state.

nutrient_topic

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

plain_language

Removing a signaling component prevented the rebound.

primary_references

A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25533949/ · DOI 10.1038/nature14028

trigger_kind

machinery_impairment Imported condition classification; unverified.

Resveratrol: metabolites, target selectivity and cross-nutrient mechanisms (2026-09-19) · lines 318–324

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · siRNA experiments; 5 micromolar resveratrol. · source_derived_draft · unverified_draft

## resveratrol-tyrrs-loss Removing a signaling component prevented the rebound. Silencing TyrRS abolished the one-hour NAD increase induced by low-dose resveratrol in human HeLa cells. Model: siRNA experiments; 5 micromolar resveratrol. Limitations: Cell-model dependency, not a dietary resveratrol-deficiency state. Evidence access: Primary full text A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25533949/ · DOI 10.1038/nature14028

evidence_access

Primary full text

experimental_model

Purified-protein interaction/activation assays.

limitations

Greater PARylation need not imply greater net NAD stores.

nutrient_topic

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

plain_language

This signaling step consumes a niacin-derived cofactor.

primary_references

A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25533949/ · DOI 10.1038/nature14028

Resveratrol: metabolites, target selectivity and cross-nutrient mechanisms (2026-09-19) · lines 302–308

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Purified-protein interaction/activation assays. · source_derived_draft · unverified_draft

## resveratrol-tyrrs-parp This signaling step consumes a niacin-derived cofactor. In the resveratrol study, human TyrRS stimulated NAD-dependent PARP1 auto-poly-ADP-ribosylation in biochemical experiments. Model: Purified-protein interaction/activation assays. Limitations: Greater PARylation need not imply greater net NAD stores. Evidence access: Primary full text A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25533949/ · DOI 10.1038/nature14028

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Prevents equating altered tryptophan metabolism with universal niacin depletion.

evidence_location

Abstract

experimental_model

Dietary riboflavin-deficient, pyridoxine-deficient, pair-fed and natural-diet baboons; urinary and erythrocyte measurements.

exposure

Experimental riboflavin-deficient diet

limitations

The abstract reports an aggregate red-cell readout; it does not resolve synthesis flux, other tissues or every NAD species.

nutrient_topic

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

organism

Papio species (baboon)

plain_language

The B2-related urine change did not establish a fall in this red-cell nucleotide pool.

primary_references

[verjee1975] Tryptophan metabolism in baboons: effect of riboflavin and pyridoxine deficiency. (1975). https://pubmed.ncbi.nlm.nih.gov/23659/

tissue_or_cell_type

Erythrocytes

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1290–1302

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Dietary riboflavin-deficient, pyridoxine-deficient, pair-fed and natural-diet baboons; urinary and erythrocyte measurements. · source_derived_draft · unverified_draft

### b2-baboon-pyridine-nucleotide-boundary Red-cell pyridine nucleotides decreased in pyridoxine-deficient baboons, but not in the riboflavin-deficient group. Condition category: nutrient_deficiency nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The B2-related urine change did not establish a fall in this red-cell nucleotide pool. organism: Papio species (baboon) tissue_or_cell_type: Erythrocytes experimental_model: Dietary riboflavin-deficient, pyridoxine-deficient, pair-fed and natural-diet baboons; urinary and erythrocyte measurements. limitations: The abstract reports an aggregate red-cell readout; it does not resolve synthesis flux, other tissues or every NAD species. exposure: Experimental riboflavin-deficient diet cross_nutrient: Prevents equating altered tryptophan metabolism with universal niacin depletion. evidence_location: Abstract [verjee1975] Tryptophan metabolism in baboons: effect of riboflavin and pyridoxine deficiency. (1975). https://pubmed.ncbi.nlm.nih.gov/23659/

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

DLD is reused from the B1 complexes; its flavin/NAD step is distinct from upstream thiamine diphosphate chemistry.

evidence_spans

[{"source_bundle": "artifacts/riboflavin_metabolism_sources.json", "source_key": "PMC10341545", "locator": "XML .//body//p", "paragraph_index": 19, "char_start": 0, "char_end": 871, "evidence_access": "full-text"}]

experimental_model

Recombinant human DLD variants expressed in E. coli BL21(DE3), FAD quantification, activity, chromatography and crystallography.

exposure

I12T mutagenesis, purified-protein FAD and activity assays.

limitations

Purification instability can affect measured occupancy; correlation does not prove FAD loss alone caused all activity loss.

nutrient_topic

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

organism

Homo sapiens

plain_language

This DLD variant poorly retained FAD and had very low catalytic activity.

primary_references

[szabo-2023-dld-variants] Structural and Biochemical Investigation of Selected Pathogenic Mutants of the Human Dihydrolipoamide Dehydrogenase (2023). https://pubmed.ncbi.nlm.nih.gov/37446004/ DOI: 10.3390/ijms241310826

tissue_or_cell_type

Recombinant DLD expressed in E. coli

trigger_kind

machinery_impairment Imported condition classification; unverified.

Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 847–859

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human DLD variants expressed in E. coli BL21(DE3), FAD quantification, activity, chromatography and crystallography. · source_derived_draft · unverified_draft

### b2-met-dld-i12t-fad-retention Purified human DLD I12T retained about 0.15 FAD per monomer versus approximately one in wild type, with forward and reverse activities of about 8% and 2%. Condition category: machinery_impairment nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: This DLD variant poorly retained FAD and had very low catalytic activity. organism: Homo sapiens tissue_or_cell_type: Recombinant DLD expressed in E. coli experimental_model: Recombinant human DLD variants expressed in E. coli BL21(DE3), FAD quantification, activity, chromatography and crystallography. limitations: Purification instability can affect measured occupancy; correlation does not prove FAD loss alone caused all activity loss. exposure: I12T mutagenesis, purified-protein FAD and activity assays. cross_nutrient: DLD is reused from the B1 complexes; its flavin/NAD step is distinct from upstream thiamine diphosphate chemistry. evidence_spans: [{"source_bundle": "artifacts/riboflavin_metabolism_sources.json", "source_key": "PMC10341545", "locator": "XML .//body//p", "paragraph_index": 19, "char_start": 0, "char_end": 871, "evidence_access": "full-text"}] [szabo-2023-dld-variants] Structural and Biochemical Investigation of Selected Pathogenic Mutants of the Human Dihydrolipoamide Dehydrogenase (2023). https://pubmed.ncbi.nlm.nih.gov/37446004/ DOI: 10.3390/ijms241310826

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human knockout cells, patient fibroblasts and isotope tracing.

limitations

The impairment depended on culture conditions and was more pronounced under galactose stress.

nutrient_topic

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

plain_language

Damaged cofactor can block a pathway even when the enzyme is still present.

primary_references

Failure to repair damaged NAD(P)H blocks de novo serine synthesis in human cells. · 2025 · https://pubmed.ncbi.nlm.nih.gov/39789421/ · DOI 10.1186/s11658-024-00681-8

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Human knockout cells, patient fibroblasts and isotope tracing. · source_derived_draft · unverified_draft

## l-serine-naxd-block Damaged cofactor can block a pathway even when the enzyme is still present. NAXD loss caused NADHX accumulation and impaired de novo serine synthesis in human HAP1 cells under galactose stress and in patient-derived fibroblasts. Model: Human knockout cells, patient fibroblasts and isotope tracing. Limitations: The impairment depended on culture conditions and was more pronounced under galactose stress. Evidence access: Primary full text Failure to repair damaged NAD(P)H blocks de novo serine synthesis in human cells. · 2025 · https://pubmed.ncbi.nlm.nih.gov/39789421/ · DOI 10.1186/s11658-024-00681-8

evidence_access

Primary abstract

experimental_model

Recombinant human PHGDH catalytic-domain structure and enzyme assays.

limitations

The truncated dimeric structure does not define the complete native oligomer.

nutrient_topic

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

plain_language

A glycolysis intermediate can be diverted into serine production.

primary_references

Structural insights into the enzymatic activity and potential substrate promiscuity of human 3-phosphoglycerate dehydrogenase (PHGDH). · 2017 · https://pubmed.ncbi.nlm.nih.gov/29262655/ · DOI 10.18632/oncotarget.22327

L-Serine: synthesis, one-carbon metabolism, lipids 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 · Recombinant human PHGDH catalytic-domain structure and enzyme assays. · source_derived_draft · unverified_draft

## l-serine-phgdh-reaction A glycolysis intermediate can be diverted into serine production. Human PHGDH catalyzes the NAD+-dependent oxidation of 3-phosphoglycerate to phosphohydroxypyruvate, the first step of phosphorylated serine biosynthesis. Model: Recombinant human PHGDH catalytic-domain structure and enzyme assays. Limitations: The truncated dimeric structure does not define the complete native oligomer. Evidence access: Primary abstract Structural insights into the enzymatic activity and potential substrate promiscuity of human 3-phosphoglycerate dehydrogenase (PHGDH). · 2017 · https://pubmed.ncbi.nlm.nih.gov/29262655/ · DOI 10.18632/oncotarget.22327

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Recombinant human mutant/wild-type structures and kinetic analysis.

limitations

This tests one inherited variant and does not establish a nutrient-addition rescue.

nutrient_topic

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

plain_language

A structural defect can block proline breakdown even when substrate is plentiful.

primary_references

The three-dimensional structural basis of type II hyperprolinemia. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22516612/ · DOI 10.1016/j.jmb.2012.04.010

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 110–116

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Recombinant human mutant/wild-type structures and kinetic analysis. · source_derived_draft · unverified_draft

## l-proline-aldh4-failure A structural defect can block proline breakdown even when substrate is plentiful. The human ALDH4A1 S352L disease-associated variant abolished catalytic activity and NAD+ binding, with a major rearrangement of the catalytic loop. Model: Recombinant human mutant/wild-type structures and kinetic analysis. Limitations: This tests one inherited variant and does not establish a nutrient-addition rescue. Evidence access: Primary abstract The three-dimensional structural basis of type II hyperprolinemia. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22516612/ · DOI 10.1016/j.jmb.2012.04.010

evidence_access

Primary abstract

experimental_model

Human enzyme structures and kinetics; mouse enzyme complexes supplied high-resolution ligand views.

limitations

P5C and glutamate semialdehyde interconvert; the aldehyde is the oxidation substrate. Mouse ligand structures are not relabeled as human complexes.

nutrient_topic

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

plain_language

A second enzyme turns the breakdown intermediate into glutamate.

primary_references

The three-dimensional structural basis of type II hyperprolinemia. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22516612/ · DOI 10.1016/j.jmb.2012.04.010

L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 102–108

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human enzyme structures and kinetics; mouse enzyme complexes supplied high-resolution ligand views. · source_derived_draft · unverified_draft

## l-proline-aldh4-oxidation A second enzyme turns the breakdown intermediate into glutamate. ALDH4A1 catalyzes NAD+-dependent oxidation of glutamate semialdehyde to glutamate, completing the second enzymatic stage of proline catabolism. Model: Human enzyme structures and kinetics; mouse enzyme complexes supplied high-resolution ligand views. Limitations: P5C and glutamate semialdehyde interconvert; the aldehyde is the oxidation substrate. Mouse ligand structures are not relabeled as human complexes. Evidence access: Primary abstract The three-dimensional structural basis of type II hyperprolinemia. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22516612/ · DOI 10.1016/j.jmb.2012.04.010

evidence_access

Primary full text

experimental_model

Human cancer-cell hypoxia experiments and three-dimensional/xenograft models.

limitations

A benefit to tumor-cell survival is not a health benefit of supplementation; proline production is part of the reaction that consumes NADH.

nutrient_topic

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

plain_language

Making proline can also help rebalance mitochondrial reducing power.

primary_references

Proline synthesis through PYCR1 is required to support cancer cell proliferation and survival in oxygen-limiting conditions. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35108535/ · DOI 10.1016/j.celrep.2022.110320

L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 350–356

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human cancer-cell hypoxia experiments and three-dimensional/xenograft models. · source_derived_draft · unverified_draft

## l-proline-pycr1-hypoxic-redox Making proline can also help rebalance mitochondrial reducing power. In hypoxic cancer models, increased PYCR1-dependent proline synthesis oxidized NADH and helped sustain TCA-cycle activity. Model: Human cancer-cell hypoxia experiments and three-dimensional/xenograft models. Limitations: A benefit to tumor-cell survival is not a health benefit of supplementation; proline production is part of the reaction that consumes NADH. Evidence access: Primary full text Proline synthesis through PYCR1 is required to support cancer cell proliferation and survival in oxygen-limiting conditions. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35108535/ · DOI 10.1016/j.celrep.2022.110320

evidence_access

Primary abstract

experimental_model

Recombinant human ALDH9 compared with purified and recombinant rat enzyme.

limitations

NAD+ dependence does not establish benefit from niacin supplementation.

nutrient_topic

L-Carnitine collection; isomer, preparation, species, exposure and manipulation remain explicit. · L-Carnitine

plain_language

A niacin-derived coenzyme participates in making carnitine.

primary_references

Molecular and biochemical characterization of rat gamma-trimethylaminobutyraldehyde dehydrogenase and evidence for the involvement of human aldehyde dehydrogenase 9 in carnitine biosynthesis. · 2000 · https://pubmed.ncbi.nlm.nih.gov/10702312/ · DOI 10.1074/jbc.275.10.7390

L-Carnitine: synthesis, acyl-group transport, fuel selection and nutrient interactions (2026-09-19) · lines 18–24

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Recombinant human ALDH9 compared with purified and recombinant rat enzyme. · source_derived_draft · unverified_draft

## l-carnitine-aldehyde-step A niacin-derived coenzyme participates in making carnitine. Expressing human ALDH9 in bacteria produced NAD+-dependent trimethylaminobutyraldehyde dehydrogenase activity, completing the aldehyde-to-gamma-butyrobetaine step. Model: Recombinant human ALDH9 compared with purified and recombinant rat enzyme. Limitations: NAD+ dependence does not establish benefit from niacin supplementation. Evidence access: Primary abstract Molecular and biochemical characterization of rat gamma-trimethylaminobutyraldehyde dehydrogenase and evidence for the involvement of human aldehyde dehydrogenase 9 in carnitine biosynthesis. · 2000 · https://pubmed.ncbi.nlm.nih.gov/10702312/ · DOI 10.1074/jbc.275.10.7390

evidence_access

Primary abstract

experimental_model

Rat liver and mitochondrial experiments.

limitations

The ketone ratio is a redox proxy, not a direct measurement of all NAD pools.

nutrient_topic

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

plain_language

The metabolic redox state shifted toward oxidation.

primary_references

Prooxidant activity of fisetin: effects on energy metabolism in the rat liver. · 2011 · https://pubmed.ncbi.nlm.nih.gov/20957679/ · DOI 10.1002/jbt.20367

Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 344–350

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

## fisetin-rat-redox-ketones The metabolic redox state shifted toward oxidation. In perfused fasted-rat liver, fisetin reduced ketogenesis and the beta-hydroxybutyrate/acetoacetate ratio. Model: Rat liver and mitochondrial experiments. Limitations: The ketone ratio is a redox proxy, not a direct measurement of all NAD pools. Evidence access: Primary abstract Prooxidant activity of fisetin: effects on energy metabolism in the rat liver. · 2011 · https://pubmed.ncbi.nlm.nih.gov/20957679/ · DOI 10.1002/jbt.20367

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 NADH reaction did not simply regenerate normal NAD+.

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 256–262

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-nadh The NADH reaction did not simply regenerate normal NAD+. LPO/H2O2/iodide oxidized NADH to a product chemically distinct from NAD+, unlike the thiocyanate and bromide systems. 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

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experimental_model

Purified Aplysia cyclase kinetics and electrospray complex analysis

exposure

Noncompetitive inhibition Ki 40.5 ± 0.5 mM boric acid; cADPR-binding assay pH 10.3

limitations

The enzyme was Aplysia cyclase, not human CD38. Millimolar enzyme inhibition and alkaline binding data do not establish effects of ordinary dietary boron.

nutrient_topic

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

organism

Aplysia enzyme; cell-free chemistry

plain_language

High boric-acid concentrations slowed an enzyme that makes a calcium messenger; this was a sea-hare enzyme experiment.

primary_references

[boron-p16545389] Boric acid inhibits adenosine diphosphate-ribosyl cyclase non-competitively. (2006). https://pubmed.ncbi.nlm.nih.gov/16545389/ DOI: 10.1016/j.chroma.2006.02.066

tissue_or_cell_type

Purified enzyme and metabolites

Boron: chemistry, nutrient interactions, low-intake studies and mechanistic uncertainties (2026-09-17) · lines 157–168

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified Aplysia cyclase kinetics and electrospray complex analysis · source_derived_draft · unverified_draft

### boron-aplysia-cyclase-inhibition Boric acid inhibited purified Aplysia ADP-ribosyl cyclase noncompetitively with a reported Ki of 40.5 ± 0.5 mM. Condition category: normal nutrient_topic: Boron research collection; topical membership is not evidence of a direct dietary effect. plain_language: High boric-acid concentrations slowed an enzyme that makes a calcium messenger; this was a sea-hare enzyme experiment. organism: Aplysia enzyme; cell-free chemistry tissue_or_cell_type: Purified enzyme and metabolites experimental_model: Purified Aplysia cyclase kinetics and electrospray complex analysis limitations: The enzyme was Aplysia cyclase, not human CD38. Millimolar enzyme inhibition and alkaline binding data do not establish effects of ordinary dietary boron. exposure: Noncompetitive inhibition Ki 40.5 ± 0.5 mM boric acid; cADPR-binding assay pH 10.3 evidence_span: {"source_cache": "artifacts/boron-research/16545389.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "720b1c99bd2628157e48db8085947552afc30029faeb65fb9235541b95c4b655", "start_char": 0, "end_char": 724, "text_sha256": "720b1c99bd2628157e48db8085947552afc30029faeb65fb9235541b95c4b655"} [boron-p16545389] Boric acid inhibits adenosine diphosphate-ribosyl cyclase non-competitively. (2006). https://pubmed.ncbi.nlm.nih.gov/16545389/ DOI: 10.1016/j.chroma.2006.02.066

evidence_span

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experimental_model

Human prostate cancer cell culture and mass spectrometry

exposure

Boric acid 100–1,000 µM; methylboronic acid comparator

limitations

These are cell-culture exposures, including concentrations far above usual circulating levels. Adduct detection and calcium responses do not prove cancer prevention or direct channel binding.

nutrient_topic

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

organism

Human DU-145 cells; cell-free complex analysis

plain_language

At the tested concentrations, boric acid reduced several ways these cancer cells released stored calcium.

primary_references

[boron-p18516691] Boric acid inhibits stored Ca2+ release in DU-145 prostate cancer cells. (2009). https://pubmed.ncbi.nlm.nih.gov/18516691/ DOI: 10.1007/s10565-008-9085-7

tissue_or_cell_type

Prostate cancer cells

Boron: chemistry, nutrient interactions, low-intake studies and mechanistic uncertainties (2026-09-17) · lines 274–285

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human prostate cancer cell culture and mass spectrometry · source_derived_draft · unverified_draft

### boron-nad-calcium-response Boric acid partly inhibited NAD+-evoked calcium transients at 250 µM and completely at 1,000 µM in DU-145 cells; NADP+-evoked and mechanical responses were inhibited at 1,000 µM. Condition category: normal nutrient_topic: Boron research collection; topical membership is not evidence of a direct dietary effect. plain_language: At the tested concentrations, boric acid reduced several ways these cancer cells released stored calcium. organism: Human DU-145 cells; cell-free complex analysis tissue_or_cell_type: Prostate cancer cells experimental_model: Human prostate cancer cell culture and mass spectrometry limitations: These are cell-culture exposures, including concentrations far above usual circulating levels. Adduct detection and calcium responses do not prove cancer prevention or direct channel binding. exposure: Boric acid 100–1,000 µM; methylboronic acid comparator evidence_span: {"source_cache": "artifacts/boron-research/18516691.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5fc4f02e11634c2a2d111a99ee4c6175fe8839a8f28152b656b3c29be6745206", "start_char": 0, "end_char": 1733, "text_sha256": "5fc4f02e11634c2a2d111a99ee4c6175fe8839a8f28152b656b3c29be6745206"} [boron-p18516691] Boric acid inhibits stored Ca2+ release in DU-145 prostate cancer cells. (2009). https://pubmed.ncbi.nlm.nih.gov/18516691/ DOI: 10.1007/s10565-008-9085-7

evidence_access

Primary abstract

experimental_model

Human enzyme, NAD, labeled protein and diamine substrate.

limitations

No in-vivo flux or dominant recycling contribution established.

nutrient_topic

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

plain_language

An unfinished protein modification can be reversed in vitro.

primary_references

Reversal of the deoxyhypusine synthesis reaction. Generation of spermidine or homospermidine from deoxyhypusine by deoxyhypusine synthase. · 2003 · https://pubmed.ncbi.nlm.nih.gov/12788913/ · DOI 10.1074/jbc.M304247200

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 38–44

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human enzyme, NAD, labeled protein and diamine substrate. · source_derived_draft · unverified_draft

## spermidine-dhps-reversal An unfinished protein modification can be reversed in vitro. Purified human DHPS transferred radiolabeled aminobutyl from deoxyhypusine-eIF5A to 1,3-diaminopropane, regenerating spermidine. Model: Human enzyme, NAD, labeled protein and diamine substrate. Limitations: No in-vivo flux or dominant recycling contribution established. Evidence access: Primary abstract Reversal of the deoxyhypusine synthesis reaction. Generation of spermidine or homospermidine from deoxyhypusine by deoxyhypusine synthase. · 2003 · https://pubmed.ncbi.nlm.nih.gov/12788913/ · DOI 10.1074/jbc.M304247200

evidence_span

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experimental_model

Rat antisense-oligonucleotide knockdown, whole-body knockout mice and hepatic redox measurements

exposure

Acute and chronic low-dose metformin; mGPD knockdown and knockout

limitations

A redox-shuttle mechanism established in rodents at low doses; it does not by itself exclude complex I or AMPK contributions in other tissues.

nutrient_topic

Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin

organism

Rat and mouse

plain_language

Blocking the shuttle leaves reducing power stranded in the cell fluid.

primary_references

[metformin-p24847880] Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. (2014). https://pubmed.ncbi.nlm.nih.gov/24847880/ DOI: 10.1038/nature13270

tissue_or_cell_type

Liver

Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 476–487

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat antisense-oligonucleotide knockdown, whole-body knockout mice and hepatic redox measurements · source_derived_draft · unverified_draft

### metformin-mgpd-redox Low-dose metformin increased the cytosolic redox state and decreased the mitochondrial redox state in the liver. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Blocking the shuttle leaves reducing power stranded in the cell fluid. organism: Rat and mouse tissue_or_cell_type: Liver experimental_model: Rat antisense-oligonucleotide knockdown, whole-body knockout mice and hepatic redox measurements limitations: A redox-shuttle mechanism established in rodents at low doses; it does not by itself exclude complex I or AMPK contributions in other tissues. exposure: Acute and chronic low-dose metformin; mGPD knockdown and knockout evidence_span: {"source_cache": "artifacts/metformin-research/24847880.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8378baac19afd12fd3ca66206d079db20e7229a9295414e9678979352e10d92b", "start_char": 0, "end_char": 1499, "text_sha256": "8378baac19afd12fd3ca66206d079db20e7229a9295414e9678979352e10d92b"} [metformin-p24847880] Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. (2014). https://pubmed.ncbi.nlm.nih.gov/24847880/ DOI: 10.1038/nature13270

evidence_span

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experimental_model

Cancer cells in varied culture environments with complex I inhibitors

exposure

Metformin and other complex I inhibitors across environments differing in NAD+ regeneration and aspartate supply

limitations

Establishes that sensitivity is environment-dependent; it argues against reading a culture concentration as a fixed drug property.

nutrient_topic

Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin

organism

Human and mouse cancer cells

plain_language

The real shortage is the carrier the chain recycles and the amino acid that depends on it.

primary_references

[metformin-p27746050] Environment Dictates Dependence on Mitochondrial Complex I for NAD+ and Aspartate Production and Determines Cancer Cell Sensitivity to Metformin. (2016). https://pubmed.ncbi.nlm.nih.gov/27746050/ DOI: 10.1016/j.cmet.2016.09.006

tissue_or_cell_type

Cancer cells in culture and in vivo

Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 710–721

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cancer cells in varied culture environments with complex I inhibitors · source_derived_draft · unverified_draft

### metformin-nad-aspartate The anti-proliferative effect of metformin was due to loss of NAD+/NADH homeostasis and inhibition of aspartate biosynthesis, because complex I supports proliferation by regenerating NAD+. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The real shortage is the carrier the chain recycles and the amino acid that depends on it. organism: Human and mouse cancer cells tissue_or_cell_type: Cancer cells in culture and in vivo experimental_model: Cancer cells in varied culture environments with complex I inhibitors limitations: Establishes that sensitivity is environment-dependent; it argues against reading a culture concentration as a fixed drug property. exposure: Metformin and other complex I inhibitors across environments differing in NAD+ regeneration and aspartate supply evidence_span: {"source_cache": "artifacts/metformin-research/27746050.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "661b69cac488b8ac530cc9385bff10b367b48327d01fe1c29c75bee56ee4f6b3", "start_char": 0, "end_char": 1079, "text_sha256": "661b69cac488b8ac530cc9385bff10b367b48327d01fe1c29c75bee56ee4f6b3"} [metformin-p27746050] Environment Dictates Dependence on Mitochondrial Complex I for NAD+ and Aspartate Production and Determines Cancer Cell Sensitivity to Metformin. (2016). https://pubmed.ncbi.nlm.nih.gov/27746050/ DOI: 10.1016/j.cmet.2016.09.006

evidence_access

Primary full text

experimental_model

Young versus aged mice; flow cytometry, histology and macrophage experiments.

limitations

Cell abundance and expression observations do not alone quantify absolute tissue NAD flux.

nutrient_topic

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

plain_language

More NAD-consuming immune cells can change a tissue metabolite pool.

primary_references

CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels. · 2020 · https://pubmed.ncbi.nlm.nih.gov/33199925/ · DOI 10.1038/s42255-020-00298-z

NAD+: compartmental supply, consumption and cross-nutrient mechanisms (2026-09-19) · lines 100–106

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Young versus aged mice; flow cytometry, histology and macrophage experiments. · source_derived_draft · unverified_draft

## nad-plus-aging-cd38 More NAD-consuming immune cells can change a tissue metabolite pool. Aged mouse liver and white adipose tissue accumulated CD38-positive immune cells, including macrophages/monocytes, with increased expression per cell in several comparisons. Model: Young versus aged mice; flow cytometry, histology and macrophage experiments. Limitations: Cell abundance and expression observations do not alone quantify absolute tissue NAD flux. Evidence access: Primary full text CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels. · 2020 · https://pubmed.ncbi.nlm.nih.gov/33199925/ · DOI 10.1038/s42255-020-00298-z

evidence_access

Primary full text

experimental_model

Mouse isotope tracing and mass spectrometry across tissues.

limitations

Tissue-specific animal flux; expression of one enzyme or a static human blood test cannot substitute for this measurement.

nutrient_topic

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

plain_language

A smaller pool does not necessarily mean slower production.

primary_references

NAD+ flux is maintained in aged mice despite lower tissue concentrations. · 2021 · https://pubmed.ncbi.nlm.nih.gov/34559996/ · DOI 10.1016/j.cels.2021.09.001

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse isotope tracing and mass spectrometry across tissues. · source_derived_draft · unverified_draft

## nad-plus-aging-flux A smaller pool does not necessarily mean slower production. Isotope tracing found a median tissue NAD+ decrease of about 30% in aged mice while absolute synthesis was maintained in most tissues through faster turnover of the smaller pool. Model: Mouse isotope tracing and mass spectrometry across tissues. Limitations: Tissue-specific animal flux; expression of one enzyme or a static human blood test cannot substitute for this measurement. Evidence access: Primary full text NAD+ flux is maintained in aged mice despite lower tissue concentrations. · 2021 · https://pubmed.ncbi.nlm.nih.gov/34559996/ · DOI 10.1016/j.cels.2021.09.001

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Mammalian cell-culture respiration perturbation and rescue.

limitations

Cell-culture rescue does not establish oral aspartate delivery or therapeutic efficacy in people.

nutrient_topic

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

plain_language

Supplying the missing product can bypass a biosynthetic bottleneck.

primary_references

Supporting Aspartate Biosynthesis Is an Essential Function of Respiration in Proliferating Cells. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26232225/ · DOI 10.1016/j.cell.2015.07.017

trigger_kind

machinery_impairment Imported condition classification; unverified.

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mammalian cell-culture respiration perturbation and rescue. · source_derived_draft · unverified_draft

## nad-plus-aspartate-rescue Supplying the missing product can bypass a biosynthetic bottleneck. Aspartate supplementation rescued proliferation of the tested respiration-deficient cells. Model: Mammalian cell-culture respiration perturbation and rescue. Limitations: Cell-culture rescue does not establish oral aspartate delivery or therapeutic efficacy in people. Evidence access: Primary full text Supporting Aspartate Biosynthesis Is an Essential Function of Respiration in Proliferating Cells. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26232225/ · DOI 10.1016/j.cell.2015.07.017

evidence_access

Primary full text

experimental_model

Calorie-restricted versus control mice.

limitations

Not a universal fasting schedule or demonstrated human lifespan mechanism.

nutrient_topic

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

plain_language

Changing demand can preserve a metabolite without increasing supply.

primary_references

NAD+ flux is maintained in aged mice despite lower tissue concentrations. · 2021 · https://pubmed.ncbi.nlm.nih.gov/34559996/ · DOI 10.1016/j.cels.2021.09.001

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Calorie-restricted versus control mice. · source_derived_draft · unverified_draft

## nad-plus-calorie-restriction-flux Changing demand can preserve a metabolite without increasing supply. Calorie restriction partially mitigated age-associated NAD+ decline by decreasing consumption in the mouse isotope-tracing study. Model: Calorie-restricted versus control mice. Limitations: Not a universal fasting schedule or demonstrated human lifespan mechanism. Evidence access: Primary full text NAD+ flux is maintained in aged mice despite lower tissue concentrations. · 2021 · https://pubmed.ncbi.nlm.nih.gov/34559996/ · DOI 10.1016/j.cels.2021.09.001

evidence_access

Primary full text

experimental_model

Human cancer-cell CRISPR knockout and precursor supplementation.

limitations

Does not identify a universal alternative uptake route or prove intact NAD crossed the plasma membrane.

nutrient_topic

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

plain_language

Cells could still use outside precursor material without CD73.

primary_references

Extracellular NAD+ enhances PARP-dependent DNA repair capacity independently of CD73 activity. · 2020 · https://pubmed.ncbi.nlm.nih.gov/31959836/ · DOI 10.1038/s41598-020-57506-9

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human cancer-cell CRISPR knockout and precursor supplementation. · source_derived_draft · unverified_draft

## nad-plus-cd73-knockout Cells could still use outside precursor material without CD73. CD73 knockout did not prevent human cancer cells from using extracellular NAD+ or NMN to restore intracellular NAD+ under the tested conditions. Model: Human cancer-cell CRISPR knockout and precursor supplementation. Limitations: Does not identify a universal alternative uptake route or prove intact NAD crossed the plasma membrane. Evidence access: Primary full text Extracellular NAD+ enhances PARP-dependent DNA repair capacity independently of CD73 activity. · 2020 · https://pubmed.ncbi.nlm.nih.gov/31959836/ · DOI 10.1038/s41598-020-57506-9

evidence_access

Primary full text

experimental_model

Human recombinant enzyme; biochemical substrate assays.

limitations

Do not erase the earlier cellular result. Preparation, assay sensitivity and indirect cellular effects require reconciliation.

nutrient_topic

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

plain_language

A later direct assay challenged the proposed precursor-processing enzyme.

primary_references

Extracellular NAD+ enhances PARP-dependent DNA repair capacity independently of CD73 activity. · 2020 · https://pubmed.ncbi.nlm.nih.gov/31959836/ · DOI 10.1038/s41598-020-57506-9

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

## nad-plus-cd73-negative A later direct assay challenged the proposed precursor-processing enzyme. Recombinant human CD73 did not process NAD+ and processed NMN poorly in the reported biochemical assays. Model: Human recombinant enzyme; biochemical substrate assays. Limitations: Do not erase the earlier cellular result. Preparation, assay sensitivity and indirect cellular effects require reconciliation. Evidence access: Primary full text Extracellular NAD+ enhances PARP-dependent DNA repair capacity independently of CD73 activity. · 2020 · https://pubmed.ncbi.nlm.nih.gov/31959836/ · DOI 10.1038/s41598-020-57506-9

evidence_access

Primary abstract

experimental_model

Human tumor-cell CD73 overexpression/silencing and FK866 experiments.

limitations

Mechanistic assignment is disputed by the later human recombinant-enzyme and knockout study. Primary abstract accessed here; direct catalytic attribution is retained as reported.

nutrient_topic

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

plain_language

One study found that CD73 helped cells use an outside NAD precursor.

primary_references

CD73 protein as a source of extracellular precursors for sustained NAD+ biosynthesis in FK866-treated tumor cells. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23880765/ · DOI 10.1074/jbc.M113.470435

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human tumor-cell CD73 overexpression/silencing and FK866 experiments. · source_derived_draft · unverified_draft

## nad-plus-cd73-positive One study found that CD73 helped cells use an outside NAD precursor. CD73 silencing or pharmacological inhibition reduced NMN-supported survival after NAMPT inhibition in human tumor cells; the authors assigned CD73 a role in converting extracellular NMN to NR. Model: Human tumor-cell CD73 overexpression/silencing and FK866 experiments. Limitations: Mechanistic assignment is disputed by the later human recombinant-enzyme and knockout study. Primary abstract accessed here; direct catalytic attribution is retained as reported. Evidence access: Primary abstract CD73 protein as a source of extracellular precursors for sustained NAD+ biosynthesis in FK866-treated tumor cells. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23880765/ · DOI 10.1074/jbc.M113.470435

evidence_access

Primary full text

experimental_model

Mouse biochemical, cellular and ecto-CD38 antibody experiments.

limitations

Not established clinical benefit from an over-the-counter CD38 inhibitor.

nutrient_topic

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

plain_language

A precursor can be destroyed before a neighboring cell uses it.

primary_references

CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels. · 2020 · https://pubmed.ncbi.nlm.nih.gov/33199925/ · DOI 10.1038/s42255-020-00298-z

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse biochemical, cellular and ecto-CD38 antibody experiments. · source_derived_draft · unverified_draft

## nad-plus-ecto-cd38-nmn A precursor can be destroyed before a neighboring cell uses it. The study linked extracellular CD38 enzymatic activity to NMN degradation and lower precursor availability; selective blockade of ecto-CD38 increased NAD+ in mouse experiments. Model: Mouse biochemical, cellular and ecto-CD38 antibody experiments. Limitations: Not established clinical benefit from an over-the-counter CD38 inhibitor. Evidence access: Primary full text CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels. · 2020 · https://pubmed.ncbi.nlm.nih.gov/33199925/ · DOI 10.1038/s42255-020-00298-z

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Cultured proliferating mammalian cells with impaired respiration.

limitations

ATP is not generally dispensable; this experiment isolates an electron-acceptor bottleneck in supplied culture conditions.

nutrient_topic

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

plain_language

Respiration supports building material by restoring electron acceptors, as well as producing ATP.

primary_references

Supporting Aspartate Biosynthesis Is an Essential Function of Respiration in Proliferating Cells. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26232225/ · DOI 10.1016/j.cell.2015.07.017

trigger_kind

machinery_impairment Imported condition classification; unverified.

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Cultured proliferating mammalian cells with impaired respiration. · source_derived_draft · unverified_draft

## nad-plus-electron-acceptor-aspartate Respiration supports building material by restoring electron acceptors, as well as producing ATP. Respiration-deficient proliferating cells became limited in aspartate synthesis; alpha-ketobutyrate restored proliferation as an electron acceptor without supplying carbon or ATP. Model: Cultured proliferating mammalian cells with impaired respiration. Limitations: ATP is not generally dispensable; this experiment isolates an electron-acceptor bottleneck in supplied culture conditions. Evidence access: Primary full text Supporting Aspartate Biosynthesis Is an Essential Function of Respiration in Proliferating Cells. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26232225/ · DOI 10.1016/j.cell.2015.07.017

evidence_access

Primary full text

experimental_model

Mouse regulatory T-cell experiments with ART2.2 blockade.

limitations

Mouse pathway; not a demonstrated human IV-NAD mechanism or toxicity threshold.

nutrient_topic

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

plain_language

Outside the cell, NAD can act as a signaling substrate rather than an energy supplement.

primary_references

Extracellular NAD+ shapes the Foxp3+ regulatory T cell compartment through the ART2-P2X7 pathway. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20975043/ · DOI 10.1084/jem.20091154

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse regulatory T-cell experiments with ART2.2 blockade. · source_derived_draft · unverified_draft

## nad-plus-extracellular-art2 Outside the cell, NAD can act as a signaling substrate rather than an energy supplement. Extracellular NAD supported ART2.2-dependent ADP-ribosylation and activation of P2X7 in mouse regulatory T cells. Model: Mouse regulatory T-cell experiments with ART2.2 blockade. Limitations: Mouse pathway; not a demonstrated human IV-NAD mechanism or toxicity threshold. Evidence access: Primary full text Extracellular NAD+ shapes the Foxp3+ regulatory T cell compartment through the ART2-P2X7 pathway. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20975043/ · DOI 10.1084/jem.20091154

evidence_access

Primary full text

experimental_model

Human fibroblast oncogene-induced senescence with genetic perturbations.

limitations

Senescence type matters; replicative and mitochondrial-dysfunction senescence need not share this pattern.

nutrient_topic

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

plain_language

A gene regulator can increase NAD salvage in a cell that is already senescent.

primary_references

NAD+ metabolism governs the proinflammatory senescence-associated secretome. · 2019 · https://pubmed.ncbi.nlm.nih.gov/30778219/ · DOI 10.1038/s41556-019-0287-4

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human fibroblast oncogene-induced senescence with genetic perturbations. · source_derived_draft · unverified_draft

## nad-plus-hmga-nampt A gene regulator can increase NAD salvage in a cell that is already senescent. HMGA1-dependent NAMPT expression contributed to increased NAD metabolism and the proinflammatory secretory phenotype in oncogene-induced senescent human IMR90 fibroblasts. Model: Human fibroblast oncogene-induced senescence with genetic perturbations. Limitations: Senescence type matters; replicative and mitochondrial-dysfunction senescence need not share this pattern. Evidence access: Primary full text NAD+ metabolism governs the proinflammatory senescence-associated secretome. · 2019 · https://pubmed.ncbi.nlm.nih.gov/30778219/ · DOI 10.1038/s41556-019-0287-4

evidence_access

Primary full text

experimental_model

Same 11-person human pilot.

limitations

Not a quantitative map of every tissue uptake route or evidence of rejuvenation.

nutrient_topic

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

plain_language

Some infused material is broken down or excreted.

primary_references

A Pilot Study Investigating Changes in the Human Plasma and Urine NAD+ Metabolome During a 6 Hour Intravenous Infusion of NAD. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31572171/ · DOI 10.3389/fnagi.2019.00257

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Same 11-person human pilot. · source_derived_draft · unverified_draft

## nad-plus-iv-metabolites Some infused material is broken down or excreted. The six-hour NAD+ infusion altered circulating breakdown products and urinary NAD/metabolite excretion, demonstrating substantial handling of administered material. Model: Same 11-person human pilot. Limitations: Not a quantitative map of every tissue uptake route or evidence of rejuvenation. Evidence access: Primary full text A Pilot Study Investigating Changes in the Human Plasma and Urine NAD+ Metabolome During a 6 Hour Intravenous Infusion of NAD. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31572171/ · DOI 10.3389/fnagi.2019.00257

availability_state

biomarker_context Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human pilot; approximately 3 micromoles/minute; serial plasma and urine sampling.

limitations

Small pharmacokinetic study; disappearance from plasma does not prove intact tissue uptake or clinical benefit.

nutrient_topic

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

plain_language

Infusion input and measured blood concentration need not rise together immediately.

primary_references

A Pilot Study Investigating Changes in the Human Plasma and Urine NAD+ Metabolome During a 6 Hour Intravenous Infusion of NAD. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31572171/ · DOI 10.3389/fnagi.2019.00257

trigger_kind

biomarker_context Imported condition classification; unverified.

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human pilot; approximately 3 micromoles/minute; serial plasma and urine sampling. · source_derived_draft · unverified_draft

## nad-plus-iv-plasma Infusion input and measured blood concentration need not rise together immediately. In a randomized pilot with eight NAD+ recipients and three saline controls, 750 mg NAD+ over six hours produced a significant plasma NAD increase at the six-hour endpoint, with no significant early rise during the first two hours. Model: Human pilot; approximately 3 micromoles/minute; serial plasma and urine sampling. Limitations: Small pharmacokinetic study; disappearance from plasma does not prove intact tissue uptake or clinical benefit. Evidence access: Primary full text A Pilot Study Investigating Changes in the Human Plasma and Urine NAD+ Metabolome During a 6 Hour Intravenous Infusion of NAD. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31572171/ · DOI 10.3389/fnagi.2019.00257

evidence_access

Primary full text

experimental_model

Small nonrandomized retrospective clinical series.

limitations

Selection, infusion rate and clinic practices limit causal comparison; not efficacy evidence or an incidence estimate for all users.

nutrient_topic

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

plain_language

Infusion tolerability is a separate question from whether NAD biomarkers rise.

primary_references

Intravenous infusion of nicotinamide adenine dinucleotide (NAD+) versus nicotinamide riboside (NR): a retrospective tolerability pilot study in a real-world setting. · 2026 · https://pubmed.ncbi.nlm.nih.gov/41704678/ · DOI 10.3389/fragi.2026.1652582

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Small nonrandomized retrospective clinical series. · source_derived_draft · unverified_draft

## nad-plus-iv-tolerability Infusion tolerability is a separate question from whether NAD biomarkers rise. A retrospective commercial-clinic series compared six clients receiving 500 mg IV NAD+ with eight receiving 500 mg IV NR over four-day loading protocols; NAD recipients reported gastrointestinal symptoms, chest pressure or elevated heart rate and required longer infusions. Model: Small nonrandomized retrospective clinical series. Limitations: Selection, infusion rate and clinic practices limit causal comparison; not efficacy evidence or an incidence estimate for all users. Evidence access: Primary full text Intravenous infusion of nicotinamide adenine dinucleotide (NAD+) versus nicotinamide riboside (NR): a retrospective tolerability pilot study in a real-world setting. · 2026 · https://pubmed.ncbi.nlm.nih.gov/41704678/ · DOI 10.3389/fragi.2026.1652582

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human cancer-cell pharmacological inhibition and proliferation assay.

limitations

Inhibitor results do not resolve individual LDH isoforms or establish a clinical combination.

nutrient_topic

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

plain_language

Blocking the backup redox route removes its rescue effect.

primary_references

Environment Dictates Dependence on Mitochondrial Complex I for NAD+ and Aspartate Production and Determines Cancer Cell Sensitivity to Metformin. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27746050/ · DOI 10.1016/j.cmet.2016.09.006

trigger_kind

machinery_impairment Imported condition classification; unverified.

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human cancer-cell pharmacological inhibition and proliferation assay. · source_derived_draft · unverified_draft

## nad-plus-ldh-inhibition Blocking the backup redox route removes its rescue effect. The LDH inhibitor GSK2837808A partially inhibited pyruvate-to-lactate conversion and restored metformin sensitivity in pyruvate-containing cancer-cell medium. Model: Human cancer-cell pharmacological inhibition and proliferation assay. Limitations: Inhibitor results do not resolve individual LDH isoforms or establish a clinical combination. Evidence access: Primary full text Environment Dictates Dependence on Mitochondrial Complex I for NAD+ and Aspartate Production and Determines Cancer Cell Sensitivity to Metformin. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27746050/ · DOI 10.1016/j.cmet.2016.09.006

evidence_access

Primary full text

experimental_model

Mouse circulating/tissue stable-isotope flux measurements.

limitations

Does not imply that all tissues lack de novo synthesis or that liver is the only contributor under every condition.

nutrient_topic

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

plain_language

One organ can help supply another with recycled vitamin material.

primary_references

Quantitative Analysis of NAD Synthesis-Breakdown Fluxes. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29685734/ · DOI 10.1016/j.cmet.2018.03.018

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse circulating/tissue stable-isotope flux measurements. · source_derived_draft · unverified_draft

## nad-plus-liver-nam-export One organ can help supply another with recycled vitamin material. Mouse tracer experiments identified liver conversion of tryptophan to NAD followed by nicotinamide release to support other tissues. Model: Mouse circulating/tissue stable-isotope flux measurements. Limitations: Does not imply that all tissues lack de novo synthesis or that liver is the only contributor under every condition. Evidence access: Primary full text Quantitative Analysis of NAD Synthesis-Breakdown Fluxes. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29685734/ · DOI 10.1016/j.cmet.2018.03.018

evidence_access

Primary full text

experimental_model

Mouse isotope-tracing intervention.

limitations

LPS challenge is not equivalent to every chronic inflammatory condition.

nutrient_topic

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

plain_language

Acute inflammation can impair supply through a different pattern from ordinary aging.

primary_references

NAD+ flux is maintained in aged mice despite lower tissue concentrations. · 2021 · https://pubmed.ncbi.nlm.nih.gov/34559996/ · DOI 10.1016/j.cels.2021.09.001

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

## nad-plus-lps-synthesis Acute inflammation can impair supply through a different pattern from ordinary aging. Acute LPS inflammatory stress reduced NAD+ by impairing synthesis in both young and aged mice. Model: Mouse isotope-tracing intervention. Limitations: LPS challenge is not equivalent to every chronic inflammatory condition. Evidence access: Primary full text NAD+ flux is maintained in aged mice despite lower tissue concentrations. · 2021 · https://pubmed.ncbi.nlm.nih.gov/34559996/ · DOI 10.1016/j.cels.2021.09.001

evidence_access

Primary full text

experimental_model

E. coli PncA genetic experiments, mammalian cancer cells and xenografts.

limitations

PncA is bacterial; do not create a human nicotinamidase from this result.

nutrient_topic

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

plain_language

Microbes can redirect one vitamin form into another route around a blocked enzyme.

primary_references

Bacteria Boost Mammalian Host NAD Metabolism by Engaging the Deamidated Biosynthesis Pathway. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32130883/ · DOI 10.1016/j.cmet.2020.02.001

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · E. coli PncA genetic experiments, mammalian cancer cells and xenografts. · source_derived_draft · unverified_draft

## nad-plus-microbial-deamidation Microbes can redirect one vitamin form into another route around a blocked enzyme. Bacterial PncA converted nicotinamide to nicotinic acid, enabling an alternative deamidated NAD synthesis route in mammalian cells. Model: E. coli PncA genetic experiments, mammalian cancer cells and xenografts. Limitations: PncA is bacterial; do not create a human nicotinamidase from this result. Evidence access: Primary full text Bacteria Boost Mammalian Host NAD Metabolism by Engaging the Deamidated Biosynthesis Pathway. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32130883/ · DOI 10.1016/j.cmet.2020.02.001

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Microbial genetic manipulation plus mammalian cancer models.

limitations

Preclinical resistance mechanism, not guidance to manipulate microbiota during cancer treatment.

nutrient_topic

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

plain_language

An alternative precursor source can defeat a blockade of salvage.

primary_references

Bacteria Boost Mammalian Host NAD Metabolism by Engaging the Deamidated Biosynthesis Pathway. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32130883/ · DOI 10.1016/j.cmet.2020.02.001

trigger_kind

machinery_impairment Imported condition classification; unverified.

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Microbial genetic manipulation plus mammalian cancer models. · source_derived_draft · unverified_draft

## nad-plus-microbial-rescue An alternative precursor source can defeat a blockade of salvage. Removing bacterial PncA abolished, and supplying it enabled, bacterial protection against NAMPT inhibitors in the tested cancer-cell and xenograft systems. Model: Microbial genetic manipulation plus mammalian cancer models. Limitations: Preclinical resistance mechanism, not guidance to manipulate microbiota during cancer treatment. Evidence access: Primary full text Bacteria Boost Mammalian Host NAD Metabolism by Engaging the Deamidated Biosynthesis Pathway. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32130883/ · DOI 10.1016/j.cmet.2020.02.001

evidence_access

Primary full text

experimental_model

Mouse isotope tracing and microbiota-depletion experiments.

limitations

Not a measured human conversion fraction or proof that all formulations use the same route.

nutrient_topic

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

plain_language

An oral precursor may reach tissues through a microbially altered route.

primary_references

Bacteria Boost Mammalian Host NAD Metabolism by Engaging the Deamidated Biosynthesis Pathway. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32130883/ · DOI 10.1016/j.cmet.2020.02.001

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

## nad-plus-microbiota-oral-precursors An oral precursor may reach tissues through a microbially altered route. Stable-isotope tracing and microbiota depletion showed bacterial deamidation contributed substantially to tissue NAD increases after oral nicotinamide or NR in mice. Model: Mouse isotope tracing and microbiota-depletion experiments. Limitations: Not a measured human conversion fraction or proof that all formulations use the same route. Evidence access: Primary full text Bacteria Boost Mammalian Host NAD Metabolism by Engaging the Deamidated Biosynthesis Pathway. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32130883/ · DOI 10.1016/j.cmet.2020.02.001

evidence_access

Primary full text

experimental_model

Human IMR90 fibroblast senescence; NAMPT inhibition and knockdown.

limitations

Not proof that NAD supplementation causes cancer in humans or that all senescent cells respond alike.

nutrient_topic

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

plain_language

Supporting cellular metabolism can also support inflammatory secretion.

primary_references

NAD+ metabolism governs the proinflammatory senescence-associated secretome. · 2019 · https://pubmed.ncbi.nlm.nih.gov/30778219/ · DOI 10.1038/s41556-019-0287-4

NAD+: compartmental supply, consumption and cross-nutrient mechanisms (2026-09-19) · lines 156–162

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human IMR90 fibroblast senescence; NAMPT inhibition and knockdown. · source_derived_draft · unverified_draft

## nad-plus-nampt-sasp Supporting cellular metabolism can also support inflammatory secretion. NAMPT-supported NAD metabolism sustained glycolysis and respiration and promoted a proinflammatory SASP through the AMPK–p53–p38/NF-kappaB regulatory network in the tested senescent cells. Model: Human IMR90 fibroblast senescence; NAMPT inhibition and knockdown. Limitations: Not proof that NAD supplementation causes cancer in humans or that all senescent cells respond alike. Evidence access: Primary full text NAD+ metabolism governs the proinflammatory senescence-associated secretome. · 2019 · https://pubmed.ncbi.nlm.nih.gov/30778219/ · DOI 10.1038/s41556-019-0287-4

evidence_access

Primary full text

experimental_model

Ten-week randomized trial in postmenopausal women with prediabetes; clamp and muscle signaling measurements.

limitations

Small defined population, not proof of longevity, benefit in healthy adults or a proven NAD mediator.

nutrient_topic

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

plain_language

A specific physiological improvement can occur without a measured rise in total muscle NAD.

primary_references

Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33888596/ · DOI 10.1126/science.abe9985

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Ten-week randomized trial in postmenopausal women with prediabetes; clamp and muscle signaling measurements. · source_derived_draft · unverified_draft

## nad-plus-nmn-clamp A specific physiological improvement can occur without a measured rise in total muscle NAD. The same NMN trial increased insulin-stimulated glucose disposal and muscle insulin signaling relative to baseline, while placebo did not; the study did not demonstrate broad improvement in all metabolic endpoints. Model: Ten-week randomized trial in postmenopausal women with prediabetes; clamp and muscle signaling measurements. Limitations: Small defined population, not proof of longevity, benefit in healthy adults or a proven NAD mediator. Evidence access: Primary full text Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33888596/ · DOI 10.1126/science.abe9985

availability_state

biomarker_context Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Randomized double-blind trial; 13 NMN and 12 placebo; biopsies and metabolomics.

limitations

Catabolites suggest turnover but are not isotope-measured flux; total biopsy NAD can miss small subcellular pools.

nutrient_topic

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

plain_language

A blood-cell response did not mean measured muscle NAD rose.

primary_references

Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33888596/ · DOI 10.1126/science.abe9985

trigger_kind

biomarker_context Imported condition classification; unverified.

NAD+: compartmental supply, consumption and cross-nutrient mechanisms (2026-09-19) · lines 332–338

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Randomized double-blind trial; 13 NMN and 12 placebo; biopsies and metabolomics. · source_derived_draft · unverified_draft

## nad-plus-nmn-muscle-versus-blood A blood-cell response did not mean measured muscle NAD rose. In 25 postmenopausal women with prediabetes and overweight/obesity, 250 mg/day NMN for ten weeks increased basal PBMC NAD but did not increase measured muscle NAD; muscle NAD-related catabolites increased. Model: Randomized double-blind trial; 13 NMN and 12 placebo; biopsies and metabolomics. Limitations: Catabolites suggest turnover but are not isotope-measured flux; total biopsy NAD can miss small subcellular pools. Evidence access: Primary full text Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33888596/ · DOI 10.1126/science.abe9985

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Mouse shRNA and enzyme re-expression experiments.

limitations

PARP activity is not a direct measurement of all nuclear NAD-dependent reactions.

nutrient_topic

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

plain_language

DNA-associated enzymes can depend on local NAD production.

primary_references

Metabolic regulation of transcription through compartmentalized NAD+ biosynthesis. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29748257/ · DOI 10.1126/science.aan5780

trigger_kind

machinery_impairment Imported condition classification; unverified.

NAD+: compartmental supply, consumption and cross-nutrient mechanisms (2026-09-19) · lines 60–66

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse shRNA and enzyme re-expression experiments. · source_derived_draft · unverified_draft

## nad-plus-nmnat1-loss DNA-associated enzymes can depend on local NAD production. Nmnat1 knockdown reduced PARP1-mediated PARylation in mouse 3T3-L1 preadipocytes; catalytically active but not inactive NMNAT1 rescued the activity. Model: Mouse shRNA and enzyme re-expression experiments. Limitations: PARP activity is not a direct measurement of all nuclear NAD-dependent reactions. Evidence access: Primary full text Metabolic regulation of transcription through compartmentalized NAD+ biosynthesis. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29748257/ · DOI 10.1126/science.aan5780

evidence_access

Primary full text

experimental_model

Mouse preadipocyte differentiation, enzyme perturbations and compartment measurements.

limitations

Not evidence that human NMN supplements cause weight gain; enzyme location and differentiation state matter.

nutrient_topic

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

plain_language

Two compartments can compete for the same building material.

primary_references

Metabolic regulation of transcription through compartmentalized NAD+ biosynthesis. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29748257/ · DOI 10.1126/science.aan5780

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse preadipocyte differentiation, enzyme perturbations and compartment measurements. · source_derived_draft · unverified_draft

## nad-plus-nmnat2-competition Two compartments can compete for the same building material. Adipogenic induction of cytoplasmic NMNAT2 in mouse 3T3-L1 cells competed with nuclear NMNAT1 for NMN and reduced nuclear NAD+ availability. Model: Mouse preadipocyte differentiation, enzyme perturbations and compartment measurements. Limitations: Not evidence that human NMN supplements cause weight gain; enzyme location and differentiation state matter. Evidence access: Primary full text Metabolic regulation of transcription through compartmentalized NAD+ biosynthesis. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29748257/ · DOI 10.1126/science.aan5780

availability_state

biomarker_context Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Healthy adults aged 45–75; short phase 0/1b trial, NCT07336836, retrospectively registered.

limitations

Primary abstract only. Formulation-specific, no isotope-traced intact uptake, no inference about muscle or brain NAD; exclusions and assay details require full-report appraisal.

nutrient_topic

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

plain_language

A particular oral formulation increased a blood-cell-associated NAD measure.

primary_references

Oral LNAD+ rapidly elevates whole blood intracellular NAD and metabolic flux without elevating plasma NAD: evidence from a randomized controlled trial. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42530810/ · DOI 10.1007/s11357-026-02399-1

trigger_kind

biomarker_context Imported condition classification; unverified.

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Healthy adults aged 45–75; short phase 0/1b trial, NCT07336836, retrospectively registered. · source_derived_draft · unverified_draft

## nad-plus-oral-formulation-blood A particular oral formulation increased a blood-cell-associated NAD measure. A five-day placebo-controlled trial of oral LNAD+ reported whole-blood intracellular NAD 53% higher versus placebo at day six; 60 adults were randomized and 50 entered the primary analysis. Model: Healthy adults aged 45–75; short phase 0/1b trial, NCT07336836, retrospectively registered. Limitations: Primary abstract only. Formulation-specific, no isotope-traced intact uptake, no inference about muscle or brain NAD; exclusions and assay details require full-report appraisal. Evidence access: Primary abstract Oral LNAD+ rapidly elevates whole blood intracellular NAD and metabolic flux without elevating plasma NAD: evidence from a randomized controlled trial. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42530810/ · DOI 10.1007/s11357-026-02399-1

evidence_access

Primary abstract

experimental_model

Same short trial; exploratory secondary outcomes.

limitations

Five days cannot establish long-term safety, longevity or disease prevention. Retrospective registration and industry-affiliated authors remain visible in the reference record.

nutrient_topic

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

plain_language

A large biomarker change did not establish a clinical benefit.

primary_references

Oral LNAD+ rapidly elevates whole blood intracellular NAD and metabolic flux without elevating plasma NAD: evidence from a randomized controlled trial. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42530810/ · DOI 10.1007/s11357-026-02399-1

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Same short trial; exploratory secondary outcomes. · source_derived_draft · unverified_draft

## nad-plus-oral-formulation-clinical-null A large biomarker change did not establish a clinical benefit. No secondary clinical, vital-sign, wellbeing or wearable-derived endpoint survived multiplicity correction in the LNAD+ trial; one mild nausea event occurred in the active arm. Model: Same short trial; exploratory secondary outcomes. Limitations: Five days cannot establish long-term safety, longevity or disease prevention. Retrospective registration and industry-affiliated authors remain visible in the reference record. Evidence access: Primary abstract Oral LNAD+ rapidly elevates whole blood intracellular NAD and metabolic flux without elevating plasma NAD: evidence from a randomized controlled trial. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42530810/ · DOI 10.1007/s11357-026-02399-1

availability_state

biomarker_context Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Same five-day randomized trial; primary analysis n=50.

limitations

Catabolite concentration changes are consistent with metabolism but are not direct quantitative flux measurements or proof of intact uptake.

nutrient_topic

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

plain_language

Blood compartments and breakdown products can move differently.

primary_references

Oral LNAD+ rapidly elevates whole blood intracellular NAD and metabolic flux without elevating plasma NAD: evidence from a randomized controlled trial. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42530810/ · DOI 10.1007/s11357-026-02399-1

trigger_kind

biomarker_context Imported condition classification; unverified.

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Same five-day randomized trial; primary analysis n=50. · source_derived_draft · unverified_draft

## nad-plus-oral-formulation-plasma Blood compartments and breakdown products can move differently. The same LNAD+ trial found unchanged plasma NAD while methyl-nicotinamide and 2PY increased. Model: Same five-day randomized trial; primary analysis n=50. Limitations: Catabolite concentration changes are consistent with metabolism but are not direct quantitative flux measurements or proof of intact uptake. Evidence access: Primary abstract Oral LNAD+ rapidly elevates whole blood intracellular NAD and metabolic flux without elevating plasma NAD: evidence from a randomized controlled trial. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42530810/ · DOI 10.1007/s11357-026-02399-1

evidence_access

Primary full text

experimental_model

Mouse oral versus intravenous isotope-labeled precursor administration.

limitations

This study tests NR/NMN, not intact NAD infusion; it does not establish an optimal human route.

nutrient_topic

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

plain_language

Route of administration changes which molecules tissues encounter.

primary_references

Quantitative Analysis of NAD Synthesis-Breakdown Fluxes. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29685734/ · DOI 10.1016/j.cmet.2018.03.018

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse oral versus intravenous isotope-labeled precursor administration. · source_derived_draft · unverified_draft

## nad-plus-oral-versus-iv-precursors Route of administration changes which molecules tissues encounter. In mouse tracer experiments, oral NR and NMN were largely metabolized to nicotinamide, whereas intravenous administration delivered intact precursors to multiple tissues. Model: Mouse oral versus intravenous isotope-labeled precursor administration. Limitations: This study tests NR/NMN, not intact NAD infusion; it does not establish an optimal human route. Evidence access: Primary full text Quantitative Analysis of NAD Synthesis-Breakdown Fluxes. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29685734/ · DOI 10.1016/j.cmet.2018.03.018

evidence_access

Primary full text

experimental_model

Mouse 3T3-L1 transcription and differentiation experiments.

limitations

Cell differentiation mechanism, not a universal whole-body fat response.

nutrient_topic

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

plain_language

A local NAD change can alter a gene program through protein modification.

primary_references

Metabolic regulation of transcription through compartmentalized NAD+ biosynthesis. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29748257/ · DOI 10.1126/science.aan5780

NAD+: compartmental supply, consumption 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 · Mouse 3T3-L1 transcription and differentiation experiments. · source_derived_draft · unverified_draft

## nad-plus-parp-cebpb A local NAD change can alter a gene program through protein modification. In mouse preadipocytes, PARP1-dependent ADP-ribosylation repressed C/EBP beta adipogenic transcription; reduced nuclear NAD synthesis relieved this repression. Model: Mouse 3T3-L1 transcription and differentiation experiments. Limitations: Cell differentiation mechanism, not a universal whole-body fat response. Evidence access: Primary full text Metabolic regulation of transcription through compartmentalized NAD+ biosynthesis. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29748257/ · DOI 10.1126/science.aan5780

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Cultured human cells; pharmacological PARP inhibition.

limitations

Tiq-A is not a PARP1-specific genetic experiment, and did not prevent eventual depletion in all compartments.

nutrient_topic

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

plain_language

Consumption can determine how quickly a blocked supply becomes a shortage.

primary_references

Biosensor reveals multiple sources for mitochondrial NAD⁺. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27313049/ · DOI 10.1126/science.aad5168

trigger_kind

machinery_impairment Imported condition classification; unverified.

NAD+: compartmental supply, consumption and cross-nutrient mechanisms (2026-09-19) · lines 28–34

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Cultured human cells; pharmacological PARP inhibition. · source_derived_draft · unverified_draft

## nad-plus-parp-depletion-rate Consumption can determine how quickly a blocked supply becomes a shortage. The PARP inhibitor Tiq-A slowed early nuclear/cytoplasmic NAD+ depletion after NAMPT inhibition, with little effect on mitochondrial depletion. Model: Cultured human cells; pharmacological PARP inhibition. Limitations: Tiq-A is not a PARP1-specific genetic experiment, and did not prevent eventual depletion in all compartments. Evidence access: Primary full text Biosensor reveals multiple sources for mitochondrial NAD⁺. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27313049/ · DOI 10.1126/science.aad5168

evidence_access

Primary full text

experimental_model

Cancer-cell culture, complex-I-dependent respiration and nutrient manipulation.

limitations

Experimental concentrations and culture composition matter; not a medication adjustment or claim that metformin has one mechanism in all tissues.

nutrient_topic

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

plain_language

Available nutrients can change the effect of an inhibitor on the same pathway.

primary_references

Environment Dictates Dependence on Mitochondrial Complex I for NAD+ and Aspartate Production and Determines Cancer Cell Sensitivity to Metformin. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27746050/ · DOI 10.1016/j.cmet.2016.09.006

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Cancer-cell culture, complex-I-dependent respiration and nutrient manipulation. · source_derived_draft · unverified_draft

## nad-plus-pyruvate-metformin Available nutrients can change the effect of an inhibitor on the same pathway. Pyruvate supplied an alternative electron-acceptor route for NAD+ regeneration and aspartate synthesis, reducing the antiproliferative effect of metformin in the tested cancer cells. Model: Cancer-cell culture, complex-I-dependent respiration and nutrient manipulation. Limitations: Experimental concentrations and culture composition matter; not a medication adjustment or claim that metformin has one mechanism in all tissues. Evidence access: Primary full text Environment Dictates Dependence on Mitochondrial Complex I for NAD+ and Aspartate Production and Determines Cancer Cell Sensitivity to Metformin. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27746050/ · DOI 10.1016/j.cmet.2016.09.006

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human MCF-7 cells, NAMPT inhibitor, genotoxins and CometChip/PAR assays.

limitations

Genotoxin and endpoint dependent; not proof that raising NAD prevents human cancer.

nutrient_topic

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

plain_language

When salvage is blocked, repair enzymes can lose access to their substrate.

primary_references

Extracellular NAD+ enhances PARP-dependent DNA repair capacity independently of CD73 activity. · 2020 · https://pubmed.ncbi.nlm.nih.gov/31959836/ · DOI 10.1038/s41598-020-57506-9

trigger_kind

machinery_impairment Imported condition classification; unverified.

NAD+: compartmental supply, consumption 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 MCF-7 cells, NAMPT inhibitor, genotoxins and CometChip/PAR assays. · source_derived_draft · unverified_draft

## nad-plus-repair-depletion When salvage is blocked, repair enzymes can lose access to their substrate. FK866-mediated NAD depletion impaired DNA repair and damage-induced PARylation in the tested human cancer-cell experiments. Model: Human MCF-7 cells, NAMPT inhibitor, genotoxins and CometChip/PAR assays. Limitations: Genotoxin and endpoint dependent; not proof that raising NAD prevents human cancer. Evidence access: Primary full text Extracellular NAD+ enhances PARP-dependent DNA repair capacity independently of CD73 activity. · 2020 · https://pubmed.ncbi.nlm.nih.gov/31959836/ · DOI 10.1038/s41598-020-57506-9

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Cultured human-cell biosensor experiments.

limitations

Drug-induced loss does not define dietary niacin deficiency or establish equivalent depletion in every tissue.

nutrient_topic

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

plain_language

Blocking recycling empties NAD pools at different speeds.

primary_references

Biosensor reveals multiple sources for mitochondrial NAD⁺. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27313049/ · DOI 10.1126/science.aad5168

trigger_kind

machinery_impairment Imported condition classification; unverified.

NAD+: compartmental supply, consumption and cross-nutrient mechanisms (2026-09-19) · lines 20–26

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

## nad-plus-salvage-depletion Blocking recycling empties NAD pools at different speeds. FK866 inhibition of NAMPT depleted nuclear and cytoplasmic free NAD+ with approximate two-hour half-times, versus approximately eight hours in mitochondria; 16 hours reduced free NAD+ by over 85% in all three compartments. Model: Cultured human-cell biosensor experiments. Limitations: Drug-induced loss does not define dietary niacin deficiency or establish equivalent depletion in every tissue. Evidence access: Primary full text Biosensor reveals multiple sources for mitochondrial NAD⁺. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27313049/ · DOI 10.1126/science.aad5168

evidence_access

Primary full text

experimental_model

Drosophila-domain ITC and structural experiments.

limitations

The binding affinity is for a fly domain, not a full-length human protein or a human toxicity threshold.

nutrient_topic

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

plain_language

The activating precursor has a directly measured binding site.

primary_references

SARM1 is a metabolic sensor activated by an increased NMN/NAD+ ratio to trigger axon degeneration. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33657413/ · DOI 10.1016/j.neuron.2021.02.009

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Drosophila-domain ITC and structural experiments. · source_derived_draft · unverified_draft

## nad-plus-sarm-nmn-binding The activating precursor has a directly measured binding site. NMN bound the purified Drosophila SARM1 ARM domain at approximately 6.39 micromolar dissociation constant, with one ligand per domain. Model: Drosophila-domain ITC and structural experiments. Limitations: The binding affinity is for a fly domain, not a full-length human protein or a human toxicity threshold. Evidence access: Primary full text SARM1 is a metabolic sensor activated by an increased NMN/NAD+ ratio to trigger axon degeneration. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33657413/ · DOI 10.1016/j.neuron.2021.02.009

evidence_access

Primary full text

experimental_model

Purified human construct; NMR activity assays and cell experiments.

limitations

NAD+ is also the catalytic substrate, so activity cannot be inferred from ratio alone across all conditions. This does not show oral NMN causes nerve injury.

nutrient_topic

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

plain_language

The balance between a precursor and finished NAD can activate a destructive feedback loop.

primary_references

SARM1 is a metabolic sensor activated by an increased NMN/NAD+ ratio to trigger axon degeneration. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33657413/ · DOI 10.1016/j.neuron.2021.02.009

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

## nad-plus-sarm-ratio The balance between a precursor and finished NAD can activate a destructive feedback loop. Increasing NMN relative to NAD+ increased NADase activity of purified human SARM1 residues 28–724, which retain ARM, SAM and TIR domains but lack the mitochondrial targeting sequence. Model: Purified human construct; NMR activity assays and cell experiments. Limitations: NAD+ is also the catalytic substrate, so activity cannot be inferred from ratio alone across all conditions. This does not show oral NMN causes nerve injury. Evidence access: Primary full text SARM1 is a metabolic sensor activated by an increased NMN/NAD+ ratio to trigger axon degeneration. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33657413/ · DOI 10.1016/j.neuron.2021.02.009

evidence_access

Primary full text

experimental_model

Senescent-cell conditioned media and mouse interventions.

limitations

Partial rescue supports a contributing mechanism, not a single cause of every age-associated NAD decline.

nutrient_topic

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

plain_language

Signals from one cell population can change NAD availability in another.

primary_references

CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels. · 2020 · https://pubmed.ncbi.nlm.nih.gov/33199925/ · DOI 10.1038/s42255-020-00298-z

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Senescent-cell conditioned media and mouse interventions. · source_derived_draft · unverified_draft

## nad-plus-sasp-cd38 Signals from one cell population can change NAD availability in another. Senescent-cell-associated inflammatory signals promoted CD38 expression; reducing senescent-cell burden partially restored NAD+ in the reported mouse experiments. Model: Senescent-cell conditioned media and mouse interventions. Limitations: Partial rescue supports a contributing mechanism, not a single cause of every age-associated NAD decline. Evidence access: Primary full text CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels. · 2020 · https://pubmed.ncbi.nlm.nih.gov/33199925/ · DOI 10.1038/s42255-020-00298-z

evidence_access

Primary full text

experimental_model

Human cells; medium comparison, NMR precursor stability and six- versus 24-hour exposure.

limitations

Serum components are not individually identified by this result; do not assign the effect to human CD73 or infer direct uptake.

nutrient_topic

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

plain_language

The material outside a cell can determine whether an added precursor works.

primary_references

Extracellular NAD+ enhances PARP-dependent DNA repair capacity independently of CD73 activity. · 2020 · https://pubmed.ncbi.nlm.nih.gov/31959836/ · DOI 10.1038/s41598-020-57506-9

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human cells; medium comparison, NMR precursor stability and six- versus 24-hour exposure. · source_derived_draft · unverified_draft

## nad-plus-serum-processing The material outside a cell can determine whether an added precursor works. NAD+ restored XRCC1 recruitment in NAD-depleted MCF-7 cells more readily in fetal-bovine-serum-containing medium than serum-free or heat-inactivated-serum conditions; precursor metabolism and rescue also depended on incubation time. Model: Human cells; medium comparison, NMR precursor stability and six- versus 24-hour exposure. Limitations: Serum components are not individually identified by this result; do not assign the effect to human CD73 or infer direct uptake. Evidence access: Primary full text Extracellular NAD+ enhances PARP-dependent DNA repair capacity independently of CD73 activity. · 2020 · https://pubmed.ncbi.nlm.nih.gov/31959836/ · DOI 10.1038/s41598-020-57506-9

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human cultured-cell knockout, metabolomics and isolated-mitochondrial assays.

limitations

Cellular transporter disruption, not proof that oral NAD crosses all membranes or treats a transporter disorder.

nutrient_topic

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

plain_language

A functioning NAD supply outside mitochondria cannot compensate for a broken mitochondrial entry route.

primary_references

MCART1/SLC25A51 is required for mitochondrial NAD transport. · 2020 · https://pubmed.ncbi.nlm.nih.gov/33087354/ · DOI 10.1126/sciadv.abe5310

trigger_kind

machinery_impairment Imported condition classification; unverified.

NAD+: compartmental supply, consumption and cross-nutrient mechanisms (2026-09-19) · lines 36–42

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human cultured-cell knockout, metabolomics and isolated-mitochondrial assays. · source_derived_draft · unverified_draft

## nad-plus-slc51-respiration A functioning NAD supply outside mitochondria cannot compensate for a broken mitochondrial entry route. MCART1/SLC25A51-null human cells had reduced mitochondrial NAD+/NADH, TCA-cycle flux, respiration and complex-I activity. Model: Human cultured-cell knockout, metabolomics and isolated-mitochondrial assays. Limitations: Cellular transporter disruption, not proof that oral NAD crosses all membranes or treats a transporter disorder. Evidence access: Primary full text MCART1/SLC25A51 is required for mitochondrial NAD transport. · 2020 · https://pubmed.ncbi.nlm.nih.gov/33087354/ · DOI 10.1126/sciadv.abe5310

evidence_access

Primary full text

experimental_model

Human-cell overexpression and yeast complementation.

limitations

Overexpression does not establish normal tissue contribution, redundancy or human treatment efficacy.

nutrient_topic

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

plain_language

A related transporter can support mitochondrial NAD availability in experimental systems.

primary_references

SLC25A51 is a mammalian mitochondrial NAD+ transporter. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32906142/ · DOI 10.1038/s41586-020-2741-7

NAD+: compartmental supply, consumption and cross-nutrient mechanisms (2026-09-19) · lines 44–50

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human-cell overexpression and yeast complementation. · source_derived_draft · unverified_draft

## nad-plus-slc52-expression A related transporter can support mitochondrial NAD availability in experimental systems. Overexpression of human SLC25A52 increased mitochondrial NAD+ in cultured human cells and complemented yeast lacking endogenous mitochondrial NAD transporters. Model: Human-cell overexpression and yeast complementation. Limitations: Overexpression does not establish normal tissue contribution, redundancy or human treatment efficacy. Evidence access: Primary full text SLC25A51 is a mammalian mitochondrial NAD+ transporter. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32906142/ · DOI 10.1038/s41586-020-2741-7

evidence_access

Primary full text

experimental_model

Mouse in-vitro and in-vivo NAD intervention.

limitations

Species and exposure dependent; cannot be directly assigned to human regulatory T cells.

nutrient_topic

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

plain_language

A receptor-linked extracellular reaction can determine which immune cells survive.

primary_references

Extracellular NAD+ shapes the Foxp3+ regulatory T cell compartment through the ART2-P2X7 pathway. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20975043/ · DOI 10.1084/jem.20091154

NAD+: compartmental supply, consumption and cross-nutrient mechanisms (2026-09-19) · lines 276–282

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse in-vitro and in-vivo NAD intervention. · source_derived_draft · unverified_draft

## nad-plus-treg-death A receptor-linked extracellular reaction can determine which immune cells survive. NAD administration depleted mouse regulatory T cells through the ART2.2/P2X7 pathway; ART2.2-blocking antibody protected against the effect. Model: Mouse in-vitro and in-vivo NAD intervention. Limitations: Species and exposure dependent; cannot be directly assigned to human regulatory T cells. Evidence access: Primary full text Extracellular NAD+ shapes the Foxp3+ regulatory T cell compartment through the ART2-P2X7 pathway. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20975043/ · DOI 10.1084/jem.20091154

evidence_access

Primary abstract

experimental_model

Human cDNA/genomic analysis; exon-6 splice-site loss in all 23 genotyped individuals.

limitations

Do not transfer intact mouse Tdh-dependent glycine and acetyl-CoA synthesis to humans.

nutrient_topic

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

plain_language

An expressed gene is not necessarily a functioning metabolic route.

primary_references

The human L-threonine 3-dehydrogenase gene is an expressed pseudogene. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12361482/ · DOI 10.1186/1471-2156-3-18

L-Threonine: translation, intestinal barrier, metabolism and cross-nutrient mechanisms (2026-09-19) · lines 274–280

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human cDNA/genomic analysis; exon-6 splice-site loss in all 23 genotyped individuals. · source_derived_draft · unverified_draft

## l-threonine-human-tdh-boundary An expressed gene is not necessarily a functioning metabolic route. Human TDH transcripts encode truncated proteins because of splice-site disruption and a premature stop codon; the gene was classified as an expressed pseudogene. Model: Human cDNA/genomic analysis; exon-6 splice-site loss in all 23 genotyped individuals. Limitations: Do not transfer intact mouse Tdh-dependent glycine and acetyl-CoA synthesis to humans. Evidence access: Primary abstract The human L-threonine 3-dehydrogenase gene is an expressed pseudogene. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12361482/ · DOI 10.1186/1471-2156-3-18

evidence_access

Primary abstract

experimental_model

Mouse embryonic stem-cell metabolism and amino-acid withdrawal experiments.

limitations

Canonical human TDH is nonfunctional; this route is explicitly mouse-specific.

nutrient_topic

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

plain_language

A specialized mouse cell uses threonine as both carbon and one-carbon support.

primary_references

Dependence of mouse embryonic stem cells on threonine catabolism. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19589965/ · DOI 10.1126/science.1173288

L-Threonine: translation, intestinal barrier, metabolism and cross-nutrient mechanisms (2026-09-19) · lines 322–328

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse embryonic stem-cell metabolism and amino-acid withdrawal experiments. · source_derived_draft · unverified_draft

## l-threonine-mouse-tdh-flux A specialized mouse cell uses threonine as both carbon and one-carbon support. Mouse embryonic stem cells expressed abundant Tdh and used mitochondrial threonine catabolism to support glycine and acetyl-CoA generation. Model: Mouse embryonic stem-cell metabolism and amino-acid withdrawal experiments. Limitations: Canonical human TDH is nonfunctional; this route is explicitly mouse-specific. Evidence access: Primary abstract Dependence of mouse embryonic stem cells on threonine catabolism. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19589965/ · DOI 10.1126/science.1173288

cross_nutrient

true

evidence_span

{"source_cache": "artifacts/niacin-consumption-sources/cd381993.abstract.txt", "locator": "Indexed abstract", "start_char": 0, "end_char": 540, "file_sha256": "e8ba405a5300f922bcf34c358d95735b86637331f4cf15a009ac5bf8df93f1e5", "text_sha256": "e8ba405a5300f922bcf34c358d95735b86637331f4cf15a009ac5bf8df93f1e5"}

experimental_model

Human CD38 expression in monkey COS1 cells with sea-urchin microsome bioassay

exposure

CD38 cDNA transfection; NAD+ extracellular substrate

limitations

This mixed-species bioassay does not demonstrate intracellular trafficking of extracellular cADPR or calcium regulation after oral niacin.

nutrient_topic

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

organism

Human protein; African green monkey cells; sea urchin microsomes

plain_language

A CD38-generated messenger mobilized calcium in an egg-microsome bioassay.

primary_references

[b3-cons-cd381993] Human lymphocyte antigen CD38 catalyzes the production of cyclic ADP-ribose. (1993). https://pubmed.ncbi.nlm.nih.gov/8253202/ DOI: 10.1016/0014-5793(93)80735-d

tissue_or_cell_type

COS1 kidney-cell culture; sea-urchin egg microsomes

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 607–619

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human CD38 expression in monkey COS1 cells with sea-urchin microsome bioassay · source_derived_draft · unverified_draft

### b3-cons-cadpr-store-calcium Extracellular cyclic ADP-ribose generated by human CD38-expressing COS1 cells was detected by calcium release from sea-urchin egg microsomes. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: A CD38-generated messenger mobilized calcium in an egg-microsome bioassay. organism: Human protein; African green monkey cells; sea urchin microsomes tissue_or_cell_type: COS1 kidney-cell culture; sea-urchin egg microsomes experimental_model: Human CD38 expression in monkey COS1 cells with sea-urchin microsome bioassay limitations: This mixed-species bioassay does not demonstrate intracellular trafficking of extracellular cADPR or calcium regulation after oral niacin. exposure: CD38 cDNA transfection; NAD+ extracellular substrate cross_nutrient: true evidence_span: {"source_cache": "artifacts/niacin-consumption-sources/cd381993.abstract.txt", "locator": "Indexed abstract", "start_char": 0, "end_char": 540, "file_sha256": "e8ba405a5300f922bcf34c358d95735b86637331f4cf15a009ac5bf8df93f1e5", "text_sha256": "e8ba405a5300f922bcf34c358d95735b86637331f4cf15a009ac5bf8df93f1e5"} [b3-cons-cd381993] Human lymphocyte antigen CD38 catalyzes the production of cyclic ADP-ribose. (1993). https://pubmed.ncbi.nlm.nih.gov/8253202/ DOI: 10.1016/0014-5793(93)80735-d

cross_nutrient

false

evidence_span

{"source_cache": "artifacts/niacin-consumption-sources/cd381998.abstract.txt", "locator": "Indexed abstract", "start_char": 0, "end_char": 1755, "file_sha256": "39f90bb382ddfee34e808fc93c5a1afafc1d9638a9dc73f2770e815827b4f2ad", "text_sha256": "39f90bb382ddfee34e808fc93c5a1afafc1d9638a9dc73f2770e815827b4f2ad"}

experimental_model

Biochemical characterization of human CD38

exposure

NAD+ as substrate

limitations

Primary human enzyme study; source abstract used. Product proportions are assay-specific and do not establish tissue flux or supplementation outcomes.

nutrient_topic

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

organism

Human

plain_language

Some CD38 cleavage produces the cyclic calcium messenger.

primary_references

[b3-cons-cd381998] Human CD38 is an authentic NAD(P)+ glycohydrolase. (1998). https://pubmed.ncbi.nlm.nih.gov/9494110/ DOI: 10.1042/bj3301383

tissue_or_cell_type

Cell-free enzyme preparation

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 579–591

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Biochemical characterization of human CD38 · source_derived_draft · unverified_draft

### b3-cons-cd38-cyclization Human CD38 produces cyclic ADP-ribose as a low-efficiency branch of NAD+ cleavage. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Some CD38 cleavage produces the cyclic calcium messenger. organism: Human tissue_or_cell_type: Cell-free enzyme preparation experimental_model: Biochemical characterization of human CD38 limitations: Primary human enzyme study; source abstract used. Product proportions are assay-specific and do not establish tissue flux or supplementation outcomes. exposure: NAD+ as substrate cross_nutrient: false evidence_span: {"source_cache": "artifacts/niacin-consumption-sources/cd381998.abstract.txt", "locator": "Indexed abstract", "start_char": 0, "end_char": 1755, "file_sha256": "39f90bb382ddfee34e808fc93c5a1afafc1d9638a9dc73f2770e815827b4f2ad", "text_sha256": "39f90bb382ddfee34e808fc93c5a1afafc1d9638a9dc73f2770e815827b4f2ad"} [b3-cons-cd381998] Human CD38 is an authentic NAD(P)+ glycohydrolase. (1998). https://pubmed.ncbi.nlm.nih.gov/9494110/ DOI: 10.1042/bj3301383

cross_nutrient

false

evidence_span

{"source_cache": "artifacts/niacin-consumption-sources/sarm2017.txt", "locator": "Full text, normalized paragraph 25", "start_char": 16947, "end_char": 18260, "file_sha256": "fc30de231911f5c30425173d684495e62c725ba27c78d44592e6bc68433ef545", "text_sha256": "bf110010a793c4d1d3c263db9f213aa5d539bcf1501265fe30fb1ab9ed4028fa"}

experimental_model

Purified domain dose-response assay

exposure

Nicotinamide titration; starting NAD+ about 5 micromolar

limitations

Purified engineered TIR fragment rather than basal activity of intact full-length SARM1; no dietary dose inference. IC50 depends on assay conditions and is not a therapeutic plasma target.

nutrient_topic

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

organism

Human

plain_language

A product of NAD cleavage fed back to inhibit the isolated SARM1 domain.

primary_references

[b3-cons-sarm2017] The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD+ Cleavage Activity that Promotes Pathological Axonal Degeneration. (2017). https://pubmed.ncbi.nlm.nih.gov/28334607/ DOI: 10.1016/j.neuron.2017.02.022

tissue_or_cell_type

Cell-free preparation

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 705–717

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

### b3-cons-nicotinamide-sarm-inhibition Nicotinamide inhibited purified human SARM1 TIR NADase activity, with an assay IC50 of 43.8 micromolar. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: A product of NAD cleavage fed back to inhibit the isolated SARM1 domain. organism: Human tissue_or_cell_type: Cell-free preparation experimental_model: Purified domain dose-response assay limitations: Purified engineered TIR fragment rather than basal activity of intact full-length SARM1; no dietary dose inference. IC50 depends on assay conditions and is not a therapeutic plasma target. exposure: Nicotinamide titration; starting NAD+ about 5 micromolar cross_nutrient: false evidence_span: {"source_cache": "artifacts/niacin-consumption-sources/sarm2017.txt", "locator": "Full text, normalized paragraph 25", "start_char": 16947, "end_char": 18260, "file_sha256": "fc30de231911f5c30425173d684495e62c725ba27c78d44592e6bc68433ef545", "text_sha256": "bf110010a793c4d1d3c263db9f213aa5d539bcf1501265fe30fb1ab9ed4028fa"} [b3-cons-sarm2017] The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD+ Cleavage Activity that Promotes Pathological Axonal Degeneration. (2017). https://pubmed.ncbi.nlm.nih.gov/28334607/ DOI: 10.1016/j.neuron.2017.02.022

cross_nutrient

false

evidence_span

{"source_cache": "artifacts/niacin-consumption-sources/parp2017.txt", "locator": "Full text, normalized paragraph 33", "start_char": 8991, "end_char": 10338, "file_sha256": "8195abaa884a41856a21fb1d4e7ee376ce80424f11f4625ca4d597a717cef30e", "text_sha256": "ce51127814506d2aa745261fa114922afd3585ee7a97be6fc1cf3914c6609789"}

experimental_model

Recombinant human PARP/HPF1 and histone substrate reconstitution with mass spectrometry

exposure

Activated DNA and NAD+; HPF1 addition

limitations

Direct in vitro modification; protein-bound serine is not a free dietary substrate. No vitamin intake or clinical benefit measured.

nutrient_topic

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

organism

Human

plain_language

PARP1 uses NAD to add ADP-ribose to histone serines when HPF1 is present.

primary_references

[b3-cons-parp2017] Serine ADP-Ribosylation Depends on HPF1. (2017). https://pubmed.ncbi.nlm.nih.gov/28190768/ DOI: 10.1016/j.molcel.2017.01.003

tissue_or_cell_type

Cell-free histone assay

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 635–647

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human PARP/HPF1 and histone substrate reconstitution with mass spectrometry · source_derived_draft · unverified_draft

### b3-cons-parp1-h3-serine PARP1 with HPF1 and NAD+ ADP-ribosylated histone H3 at serines 10 and 28 in reconstituted assays. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: PARP1 uses NAD to add ADP-ribose to histone serines when HPF1 is present. organism: Human tissue_or_cell_type: Cell-free histone assay experimental_model: Recombinant human PARP/HPF1 and histone substrate reconstitution with mass spectrometry limitations: Direct in vitro modification; protein-bound serine is not a free dietary substrate. No vitamin intake or clinical benefit measured. exposure: Activated DNA and NAD+; HPF1 addition cross_nutrient: false evidence_span: {"source_cache": "artifacts/niacin-consumption-sources/parp2017.txt", "locator": "Full text, normalized paragraph 33", "start_char": 8991, "end_char": 10338, "file_sha256": "8195abaa884a41856a21fb1d4e7ee376ce80424f11f4625ca4d597a717cef30e", "text_sha256": "ce51127814506d2aa745261fa114922afd3585ee7a97be6fc1cf3914c6609789"} [b3-cons-parp2017] Serine ADP-Ribosylation Depends on HPF1. (2017). https://pubmed.ncbi.nlm.nih.gov/28190768/ DOI: 10.1016/j.molcel.2017.01.003

cross_nutrient

false

evidence_span

{"source_cache": "artifacts/niacin-consumption-sources/parp2017.txt", "locator": "Full text, normalized paragraph 35", "start_char": 11457, "end_char": 12178, "file_sha256": "8195abaa884a41856a21fb1d4e7ee376ce80424f11f4625ca4d597a717cef30e", "text_sha256": "289a0535244252fc3cffaceacc16ceadfa35b407b293f797cb094f2102746f19"}

experimental_model

Recombinant human PARP/HPF1 and histone substrate reconstitution with mass spectrometry

exposure

Activated DNA and NAD+; HPF1 addition

limitations

Direct in vitro modification; protein-bound serine is not a free dietary substrate. No vitamin intake or clinical benefit measured.

nutrient_topic

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

organism

Human

plain_language

PARP2 can also transfer ADP-ribose to histone serines with HPF1.

primary_references

[b3-cons-parp2017] Serine ADP-Ribosylation Depends on HPF1. (2017). https://pubmed.ncbi.nlm.nih.gov/28190768/ DOI: 10.1016/j.molcel.2017.01.003

tissue_or_cell_type

Cell-free histone assay

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 649–661

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human PARP/HPF1 and histone substrate reconstitution with mass spectrometry · source_derived_draft · unverified_draft

### b3-cons-parp2-histone-serine PARP2 combined with HPF1 supported serine ADP-ribosylation of histones in NAD+-containing reconstitutions. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: PARP2 can also transfer ADP-ribose to histone serines with HPF1. organism: Human tissue_or_cell_type: Cell-free histone assay experimental_model: Recombinant human PARP/HPF1 and histone substrate reconstitution with mass spectrometry limitations: Direct in vitro modification; protein-bound serine is not a free dietary substrate. No vitamin intake or clinical benefit measured. exposure: Activated DNA and NAD+; HPF1 addition cross_nutrient: false evidence_span: {"source_cache": "artifacts/niacin-consumption-sources/parp2017.txt", "locator": "Full text, normalized paragraph 35", "start_char": 11457, "end_char": 12178, "file_sha256": "8195abaa884a41856a21fb1d4e7ee376ce80424f11f4625ca4d597a717cef30e", "text_sha256": "289a0535244252fc3cffaceacc16ceadfa35b407b293f797cb094f2102746f19"} [b3-cons-parp2017] Serine ADP-Ribosylation Depends on HPF1. (2017). https://pubmed.ncbi.nlm.nih.gov/28190768/ DOI: 10.1016/j.molcel.2017.01.003

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

evidence_span

{"source_cache": "artifacts/niacin-consumption-sources/sarm2017.txt", "locator": "Full text, normalized paragraph 29", "start_char": 20432, "end_char": 22775, "file_sha256": "fc30de231911f5c30425173d684495e62c725ba27c78d44592e6bc68433ef545", "text_sha256": "e75c162a4b5f51b7e6ef5e20612ed8ebfbe035a41abf81284cb055dfcf860333"}

experimental_model

Reconstitution of Sarm1-null E13.5 mouse DRG neurons with SARM1 constructs

exposure

Lentiviral transduction on DIV1; axotomy on DIV7

limitations

Human protein was expressed in mouse neurons; injury model, not nutritional depletion or proof of human therapeutic benefit.

nutrient_topic

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

organism

Human construct in mouse neurons

plain_language

The catalytic mutant spared axonal NAD after experimental nerve injury.

primary_references

[b3-cons-sarm2017] The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD+ Cleavage Activity that Promotes Pathological Axonal Degeneration. (2017). https://pubmed.ncbi.nlm.nih.gov/28334607/ DOI: 10.1016/j.neuron.2017.02.022

tissue_or_cell_type

Cultured dorsal-root-ganglion axons

trigger_kind

machinery_impairment Imported condition classification; unverified.

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 733–745

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Reconstitution of Sarm1-null E13.5 mouse DRG neurons with SARM1 constructs · source_derived_draft · unverified_draft

### b3-cons-sarm-axotomy-nad After axotomy of Sarm1-null mouse DRG neurons, re-expression of active human SARM1 restored rapid axonal NAD+ depletion, whereas E642A did not. Condition category: machinery_impairment nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The catalytic mutant spared axonal NAD after experimental nerve injury. organism: Human construct in mouse neurons tissue_or_cell_type: Cultured dorsal-root-ganglion axons experimental_model: Reconstitution of Sarm1-null E13.5 mouse DRG neurons with SARM1 constructs limitations: Human protein was expressed in mouse neurons; injury model, not nutritional depletion or proof of human therapeutic benefit. exposure: Lentiviral transduction on DIV1; axotomy on DIV7 cross_nutrient: false evidence_span: {"source_cache": "artifacts/niacin-consumption-sources/sarm2017.txt", "locator": "Full text, normalized paragraph 29", "start_char": 20432, "end_char": 22775, "file_sha256": "fc30de231911f5c30425173d684495e62c725ba27c78d44592e6bc68433ef545", "text_sha256": "e75c162a4b5f51b7e6ef5e20612ed8ebfbe035a41abf81284cb055dfcf860333"} [b3-cons-sarm2017] The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD+ Cleavage Activity that Promotes Pathological Axonal Degeneration. (2017). https://pubmed.ncbi.nlm.nih.gov/28334607/ DOI: 10.1016/j.neuron.2017.02.022

cross_nutrient

false

evidence_span

{"source_cache": "artifacts/niacin-consumption-sources/sarm2017.txt", "locator": "Full text, normalized paragraph 24", "start_char": 15550, "end_char": 16946, "file_sha256": "fc30de231911f5c30425173d684495e62c725ba27c78d44592e6bc68433ef545", "text_sha256": "9a9b91a772186c34d8b6305a04bbcf6d3acc40b0448e6f478811527c5174981e"}

experimental_model

Purified human SARM1 TIR domain; HPLC and LC-MS/MS

exposure

NAD+ incubation

limitations

Purified engineered TIR fragment rather than basal activity of intact full-length SARM1; no dietary dose inference. Drosophila product ratios differed and are not generalized to humans.

nutrient_topic

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

organism

Human

plain_language

The human SARM1 reaction also makes some cyclic ADP-ribose.

primary_references

[b3-cons-sarm2017] The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD+ Cleavage Activity that Promotes Pathological Axonal Degeneration. (2017). https://pubmed.ncbi.nlm.nih.gov/28334607/ DOI: 10.1016/j.neuron.2017.02.022

tissue_or_cell_type

Cell-free preparation

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 691–703

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human SARM1 TIR domain; HPLC and LC-MS/MS · source_derived_draft · unverified_draft

### b3-cons-sarm-cadpr Human SARM1 TIR-domain NAD+ cleavage also generated cyclic ADP-ribose as a minor product. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The human SARM1 reaction also makes some cyclic ADP-ribose. organism: Human tissue_or_cell_type: Cell-free preparation experimental_model: Purified human SARM1 TIR domain; HPLC and LC-MS/MS limitations: Purified engineered TIR fragment rather than basal activity of intact full-length SARM1; no dietary dose inference. Drosophila product ratios differed and are not generalized to humans. exposure: NAD+ incubation cross_nutrient: false evidence_span: {"source_cache": "artifacts/niacin-consumption-sources/sarm2017.txt", "locator": "Full text, normalized paragraph 24", "start_char": 15550, "end_char": 16946, "file_sha256": "fc30de231911f5c30425173d684495e62c725ba27c78d44592e6bc68433ef545", "text_sha256": "9a9b91a772186c34d8b6305a04bbcf6d3acc40b0448e6f478811527c5174981e"} [b3-cons-sarm2017] The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD+ Cleavage Activity that Promotes Pathological Axonal Degeneration. (2017). https://pubmed.ncbi.nlm.nih.gov/28334607/ DOI: 10.1016/j.neuron.2017.02.022

cross_nutrient

false

evidence_span

{"source_cache": "artifacts/niacin-consumption-sources/sirt22004.abstract.txt", "locator": "Indexed abstract", "start_char": 0, "end_char": 1423, "file_sha256": "a84f7d25c6e518d3317d4b0a41df8d8ac447cd3ef2966815c9818ca63116ef7f", "text_sha256": "a84f7d25c6e518d3317d4b0a41df8d8ac447cd3ef2966815c9818ca63116ef7f"}

experimental_model

Recombinant enzyme and monoacetylated histone H3/H4 peptide assays

exposure

Human SIRT2; yeast Sir2/Hst2 were also studied separately

limitations

Indexed abstract; rapid-kinetic details are not assigned to human SIRT2 individually. No dietary or longevity inference.

nutrient_topic

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

organism

Human

plain_language

SIRT2 consumes NAD while removing acetyl groups from histone peptides.

primary_references

[b3-cons-sirt22004] Substrate specificity and kinetic mechanism of the Sir2 family of NAD+-dependent histone/protein deacetylases. (2004). https://pubmed.ncbi.nlm.nih.gov/15274642/ DOI: 10.1021/bi049592e

tissue_or_cell_type

Cell-free assay

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 551–563

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant enzyme and monoacetylated histone H3/H4 peptide assays · source_derived_draft · unverified_draft

### b3-cons-sirt2-reaction Human SIRT2 deacetylated monoacetylated histone peptides in the NAD-consuming reaction producing nicotinamide and O-acetyl-ADP-ribose. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: SIRT2 consumes NAD while removing acetyl groups from histone peptides. organism: Human tissue_or_cell_type: Cell-free assay experimental_model: Recombinant enzyme and monoacetylated histone H3/H4 peptide assays limitations: Indexed abstract; rapid-kinetic details are not assigned to human SIRT2 individually. No dietary or longevity inference. exposure: Human SIRT2; yeast Sir2/Hst2 were also studied separately cross_nutrient: false evidence_span: {"source_cache": "artifacts/niacin-consumption-sources/sirt22004.abstract.txt", "locator": "Indexed abstract", "start_char": 0, "end_char": 1423, "file_sha256": "a84f7d25c6e518d3317d4b0a41df8d8ac447cd3ef2966815c9818ca63116ef7f", "text_sha256": "a84f7d25c6e518d3317d4b0a41df8d8ac447cd3ef2966815c9818ca63116ef7f"} [b3-cons-sirt22004] Substrate specificity and kinetic mechanism of the Sir2 family of NAD+-dependent histone/protein deacetylases. (2004). https://pubmed.ncbi.nlm.nih.gov/15274642/ DOI: 10.1021/bi049592e

cross_nutrient

Mg-ATP supplies the phosphate donor for generating niacin-derived NADP+. NADP+ production is distinct from its later reduction to NADPH.

evidence_span

{"source_cache": "artifacts/niacin-redox-sources/nadk-human-2025.fulltext.txt", "locator": "Results", "start_char": 53525, "end_char": 54577, "file_sha256": "72c7b9625e1bf4137d6833adac6ae49fc108f2cd75bb4945c5b04d72a0355f9b", "text_sha256": "db49fc47ad605562e1c1cf93e1b39596505906831ae509e7ec0031485f84ba4f"}

experimental_model

Full-length recombinant human NADK; G6PD-coupled assay

exposure

5 mM MgATP; 0.1–2 mM NAD+; 1 mM additional MgCl2; 30°C

limitations

Scoped experimental observation; no dietary niacin or magnesium deficiency threshold or treatment benefit was tested.

nutrient_topic

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

organism

Homo sapiens

plain_language

The cytosolic kinase makes the phosphorylated cofactor using magnesium-associated ATP.

primary_references

[nadk-human-2025] Cryo-EM structure and regulation of human NAD kinase. (2025). https://pubmed.ncbi.nlm.nih.gov/39854463/ DOI: 10.1126/sciadv.ads2664

tissue_or_cell_type

Purified enzyme

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 831–843

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Full-length recombinant human NADK; G6PD-coupled assay · source_derived_draft · unverified_draft

### b3-redox-nadk-mgatp Purified full-length human NADK catalyzed NADP+ production from NAD+ in a coupled assay supplied with 5 mM MgATP. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The cytosolic kinase makes the phosphorylated cofactor using magnesium-associated ATP. organism: Homo sapiens tissue_or_cell_type: Purified enzyme experimental_model: Full-length recombinant human NADK; G6PD-coupled assay limitations: Scoped experimental observation; no dietary niacin or magnesium deficiency threshold or treatment benefit was tested. exposure: 5 mM MgATP; 0.1–2 mM NAD+; 1 mM additional MgCl2; 30°C cross_nutrient: Mg-ATP supplies the phosphate donor for generating niacin-derived NADP+. NADP+ production is distinct from its later reduction to NADPH. evidence_span: {"source_cache": "artifacts/niacin-redox-sources/nadk-human-2025.fulltext.txt", "locator": "Results", "start_char": 53525, "end_char": 54577, "file_sha256": "72c7b9625e1bf4137d6833adac6ae49fc108f2cd75bb4945c5b04d72a0355f9b", "text_sha256": "db49fc47ad605562e1c1cf93e1b39596505906831ae509e7ec0031485f84ba4f"} [nadk-human-2025] Cryo-EM structure and regulation of human NAD kinase. (2025). https://pubmed.ncbi.nlm.nih.gov/39854463/ DOI: 10.1126/sciadv.ads2664

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/niacin-redox-sources/nadk2-2012.fulltext.txt", "locator": "Results", "start_char": 16830, "end_char": 18219, "file_sha256": "65209c0b4ea7220bc95afdd182e40910f2445345172956e85552d5c6db649648", "text_sha256": "5de49f80d76c73b6a308096c07b330e8d3d53ee28c6a06f4b2a331e4798b45d7"}

experimental_model

siRNA knockdown

exposure

Three days after siRNA transfection

limitations

Scoped experimental observation; no dietary niacin or magnesium deficiency threshold or treatment benefit was tested.

nutrient_topic

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

organism

Homo sapiens

plain_language

Reducing the kinase reduced the mitochondrial capacity to make NADP+.

primary_references

[nadk2-2012] Identification and characterization of a human mitochondrial NAD kinase. (2012). https://pubmed.ncbi.nlm.nih.gov/23212377/ DOI: 10.1038/ncomms2262

tissue_or_cell_type

HEK293A mitochondrial fraction

trigger_kind

machinery_impairment Imported condition classification; unverified.

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 925–936

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

### b3-redox-nadk2-knockdown-activity NADK2 knockdown reduced measured mitochondrial-fraction NAD kinase activity to 47% of control in HEK293A cells. Condition category: machinery_impairment nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Reducing the kinase reduced the mitochondrial capacity to make NADP+. organism: Homo sapiens tissue_or_cell_type: HEK293A mitochondrial fraction experimental_model: siRNA knockdown limitations: Scoped experimental observation; no dietary niacin or magnesium deficiency threshold or treatment benefit was tested. exposure: Three days after siRNA transfection evidence_span: {"source_cache": "artifacts/niacin-redox-sources/nadk2-2012.fulltext.txt", "locator": "Results", "start_char": 16830, "end_char": 18219, "file_sha256": "65209c0b4ea7220bc95afdd182e40910f2445345172956e85552d5c6db649648", "text_sha256": "5de49f80d76c73b6a308096c07b330e8d3d53ee28c6a06f4b2a331e4798b45d7"} [nadk2-2012] Identification and characterization of a human mitochondrial NAD kinase. (2012). https://pubmed.ncbi.nlm.nih.gov/23212377/ DOI: 10.1038/ncomms2262

evidence_span

{"source_cache": "artifacts/niacin-redox-sources/nadk2-2012.fulltext.txt", "locator": "Results", "start_char": 9582, "end_char": 11594, "file_sha256": "65209c0b4ea7220bc95afdd182e40910f2445345172956e85552d5c6db649648", "text_sha256": "ffd25dd072f6f8f486b11ca632f28acf37e3ef2b0dbd2b20eecf32fce649eaf1"}

experimental_model

Purified NADK2 Δ62

exposure

ATP-dependent NADH versus NAD+ assays

limitations

Relative activity under the reported substrate conditions; not a universal cellular flux ratio.

nutrient_topic

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

organism

Homo sapiens

plain_language

NADK2 could phosphorylate NADH in this assay, but favored NAD+.

primary_references

[nadk2-2012] Identification and characterization of a human mitochondrial NAD kinase. (2012). https://pubmed.ncbi.nlm.nih.gov/23212377/ DOI: 10.1038/ncomms2262

tissue_or_cell_type

Purified enzyme

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 899–910

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified NADK2 Δ62 · source_derived_draft · unverified_draft

### b3-redox-nadk2-nadh-preference The tested NADH kinase activity of purified human NADK2 Δ62 was about 10% of its NAD+ kinase activity. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: NADK2 could phosphorylate NADH in this assay, but favored NAD+. organism: Homo sapiens tissue_or_cell_type: Purified enzyme experimental_model: Purified NADK2 Δ62 limitations: Relative activity under the reported substrate conditions; not a universal cellular flux ratio. exposure: ATP-dependent NADH versus NAD+ assays evidence_span: {"source_cache": "artifacts/niacin-redox-sources/nadk2-2012.fulltext.txt", "locator": "Results", "start_char": 9582, "end_char": 11594, "file_sha256": "65209c0b4ea7220bc95afdd182e40910f2445345172956e85552d5c6db649648", "text_sha256": "ffd25dd072f6f8f486b11ca632f28acf37e3ef2b0dbd2b20eecf32fce649eaf1"} [nadk2-2012] Identification and characterization of a human mitochondrial NAD kinase. (2012). https://pubmed.ncbi.nlm.nih.gov/23212377/ DOI: 10.1038/ncomms2262

cross_nutrient

Magnesium is present with ATP during phosphorylation of the niacin-derived dinucleotide; this assay does not quantify effects of dietary magnesium shortage.

evidence_span

[{"source_cache": "artifacts/niacin-redox-sources/nadk2-2012.fulltext.txt", "locator": "Results", "start_char": 8475, "end_char": 9580, "file_sha256": "65209c0b4ea7220bc95afdd182e40910f2445345172956e85552d5c6db649648", "text_sha256": "c86810a1a5342cd4e7ea126e070f28ed3182d81f17ea76c0fbb3833612c0f529"}, {"source_cache": "artifacts/niacin-redox-sources/nadk2-2012.fulltext.txt", "locator": "Methods, NADK activity assay", "start_char": 26694, "end_char": 28732, "file_sha256": "65209c0b4ea7220bc95afdd182e40910f2445345172956e85552d5c6db649648", "text_sha256": "907b651f0c0aae7a31306bdc42264cdfd22fb0e236e7ab8f37900467b0b0ab72"}]

experimental_model

Purified His-tagged Δ62C5orf33/NADK2

exposure

TLC: 5 mM NAD+, 5 mM ATP, 5 mM MgCl2; 37°C

limitations

Scoped experimental observation; no dietary niacin or magnesium deficiency threshold or treatment benefit was tested.

nutrient_topic

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

organism

Homo sapiens

plain_language

The mitochondrial kinase uses a phosphate-transfer reaction to create NADP+.

primary_references

[nadk2-2012] Identification and characterization of a human mitochondrial NAD kinase. (2012). https://pubmed.ncbi.nlm.nih.gov/23212377/ DOI: 10.1038/ncomms2262

tissue_or_cell_type

Purified protein

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 871–883

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified His-tagged Δ62C5orf33/NADK2 · source_derived_draft · unverified_draft

### b3-redox-nadk2-phosphorylation Purified human NADK2 Δ62 converted NAD+ to NADP+ with ATP in MgCl2-containing reactions; TLC also detected ADP formation. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The mitochondrial kinase uses a phosphate-transfer reaction to create NADP+. organism: Homo sapiens tissue_or_cell_type: Purified protein experimental_model: Purified His-tagged Δ62C5orf33/NADK2 limitations: Scoped experimental observation; no dietary niacin or magnesium deficiency threshold or treatment benefit was tested. exposure: TLC: 5 mM NAD+, 5 mM ATP, 5 mM MgCl2; 37°C cross_nutrient: Magnesium is present with ATP during phosphorylation of the niacin-derived dinucleotide; this assay does not quantify effects of dietary magnesium shortage. evidence_span: [{"source_cache": "artifacts/niacin-redox-sources/nadk2-2012.fulltext.txt", "locator": "Results", "start_char": 8475, "end_char": 9580, "file_sha256": "65209c0b4ea7220bc95afdd182e40910f2445345172956e85552d5c6db649648", "text_sha256": "c86810a1a5342cd4e7ea126e070f28ed3182d81f17ea76c0fbb3833612c0f529"}, {"source_cache": "artifacts/niacin-redox-sources/nadk2-2012.fulltext.txt", "locator": "Methods, NADK activity assay", "start_char": 26694, "end_char": 28732, "file_sha256": "65209c0b4ea7220bc95afdd182e40910f2445345172956e85552d5c6db649648", "text_sha256": "907b651f0c0aae7a31306bdc42264cdfd22fb0e236e7ab8f37900467b0b0ab72"}] [nadk2-2012] Identification and characterization of a human mitochondrial NAD kinase. (2012). https://pubmed.ncbi.nlm.nih.gov/23212377/ DOI: 10.1038/ncomms2262

cross_nutrient

Uses phosphate polymers in a magnesium-containing enzyme assay, not a dietary phosphorus intervention.

evidence_span

{"source_cache": "artifacts/niacin-redox-sources/nadk2-2012.fulltext.txt", "locator": "Results", "start_char": 11596, "end_char": 12294, "file_sha256": "65209c0b4ea7220bc95afdd182e40910f2445345172956e85552d5c6db649648", "text_sha256": "f371b72f3f7104e6b2b1f4f28ec55e04b18b931383b51a3258872db0809a10d9"}

experimental_model

Purified NADK2 Δ62

exposure

Metaphosphate, hexametaphosphate and tetrapolyphosphate tested

limitations

In vitro substrate capacity; physiological flux from polyphosphate in human mitochondria was not established. Monomeric phosphate is not interchangeable with these polymers.

nutrient_topic

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

organism

Homo sapiens

plain_language

The recombinant mitochondrial enzyme accepted some polyphosphate preparations in vitro.

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 885–897

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-polyphosphate Purified human NADK2 Δ62 also supported NADP+ formation using inorganic polyphosphate preparations as phosphate donors. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The recombinant mitochondrial enzyme accepted some polyphosphate preparations in vitro. organism: Homo sapiens tissue_or_cell_type: Purified enzyme experimental_model: Purified NADK2 Δ62 limitations: In vitro substrate capacity; physiological flux from polyphosphate in human mitochondria was not established. Monomeric phosphate is not interchangeable with these polymers. exposure: Metaphosphate, hexametaphosphate and tetrapolyphosphate tested cross_nutrient: Uses phosphate polymers in a magnesium-containing enzyme assay, not a dietary phosphorus intervention. evidence_span: {"source_cache": "artifacts/niacin-redox-sources/nadk2-2012.fulltext.txt", "locator": "Results", "start_char": 11596, "end_char": 12294, "file_sha256": "65209c0b4ea7220bc95afdd182e40910f2445345172956e85552d5c6db649648", "text_sha256": "f371b72f3f7104e6b2b1f4f28ec55e04b18b931383b51a3258872db0809a10d9"} [nadk2-2012] Identification and characterization of a human mitochondrial NAD kinase. (2012). https://pubmed.ncbi.nlm.nih.gov/23212377/ DOI: 10.1038/ncomms2262

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

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/niacin-redox-sources/slc25a51-2020.author.txt", "locator": "Publisher PDF, results; page/figure identified by adjacent text", "start_char": 18765, "end_char": 19491, "file_sha256": "8348dbfda6d16d576bb64301f0c75f1488e90e33c4a72213b69756bed21d047d", "text_sha256": "151d453cb71149ec656b6e82375a1e679d977643e107133d197cac4a5df0f7b9"}

experimental_model

HEK293T knockdown and HAP1 knockout mitochondria with genetic rescue

exposure

1 mM exogenous NAD+; 40-min uptake incubation

limitations

Scoped experimental observation; no dietary niacin or magnesium deficiency threshold or treatment benefit was tested.

nutrient_topic

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

organism

Homo sapiens

plain_language

The transporter restored mitochondrial entry of intact NAD+.

primary_references

[slc25a51-2020] SLC25A51 is a mammalian mitochondrial NAD+ transporter. (2020). https://pubmed.ncbi.nlm.nih.gov/32906142/ DOI: 10.1038/s41586-020-2741-7

tissue_or_cell_type

Isolated mitochondria

trigger_kind

machinery_impairment Imported condition classification; unverified.

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 1029–1040

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · HEK293T knockdown and HAP1 knockout mitochondria with genetic rescue · source_derived_draft · unverified_draft

### b3-redox-slc25a51-import Re-expression of SLC25A51 restored exogenous NAD+ uptake into mitochondria isolated from SLC25A51-deficient cells. Condition category: machinery_impairment nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The transporter restored mitochondrial entry of intact NAD+. organism: Homo sapiens tissue_or_cell_type: Isolated mitochondria experimental_model: HEK293T knockdown and HAP1 knockout mitochondria with genetic rescue limitations: Scoped experimental observation; no dietary niacin or magnesium deficiency threshold or treatment benefit was tested. exposure: 1 mM exogenous NAD+; 40-min uptake incubation evidence_span: {"source_cache": "artifacts/niacin-redox-sources/slc25a51-2020.author.txt", "locator": "Publisher PDF, results; page/figure identified by adjacent text", "start_char": 18765, "end_char": 19491, "file_sha256": "8348dbfda6d16d576bb64301f0c75f1488e90e33c4a72213b69756bed21d047d", "text_sha256": "151d453cb71149ec656b6e82375a1e679d977643e107133d197cac4a5df0f7b9"} [slc25a51-2020] SLC25A51 is a mammalian mitochondrial NAD+ transporter. (2020). https://pubmed.ncbi.nlm.nih.gov/32906142/ DOI: 10.1038/s41586-020-2741-7

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/niacin-redox-sources/slc25a51-2020.author.txt", "locator": "Publisher PDF, results; page/figure identified by adjacent text", "start_char": 6119, "end_char": 6538, "file_sha256": "8348dbfda6d16d576bb64301f0c75f1488e90e33c4a72213b69756bed21d047d", "text_sha256": "024f4688a65e3279f2865ef892f19ed4d5357469c71a5e2e6fb27fe1a2dd4043"}

experimental_model

Multiple shRNA/siRNA perturbations; mitochondrial assays and biosensors

exposure

SLC25A51 RNA interference

limitations

Scoped experimental observation; no dietary niacin or magnesium deficiency threshold or treatment benefit was tested.

nutrient_topic

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

organism

Homo sapiens

plain_language

Cells can lose mitochondrial NAD even when the total-cell pool is maintained.

primary_references

[slc25a51-2020] SLC25A51 is a mammalian mitochondrial NAD+ transporter. (2020). https://pubmed.ncbi.nlm.nih.gov/32906142/ DOI: 10.1038/s41586-020-2741-7

tissue_or_cell_type

Human cultured cells

trigger_kind

machinery_impairment Imported condition classification; unverified.

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 1042–1053

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Multiple shRNA/siRNA perturbations; mitochondrial assays and biosensors · source_derived_draft · unverified_draft

### b3-redox-slc25a51-mito-pool SLC25A51 loss reduced mitochondrial NAD+ availability in the tested human cell models. Condition category: machinery_impairment nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Cells can lose mitochondrial NAD even when the total-cell pool is maintained. organism: Homo sapiens tissue_or_cell_type: Human cultured cells experimental_model: Multiple shRNA/siRNA perturbations; mitochondrial assays and biosensors limitations: Scoped experimental observation; no dietary niacin or magnesium deficiency threshold or treatment benefit was tested. exposure: SLC25A51 RNA interference evidence_span: {"source_cache": "artifacts/niacin-redox-sources/slc25a51-2020.author.txt", "locator": "Publisher PDF, results; page/figure identified by adjacent text", "start_char": 6119, "end_char": 6538, "file_sha256": "8348dbfda6d16d576bb64301f0c75f1488e90e33c4a72213b69756bed21d047d", "text_sha256": "024f4688a65e3279f2865ef892f19ed4d5357469c71a5e2e6fb27fe1a2dd4043"} [slc25a51-2020] SLC25A51 is a mammalian mitochondrial NAD+ transporter. (2020). https://pubmed.ncbi.nlm.nih.gov/32906142/ DOI: 10.1038/s41586-020-2741-7

evidence_span

{"source_cache": "artifacts/niacin-redox-sources/slc25a51-2020.author.txt", "locator": "Publisher PDF, results; page/figure identified by adjacent text", "start_char": 18765, "end_char": 19225, "file_sha256": "8348dbfda6d16d576bb64301f0c75f1488e90e33c4a72213b69756bed21d047d", "text_sha256": "121f48fd5cc272acc24a9ca1610c801423a98e3e44f7851e649c8454750e7fb0"}

experimental_model

Isolated mitochondria substrate comparison

exposure

Exogenous NAD+, nicotinamide or NMN

limitations

Does not imply oral NAM/NMN cannot contribute to mitochondrial NAD after extramitochondrial metabolism; this is an isolated-organelle test.

nutrient_topic

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

organism

Homo sapiens

plain_language

These precursors were not interchangeable with intact NAD in this uptake experiment.

primary_references

[slc25a51-2020] SLC25A51 is a mammalian mitochondrial NAD+ transporter. (2020). https://pubmed.ncbi.nlm.nih.gov/32906142/ DOI: 10.1038/s41586-020-2741-7

tissue_or_cell_type

Isolated human-cell mitochondria

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 1068–1079

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

### b3-redox-slc25a51-nam-nmn-null Unlike NAD+, exogenous nicotinamide or NMN did not replenish matrix NAD+ in the isolated-mitochondrial assay. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: These precursors were not interchangeable with intact NAD in this uptake experiment. organism: Homo sapiens tissue_or_cell_type: Isolated human-cell mitochondria experimental_model: Isolated mitochondria substrate comparison limitations: Does not imply oral NAM/NMN cannot contribute to mitochondrial NAD after extramitochondrial metabolism; this is an isolated-organelle test. exposure: Exogenous NAD+, nicotinamide or NMN evidence_span: {"source_cache": "artifacts/niacin-redox-sources/slc25a51-2020.author.txt", "locator": "Publisher PDF, results; page/figure identified by adjacent text", "start_char": 18765, "end_char": 19225, "file_sha256": "8348dbfda6d16d576bb64301f0c75f1488e90e33c4a72213b69756bed21d047d", "text_sha256": "121f48fd5cc272acc24a9ca1610c801423a98e3e44f7851e649c8454750e7fb0"} [slc25a51-2020] SLC25A51 is a mammalian mitochondrial NAD+ transporter. (2020). https://pubmed.ncbi.nlm.nih.gov/32906142/ DOI: 10.1038/s41586-020-2741-7

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

[{"source_cache": "artifacts/niacin-redox-sources/slc25a51-2020.author.txt", "locator": "Publisher PDF, results; page/figure identified by adjacent text", "start_char": 19922, "end_char": 20160, "file_sha256": "8348dbfda6d16d576bb64301f0c75f1488e90e33c4a72213b69756bed21d047d", "text_sha256": "78e9cfd3c25b8d33b54ac67bebc01314eed3925b3b6a4bdea527d48191da0977"}, {"source_cache": "artifacts/niacin-redox-sources/slc25a51-2020.author.txt", "locator": "Publisher PDF, results; page/figure identified by adjacent text", "start_char": 24477, "end_char": 24725, "file_sha256": "8348dbfda6d16d576bb64301f0c75f1488e90e33c4a72213b69756bed21d047d", "text_sha256": "7125713c87024da0a0f8c1d4442115144c9ff20543fbd39cfc4cfc46de135cad"}]

experimental_model

HeLa siRNA and mitochondrial NAD biosensor

exposure

100 μM NR for 16 h after siRNA transfection three days earlier

limitations

Cultured-cell precursor response; no direct clinical inference or generic claim that every NAD-raising intervention fails.

nutrient_topic

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

organism

Homo sapiens

plain_language

Precursor provision still required functional mitochondrial import in these cells.

primary_references

[slc25a51-2020] SLC25A51 is a mammalian mitochondrial NAD+ transporter. (2020). https://pubmed.ncbi.nlm.nih.gov/32906142/ DOI: 10.1038/s41586-020-2741-7

tissue_or_cell_type

HeLa cells

trigger_kind

machinery_impairment Imported condition classification; unverified.

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 1094–1105

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · HeLa siRNA and mitochondrial NAD biosensor · source_derived_draft · unverified_draft

### b3-redox-slc25a51-nr-dependence Restoration of mitochondrial NAD+ by nicotinamide riboside in the intact-cell biosensor experiment depended on SLC25A51. Condition category: machinery_impairment nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Precursor provision still required functional mitochondrial import in these cells. organism: Homo sapiens tissue_or_cell_type: HeLa cells experimental_model: HeLa siRNA and mitochondrial NAD biosensor limitations: Cultured-cell precursor response; no direct clinical inference or generic claim that every NAD-raising intervention fails. exposure: 100 μM NR for 16 h after siRNA transfection three days earlier evidence_span: [{"source_cache": "artifacts/niacin-redox-sources/slc25a51-2020.author.txt", "locator": "Publisher PDF, results; page/figure identified by adjacent text", "start_char": 19922, "end_char": 20160, "file_sha256": "8348dbfda6d16d576bb64301f0c75f1488e90e33c4a72213b69756bed21d047d", "text_sha256": "78e9cfd3c25b8d33b54ac67bebc01314eed3925b3b6a4bdea527d48191da0977"}, {"source_cache": "artifacts/niacin-redox-sources/slc25a51-2020.author.txt", "locator": "Publisher PDF, results; page/figure identified by adjacent text", "start_char": 24477, "end_char": 24725, "file_sha256": "8348dbfda6d16d576bb64301f0c75f1488e90e33c4a72213b69756bed21d047d", "text_sha256": "7125713c87024da0a0f8c1d4442115144c9ff20543fbd39cfc4cfc46de135cad"}] [slc25a51-2020] SLC25A51 is a mammalian mitochondrial NAD+ transporter. (2020). https://pubmed.ncbi.nlm.nih.gov/32906142/ DOI: 10.1038/s41586-020-2741-7

evidence_span

{"source_cache": "artifacts/niacin-redox-sources/slc25a51-2020.author.txt", "locator": "Publisher PDF, results; page/figure identified by adjacent text", "start_char": 19115, "end_char": 19225, "file_sha256": "8348dbfda6d16d576bb64301f0c75f1488e90e33c4a72213b69756bed21d047d", "text_sha256": "71f08e5c405c67340bfbe5e1d027cebc9c0f37a2e64bdbd4205020f1ee23e005"}

experimental_model

Competition assay with isolated human-cell mitochondria

exposure

Excess precursor alongside NAD+

limitations

Assay-specific negative competition; no assertion that every derivative is excluded from all transporters.

nutrient_topic

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

organism

Homo sapiens

plain_language

The two precursors did not block the measured NAD import route.

primary_references

[slc25a51-2020] SLC25A51 is a mammalian mitochondrial NAD+ transporter. (2020). https://pubmed.ncbi.nlm.nih.gov/32906142/ DOI: 10.1038/s41586-020-2741-7

tissue_or_cell_type

Mitochondria

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 1081–1092

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Competition assay with isolated human-cell mitochondria · source_derived_draft · unverified_draft

### b3-redox-slc25a51-precursor-competition-null Excess NMN or nicotinamide did not compete with NAD+ uptake in the isolated-mitochondrial competition assay. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The two precursors did not block the measured NAD import route. organism: Homo sapiens tissue_or_cell_type: Mitochondria experimental_model: Competition assay with isolated human-cell mitochondria limitations: Assay-specific negative competition; no assertion that every derivative is excluded from all transporters. exposure: Excess precursor alongside NAD+ evidence_span: {"source_cache": "artifacts/niacin-redox-sources/slc25a51-2020.author.txt", "locator": "Publisher PDF, results; page/figure identified by adjacent text", "start_char": 19115, "end_char": 19225, "file_sha256": "8348dbfda6d16d576bb64301f0c75f1488e90e33c4a72213b69756bed21d047d", "text_sha256": "71f08e5c405c67340bfbe5e1d027cebc9c0f37a2e64bdbd4205020f1ee23e005"} [slc25a51-2020] SLC25A51 is a mammalian mitochondrial NAD+ transporter. (2020). https://pubmed.ncbi.nlm.nih.gov/32906142/ DOI: 10.1038/s41586-020-2741-7

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/niacin-redox-sources/slc25a51-2020.author.txt", "locator": "Publisher PDF, results; page/figure identified by adjacent text", "start_char": 6119, "end_char": 6538, "file_sha256": "8348dbfda6d16d576bb64301f0c75f1488e90e33c4a72213b69756bed21d047d", "text_sha256": "024f4688a65e3279f2865ef892f19ed4d5357469c71a5e2e6fb27fe1a2dd4043"}

experimental_model

RNA interference and whole-cell NAD measurements

exposure

SLC25A51 depletion

limitations

Scoped null result; total NAD is not a universal proxy for mitochondrial NAD availability.

nutrient_topic

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

organism

Homo sapiens

plain_language

A total-cell measurement did not reveal the compartment-specific deficit.

primary_references

[slc25a51-2020] SLC25A51 is a mammalian mitochondrial NAD+ transporter. (2020). https://pubmed.ncbi.nlm.nih.gov/32906142/ DOI: 10.1038/s41586-020-2741-7

tissue_or_cell_type

Human cell lines

trigger_kind

machinery_impairment Imported condition classification; unverified.

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 1055–1066

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · RNA interference and whole-cell NAD measurements · source_derived_draft · unverified_draft

### b3-redox-slc25a51-whole-cell-null SLC25A51 loss did not reduce whole-cell NAD+ content in the comparisons that showed mitochondrial depletion. Condition category: machinery_impairment nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: A total-cell measurement did not reveal the compartment-specific deficit. organism: Homo sapiens tissue_or_cell_type: Human cell lines experimental_model: RNA interference and whole-cell NAD measurements limitations: Scoped null result; total NAD is not a universal proxy for mitochondrial NAD availability. exposure: SLC25A51 depletion evidence_span: {"source_cache": "artifacts/niacin-redox-sources/slc25a51-2020.author.txt", "locator": "Publisher PDF, results; page/figure identified by adjacent text", "start_char": 6119, "end_char": 6538, "file_sha256": "8348dbfda6d16d576bb64301f0c75f1488e90e33c4a72213b69756bed21d047d", "text_sha256": "024f4688a65e3279f2865ef892f19ed4d5357469c71a5e2e6fb27fe1a2dd4043"} [slc25a51-2020] SLC25A51 is a mammalian mitochondrial NAD+ transporter. (2020). https://pubmed.ncbi.nlm.nih.gov/32906142/ DOI: 10.1038/s41586-020-2741-7

cross_nutrient

Nicotinamide adenine dinucleotide, oxidized (coenzyme); PBMC NAD+ content (separate_compartment_marker); N1-methylnicotinamide (muscle_metabolite)

evidence_span

{"source_cache": "artifacts/niacin-clinical-sources/yoshino2021.txt", "locator": "Primary full report; exact character range, zero-based and end-exclusive", "file_sha256": "e4999dc5b9d3392d8180280727c424044b35249bb24c999c3bc863cd23e6c856", "start_char": 4842, "end_char": 6119, "text_sha256": "bb73c5ac9d2ac503143ede8627aaa6be34763fdd501bf48a32528a332b89016c"}

experimental_model

Randomized double-blind trial; 25 overweight or obese postmenopausal women with prediabetes completed

exposure

NMN 250 mg/day for 10 weeks; 13 NMN and 12 placebo participants

limitations

Small selected female cohort. Tissue NAD concentration, NAD turnover and clinical outcomes differ. No lifespan or diabetes-prevention endpoint. Positive muscle findings do not establish whole-body or cross-population benefit.

nutrient_topic

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

organism

Homo sapiens

plain_language

More NAD-related activity did not necessarily mean a larger standing NAD pool in muscle.

primary_references

[nia-clin-yoshino2021] Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. (2021). https://pubmed.ncbi.nlm.nih.gov/33888596/ DOI: 10.1126/science.abe9985

tissue_or_cell_type

Skeletal muscle, PBMCs, liver and adipose insulin sensitivity

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 1515–1527

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized double-blind trial; 25 overweight or obese postmenopausal women with prediabetes completed · source_derived_draft · unverified_draft

### nia-clin-nmn-muscle-nad Muscle NAD+ content did not rise after NMN even though PBMC NAD+ and muscle methylated niacin metabolites increased; authors interpreted the latter as consistent with increased turnover. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: More NAD-related activity did not necessarily mean a larger standing NAD pool in muscle. organism: Homo sapiens tissue_or_cell_type: Skeletal muscle, PBMCs, liver and adipose insulin sensitivity experimental_model: Randomized double-blind trial; 25 overweight or obese postmenopausal women with prediabetes completed limitations: Small selected female cohort. Tissue NAD concentration, NAD turnover and clinical outcomes differ. No lifespan or diabetes-prevention endpoint. Positive muscle findings do not establish whole-body or cross-population benefit. exposure: NMN 250 mg/day for 10 weeks; 13 NMN and 12 placebo participants cross_nutrient: Nicotinamide adenine dinucleotide, oxidized (coenzyme); PBMC NAD+ content (separate_compartment_marker); N1-methylnicotinamide (muscle_metabolite) evidence_span: {"source_cache": "artifacts/niacin-clinical-sources/yoshino2021.txt", "locator": "Primary full report; exact character range, zero-based and end-exclusive", "file_sha256": "e4999dc5b9d3392d8180280727c424044b35249bb24c999c3bc863cd23e6c856", "start_char": 4842, "end_char": 6119, "text_sha256": "bb73c5ac9d2ac503143ede8627aaa6be34763fdd501bf48a32528a332b89016c"} [nia-clin-yoshino2021] Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. (2021). https://pubmed.ncbi.nlm.nih.gov/33888596/ DOI: 10.1126/science.abe9985

cross_nutrient

Nicotinamide adenine dinucleotide, oxidized (measured_pool); Oxidized nicotinamide adenine dinucleotide phosphate (separate_measured_pool)

evidence_span

{"source_cache": "artifacts/niacin-clinical-sources/martens2018.txt", "locator": "Primary full report; exact character range, zero-based and end-exclusive", "file_sha256": "6743a5d9ad919ee67fb74af7f173b24bda66943d9c8878d6bc3bb72c80b2c37e", "start_char": 14418, "end_char": 14971, "text_sha256": "412dc909ef2a01bb3f0b5c429c6b594e084262779bbf4e6ad4005f0f1edb8767"}

experimental_model

Randomized double-blind crossover; 30 randomized, 24 healthy adults aged 55–79 completed

exposure

Nicotinamide riboside chloride 500 mg twice daily versus placebo, six weeks each

limitations

Small short trial, no formal washout, directional tests; secondary endpoints adjusted for multiple comparisons. PBMC NAD is not all-tissue NAD or evidence of lifespan extension.

nutrient_topic

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

organism

Homo sapiens

plain_language

NR raised NAD in sampled blood immune cells, while a matching rise in NADP was not established.

primary_references

[nia-clin-martens2018] Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. (2018). https://pubmed.ncbi.nlm.nih.gov/29599478/ DOI: 10.1038/s41467-018-03421-7

tissue_or_cell_type

Peripheral blood mononuclear cells and vascular physiology

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 1459–1471

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized double-blind crossover; 30 randomized, 24 healthy adults aged 55–79 completed · source_derived_draft · unverified_draft

### nia-clin-nr-pbmc Six weeks of NR increased PBMC NAD+ by approximately 60% relative to placebo; the NADP+ increase was not statistically significant. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: NR raised NAD in sampled blood immune cells, while a matching rise in NADP was not established. organism: Homo sapiens tissue_or_cell_type: Peripheral blood mononuclear cells and vascular physiology experimental_model: Randomized double-blind crossover; 30 randomized, 24 healthy adults aged 55–79 completed limitations: Small short trial, no formal washout, directional tests; secondary endpoints adjusted for multiple comparisons. PBMC NAD is not all-tissue NAD or evidence of lifespan extension. exposure: Nicotinamide riboside chloride 500 mg twice daily versus placebo, six weeks each cross_nutrient: Nicotinamide adenine dinucleotide, oxidized (measured_pool); Oxidized nicotinamide adenine dinucleotide phosphate (separate_measured_pool) evidence_span: {"source_cache": "artifacts/niacin-clinical-sources/martens2018.txt", "locator": "Primary full report; exact character range, zero-based and end-exclusive", "file_sha256": "6743a5d9ad919ee67fb74af7f173b24bda66943d9c8878d6bc3bb72c80b2c37e", "start_char": 14418, "end_char": 14971, "text_sha256": "412dc909ef2a01bb3f0b5c429c6b594e084262779bbf4e6ad4005f0f1edb8767"} [nia-clin-martens2018] Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. (2018). https://pubmed.ncbi.nlm.nih.gov/29599478/ DOI: 10.1038/s41467-018-03421-7

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

L-Tryptophan (alternative_precursor); Nicotinamide adenine dinucleotide, oxidized (measured_coenzyme)

evidence_span

{"source_cache": "artifacts/niacin-clinical-sources/fu1989.abstract.txt", "locator": "Indexed primary abstract", "file_sha256": "ca6d94c101aca84f1e41f35898434f44770ca563c5bff986fe52e33f797b0fbc", "start_char": 0, "end_char": 1340, "text_sha256": "ca6d94c101aca84f1e41f35898434f44770ca563c5bff986fe52e33f797b0fbc"}

experimental_model

Controlled metabolic-unit feeding; seven men, 80 days

exposure

6.1 or 10.1 niacin equivalents/day, followed by adequate/high intakes; repletion with or without 7.8 g/day leucine

limitations

Small controlled male metabolic-unit study. Erythrocytes are not every tissue; historical adequate intake is not a current recommendation. Jacob and Fu reports may describe related participants and are not counted as independent trials.

nutrient_topic

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

organism

Homo sapiens

plain_language

With too little niacin and tryptophan, red blood cells lost much of their NAD supply; restoring intake raised it.

primary_references

[nia-clin-fu1989] Biochemical markers for assessment of niacin status in young men: levels of erythrocyte niacin coenzymes and plasma tryptophan. (1989). https://pubmed.ncbi.nlm.nih.gov/2621487/ DOI: 10.1093/jn/119.12.1949

tissue_or_cell_type

Erythrocytes and plasma

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 1107–1119

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Controlled metabolic-unit feeding; seven men, 80 days · source_derived_draft · unverified_draft

### nia-clin-restriction-nad At both low niacin-equivalent intakes, erythrocyte NAD fell by about 70% in the seven-man feeding study and increased during adequate-intake repletion. Condition category: nutrient_deficiency nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: With too little niacin and tryptophan, red blood cells lost much of their NAD supply; restoring intake raised it. organism: Homo sapiens tissue_or_cell_type: Erythrocytes and plasma experimental_model: Controlled metabolic-unit feeding; seven men, 80 days limitations: Small controlled male metabolic-unit study. Erythrocytes are not every tissue; historical adequate intake is not a current recommendation. Jacob and Fu reports may describe related participants and are not counted as independent trials. exposure: 6.1 or 10.1 niacin equivalents/day, followed by adequate/high intakes; repletion with or without 7.8 g/day leucine cross_nutrient: L-Tryptophan (alternative_precursor); Nicotinamide adenine dinucleotide, oxidized (measured_coenzyme) evidence_span: {"source_cache": "artifacts/niacin-clinical-sources/fu1989.abstract.txt", "locator": "Indexed primary abstract", "file_sha256": "ca6d94c101aca84f1e41f35898434f44770ca563c5bff986fe52e33f797b0fbc", "start_char": 0, "end_char": 1340, "text_sha256": "ca6d94c101aca84f1e41f35898434f44770ca563c5bff986fe52e33f797b0fbc"} [nia-clin-fu1989] Biochemical markers for assessment of niacin status in young men: levels of erythrocyte niacin coenzymes and plasma tryptophan. (1989). https://pubmed.ncbi.nlm.nih.gov/2621487/ DOI: 10.1093/jn/119.12.1949

access_level

full_text_and_supplement_review

compartment

Cardiac tissue / mitochondria

dose

400 mg/kg/day

duration

Figure 2 treatment timeline; exact intervention duration not independently resolved from narrative

endpoint

mouse-hadha-acetylation

evidence_location

IP/immunoblot; Figure 2L

experimental_model

Mouse two-hit HFpEF model: 60% fat-calorie diet plus L-NAME 0.5 g/L drinking water; additional intervention as stated

exposure

nicotinamide-riboside

limitations

Single primary study; not independently replicated here. Cardiac and recombinant findings do not establish pulmonary endothelial, viral-sepsis or ARDS effects. The experiment does not establish selective direct NR action on HADHA or prove SIRT3 is the only mediator.

nutrient_topic

Topical cross-reference only; no inheritance of another actor's effects. · NAD+

organism

Mus musculus

plain_language

Nicotinamide riboside supplementation reduced HADHA acetylation in HFpEF mouse hearts.

primary_locator

[{"cache": "artifacts/dlat-curation/heart-blocks.json", "block_index": 25, "text_sha256": "1814242d6194ed4e0b3ab78287e20f85b6bc243051183d0f24d9034c3a930257", "xml_element_id": null}, {"cache": "artifacts/dlat-curation/heart-blocks.json", "block_index": 26, "text_sha256": "61dd26202087c725d9dc65345339778ed43192b3f765d05fa8a311a6e1944b34", "xml_element_id": "Par11"}, {"cache": "artifacts/dlat-curation/heart-blocks.json", "block_index": 72, "text_sha256": "2b1ada63fe6c48d4296bbfb14a97940ac4a866b1d5171b0923851ec72f88ab15", "xml_element_id": "Par31"}]

primary_references

https://doi.org/10.1038/s41467-026-70703-w

route

Oral gavage

sample_size

3 per group

tissue_or_cell_type

Cardiac tissue and cardiomyocytes

DLAT: cardiac fatty-acid oxidation and mitochondrial glutathione evidence · lines 532–548

AI-assisted two-paper curation, 2026-09-20. Cardiac full-text/supplement review; CRC abstract only. No pulmonary endothelial validation. · supports · Mouse two-hit HFpEF model: 60% fat-calorie diet plus L-NAME 0.5 g/L drinking water; additional intervention as stated · source_derived_draft · unverified_draft

Nicotinamide riboside supplementation reduced HADHA acetylation in HFpEF mouse hearts. organism: Mus musculus tissue_or_cell_type: Cardiac tissue and cardiomyocytes experimental_model: Mouse two-hit HFpEF model: 60% fat-calorie diet plus L-NAME 0.5 g/L drinking water; additional intervention as stated compartment: Cardiac tissue / mitochondria dose: 400 mg/kg/day duration: Figure 2 treatment timeline; exact intervention duration not independently resolved from narrative route: Oral gavage primary_references: https://doi.org/10.1038/s41467-026-70703-w access_level: full_text_and_supplement_review evidence_location: IP/immunoblot; Figure 2L endpoint: mouse-hadha-acetylation exposure: nicotinamide-riboside limitations: Single primary study; not independently replicated here. Cardiac and recombinant findings do not establish pulmonary endothelial, viral-sepsis or ARDS effects. The experiment does not establish selective direct NR action on HADHA or prove SIRT3 is the only mediator. primary_locator: [{"cache": "artifacts/dlat-curation/heart-blocks.json", "block_index": 25, "text_sha256": "1814242d6194ed4e0b3ab78287e20f85b6bc243051183d0f24d9034c3a930257", "xml_element_id": null}, {"cache": "artifacts/dlat-curation/heart-blocks.json", "block_index": 26, "text_sha256": "61dd26202087c725d9dc65345339778ed43192b3f765d05fa8a311a6e1944b34", "xml_element_id": "Par11"}, {"cache": "artifacts/dlat-curation/heart-blocks.json", "block_index": 72, "text_sha256": "2b1ada63fe6c48d4296bbfb14a97940ac4a866b1d5171b0923851ec72f88ab15", "xml_element_id": "Par31"}] plain_language: Nicotinamide riboside supplementation reduced HADHA acetylation in HFpEF mouse hearts. sample_size: 3 per group

access_level

full_text_and_supplement_review

compartment

Cardiac tissue / mitochondria

dose

400 mg/kg/day

duration

Figure 2 treatment timeline; exact intervention duration not independently resolved from narrative

endpoint

mouse-cardiac-nad-pool

evidence_location

NAD+ assay kit; Figure 2I

experimental_model

Mouse two-hit HFpEF model: 60% fat-calorie diet plus L-NAME 0.5 g/L drinking water; additional intervention as stated

exposure

nicotinamide-riboside

limitations

Single primary study; not independently replicated here. Cardiac and recombinant findings do not establish pulmonary endothelial, viral-sepsis or ARDS effects.

nutrient_topic

Topical cross-reference only; no inheritance of another actor's effects. · NAD+

organism

Mus musculus

plain_language

Oral nicotinamide riboside increased the measured cardiac NAD+ pool in the two-hit HFpEF study.

primary_locator

[{"cache": "artifacts/dlat-curation/heart-blocks.json", "block_index": 25, "text_sha256": "1814242d6194ed4e0b3ab78287e20f85b6bc243051183d0f24d9034c3a930257", "xml_element_id": null}, {"cache": "artifacts/dlat-curation/heart-blocks.json", "block_index": 26, "text_sha256": "61dd26202087c725d9dc65345339778ed43192b3f765d05fa8a311a6e1944b34", "xml_element_id": "Par11"}, {"cache": "artifacts/dlat-curation/heart-blocks.json", "block_index": 72, "text_sha256": "2b1ada63fe6c48d4296bbfb14a97940ac4a866b1d5171b0923851ec72f88ab15", "xml_element_id": "Par31"}]

primary_references

https://doi.org/10.1038/s41467-026-70703-w

route

Oral gavage

sample_size

6 per group

tissue_or_cell_type

Cardiac tissue and cardiomyocytes

DLAT: cardiac fatty-acid oxidation and mitochondrial glutathione evidence · lines 513–529

AI-assisted two-paper curation, 2026-09-20. Cardiac full-text/supplement review; CRC abstract only. No pulmonary endothelial validation. · supports · Mouse two-hit HFpEF model: 60% fat-calorie diet plus L-NAME 0.5 g/L drinking water; additional intervention as stated · source_derived_draft · unverified_draft

Oral nicotinamide riboside increased the measured cardiac NAD+ pool in the two-hit HFpEF study. organism: Mus musculus tissue_or_cell_type: Cardiac tissue and cardiomyocytes experimental_model: Mouse two-hit HFpEF model: 60% fat-calorie diet plus L-NAME 0.5 g/L drinking water; additional intervention as stated compartment: Cardiac tissue / mitochondria dose: 400 mg/kg/day duration: Figure 2 treatment timeline; exact intervention duration not independently resolved from narrative route: Oral gavage primary_references: https://doi.org/10.1038/s41467-026-70703-w access_level: full_text_and_supplement_review evidence_location: NAD+ assay kit; Figure 2I endpoint: mouse-cardiac-nad-pool exposure: nicotinamide-riboside limitations: Single primary study; not independently replicated here. Cardiac and recombinant findings do not establish pulmonary endothelial, viral-sepsis or ARDS effects. primary_locator: [{"cache": "artifacts/dlat-curation/heart-blocks.json", "block_index": 25, "text_sha256": "1814242d6194ed4e0b3ab78287e20f85b6bc243051183d0f24d9034c3a930257", "xml_element_id": null}, {"cache": "artifacts/dlat-curation/heart-blocks.json", "block_index": 26, "text_sha256": "61dd26202087c725d9dc65345339778ed43192b3f765d05fa8a311a6e1944b34", "xml_element_id": "Par11"}, {"cache": "artifacts/dlat-curation/heart-blocks.json", "block_index": 72, "text_sha256": "2b1ada63fe6c48d4296bbfb14a97940ac4a866b1d5171b0923851ec72f88ab15", "xml_element_id": "Par31"}] plain_language: Oral nicotinamide riboside increased the measured cardiac NAD+ pool in the two-hit HFpEF study. sample_size: 6 per group

experimental_model

Human AASS cloning, localization and familial hyperlysinemia genetics

limitations

Biochemical capacity does not quantify flux in every human tissue.

organism

Homo sapiens

plain_language

The second AASS activity opens the next lysine breakdown step.

primary_references

[sacksteder2000] Identification of the alpha-aminoadipic semialdehyde synthase gene, which is defective in familial hyperlysinemia (2000). https://pmc.ncbi.nlm.nih.gov/articles/PMC1378037/ DOI: 10.1086/302919

tissue_or_cell_type

Mitochondrial matrix

L-Lysine: mechanism-first literature curation (2026-09-17) · lines 84–92

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human AASS cloning, localization and familial hyperlysinemia genetics · source_derived_draft · unverified_draft

### aass-saccharopine-dehydrogenase The AASS dehydrogenase domain oxidatively cleaves saccharopine, producing alpha-aminoadipate semialdehyde and glutamate with NAD+ reduction. Plain language: The second AASS activity opens the next lysine breakdown step. Condition category: normal organism: Homo sapiens tissue_or_cell_type: Mitochondrial matrix experimental_model: Human AASS cloning, localization and familial hyperlysinemia genetics limitations: Biochemical capacity does not quantify flux in every human tissue. [sacksteder2000] Identification of the alpha-aminoadipic semialdehyde synthase gene, which is defective in familial hyperlysinemia (2000). https://pmc.ncbi.nlm.nih.gov/articles/PMC1378037/ DOI: 10.1086/302919

experimental_model

Human ALDH7A1 biochemical and genetic study

limitations

Compartmental isoform distribution is not resolved by this claim.

organism

Homo sapiens

plain_language

Antiquitin clears the aldehyde intermediate.

primary_references

[luo2015] Structural Basis of Substrate Recognition by Aldehyde Dehydrogenase 7A1 (2015). https://pubmed.ncbi.nlm.nih.gov/26260980/ DOI: 10.1021/acs.biochem.5b00754

tissue_or_cell_type

Lysine-catabolizing tissues

L-Lysine: mechanism-first literature curation (2026-09-17) · lines 104–112

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human ALDH7A1 biochemical and genetic study · source_derived_draft · unverified_draft

### aldh7a1-oxidation ALDH7A1 oxidizes alpha-aminoadipate semialdehyde to alpha-aminoadipate using NAD+. Plain language: Antiquitin clears the aldehyde intermediate. Condition category: normal organism: Homo sapiens tissue_or_cell_type: Lysine-catabolizing tissues experimental_model: Human ALDH7A1 biochemical and genetic study limitations: Compartmental isoform distribution is not resolved by this claim. [luo2015] Structural Basis of Substrate Recognition by Aldehyde Dehydrogenase 7A1 (2015). https://pubmed.ncbi.nlm.nih.gov/26260980/ DOI: 10.1021/acs.biochem.5b00754

experimental_model

Rat enzyme purification and recombinant human ALDH9 comparison

limitations

ALDH9A1 has additional aldehyde substrates.

organism

Homo sapiens

plain_language

An aldehyde is converted into the immediate carnitine precursor.

primary_references

[vaz2000] Molecular and biochemical characterization of rat gamma-trimethylaminobutyraldehyde dehydrogenase and evidence for the involvement of human aldehyde dehydrogenase 9 in carnitine biosynthesis (2000). https://pubmed.ncbi.nlm.nih.gov/10702312/ DOI: 10.1074/jbc.275.10.7390

tissue_or_cell_type

Cytosolic carnitine-biosynthesis reaction

L-Lysine: mechanism-first literature curation (2026-09-17) · lines 197–205

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat enzyme purification and recombinant human ALDH9 comparison · source_derived_draft · unverified_draft

### aldh9a1-tmaba-oxidation Human ALDH9A1 oxidizes trimethylaminobutyraldehyde to gamma-butyrobetaine using NAD+. Plain language: An aldehyde is converted into the immediate carnitine precursor. Condition category: normal organism: Homo sapiens tissue_or_cell_type: Cytosolic carnitine-biosynthesis reaction experimental_model: Rat enzyme purification and recombinant human ALDH9 comparison limitations: ALDH9A1 has additional aldehyde substrates. [vaz2000] Molecular and biochemical characterization of rat gamma-trimethylaminobutyraldehyde dehydrogenase and evidence for the involvement of human aldehyde dehydrogenase 9 in carnitine biosynthesis (2000). https://pubmed.ncbi.nlm.nih.gov/10702312/ DOI: 10.1074/jbc.275.10.7390

experimental_model

Human DHPS structural biochemistry.

limitations

NAD cycles during catalysis; it is not represented as a net consumed substrate here. This reaction modifies lysine already in a protein. It does not show that extra oral lysine increases the reaction or improves a clinical outcome.

organism

Human

plain_language

A particular protein lysine becomes a specialized translation-factor residue.

primary_references

[dhps-2020] Half Way to Hypusine-Structural Basis for Substrate Recognition by Human Deoxyhypusine Synthase (2020). https://pubmed.ncbi.nlm.nih.gov/32235505/

tissue_or_cell_type

Not specified as a whole tissue; see experimental model.

L-Lysine: mechanism-first literature curation (2026-09-17) · lines 578–586

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

### dhps-eif5a-deoxyhypusine DHPS transfers spermidine-derived aminobutyl onto eIF5A Lys50 to form deoxyhypusine. Plain language: A particular protein lysine becomes a specialized translation-factor residue. Condition category: normal organism: Human tissue_or_cell_type: Not specified as a whole tissue; see experimental model. experimental_model: Human DHPS structural biochemistry. limitations: NAD cycles during catalysis; it is not represented as a net consumed substrate here. This reaction modifies lysine already in a protein. It does not show that extra oral lysine increases the reaction or improves a clinical outcome. [dhps-2020] Half Way to Hypusine-Structural Basis for Substrate Recognition by Human Deoxyhypusine Synthase (2020). https://pubmed.ncbi.nlm.nih.gov/32235505/

experimental_model

Purified recombinant human HADH; substrate/product-cofactor crystal complexes

limitations

HADH is distinct from HADHA and HSD17B10. This shared reversible reaction supports the downstream route but does not quantify lysine-specific flux in people.

organism

Homo sapiens

plain_language

The four-carbon hydroxy intermediate is oxidized to a keto intermediate.

primary_references

[barycki2000] Sequestration of the active site by interdomain shifting. Crystallographic and spectroscopic evidence for distinct conformations of L-3-hydroxyacyl-CoA dehydrogenase (2000). https://pubmed.ncbi.nlm.nih.gov/10840044/ DOI: 10.1074/jbc.M004669200

tissue_or_cell_type

Mitochondrial short-chain hydroxyacyl-CoA metabolism; recombinant protein study

L-Lysine: mechanism-first literature curation (2026-09-17) · lines 367–375

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant human HADH; substrate/product-cofactor crystal complexes · source_derived_draft · unverified_draft

### hadh-hydroxybutyryl-coa-oxidation The human HADH homodimer reversibly oxidizes (S)-3-hydroxybutyryl-CoA to acetoacetyl-CoA while reducing NAD+ to NADH. Plain language: The four-carbon hydroxy intermediate is oxidized to a keto intermediate. Condition category: normal organism: Homo sapiens tissue_or_cell_type: Mitochondrial short-chain hydroxyacyl-CoA metabolism; recombinant protein study experimental_model: Purified recombinant human HADH; substrate/product-cofactor crystal complexes limitations: HADH is distinct from HADHA and HSD17B10. This shared reversible reaction supports the downstream route but does not quantify lysine-specific flux in people. [barycki2000] Sequestration of the active site by interdomain shifting. Crystallographic and spectroscopic evidence for distinct conformations of L-3-hydroxyacyl-CoA dehydrogenase (2000). https://pubmed.ncbi.nlm.nih.gov/10840044/ DOI: 10.1074/jbc.M004669200

experimental_model

Recombinant human DHTKD1 and DLST; structural and biochemical assays; Two human patients; fibroblast isotope tracing and genetic complementation

limitations

DHTKD1 is the E1 component, not a stand-alone enzyme performing every complex reaction.

organism

Homo sapiens

plain_language

A three-enzyme complex converts the carbon skeleton into glutaryl-CoA.

primary_references

[bezerra2020] Crystal structure and interaction studies of human DHTKD1 provide insight into a mitochondrial megacomplex in lysine catabolism (2020). https://pmc.ncbi.nlm.nih.gov/articles/PMC7340257/ DOI: 10.1107/S205225252000696X [danhauser2012] DHTKD1 mutations cause 2-aminoadipic and 2-oxoadipic aciduria (2012). https://pmc.ncbi.nlm.nih.gov/articles/PMC3516599/ DOI: 10.1016/j.ajhg.2012.10.006

tissue_or_cell_type

Mitochondrial matrix

L-Lysine: mechanism-first literature curation (2026-09-17) · lines 125–134

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human DHTKD1 and DLST; structural and biochemical assays; Two human patients; fibroblast isotope tracing and genetic complementation · source_derived_draft · unverified_draft

### oxoadipate-dehydrogenase-complex DHTKD1 with DLST and DLD supports oxidative decarboxylation of 2-oxoadipate to glutaryl-CoA, with NADH and carbon dioxide formation. Plain language: A three-enzyme complex converts the carbon skeleton into glutaryl-CoA. Condition category: normal organism: Homo sapiens tissue_or_cell_type: Mitochondrial matrix experimental_model: Recombinant human DHTKD1 and DLST; structural and biochemical assays; Two human patients; fibroblast isotope tracing and genetic complementation limitations: DHTKD1 is the E1 component, not a stand-alone enzyme performing every complex reaction. [bezerra2020] Crystal structure and interaction studies of human DHTKD1 provide insight into a mitochondrial megacomplex in lysine catabolism (2020). https://pmc.ncbi.nlm.nih.gov/articles/PMC7340257/ DOI: 10.1107/S205225252000696X [danhauser2012] DHTKD1 mutations cause 2-aminoadipic and 2-oxoadipic aciduria (2012). https://pmc.ncbi.nlm.nih.gov/articles/PMC3516599/ DOI: 10.1016/j.ajhg.2012.10.006

experimental_model

Human enzyme assays and cultured-cell SIRT1 perturbation.

limitations

This reaction modifies lysine already in a protein. It does not show that extra oral lysine increases the reaction or improves a clinical outcome.

organism

Human

plain_language

A different enzyme removes a lysine modification using NAD+.

primary_references

[sirt1-2004] Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin (2004). https://pubmed.ncbi.nlm.nih.gov/15469825/ DOI: 10.1016/j.molcel.2004.08.031

tissue_or_cell_type

Not specified as a whole tissue; see experimental model.

L-Lysine: mechanism-first literature curation (2026-09-17) · lines 537–545

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human enzyme assays and cultured-cell SIRT1 perturbation. · source_derived_draft · unverified_draft

### sirt1-h4k16-deacetylation Human SIRT1 removes acetylation from histone H4 Lys16 in an NAD+-dependent reaction. Plain language: A different enzyme removes a lysine modification using NAD+. Condition category: normal organism: Human tissue_or_cell_type: Not specified as a whole tissue; see experimental model. experimental_model: Human enzyme assays and cultured-cell SIRT1 perturbation. limitations: This reaction modifies lysine already in a protein. It does not show that extra oral lysine increases the reaction or improves a clinical outcome. [sirt1-2004] Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin (2004). https://pubmed.ncbi.nlm.nih.gov/15469825/ DOI: 10.1016/j.molcel.2004.08.031

evidence_access

Reactome curated reaction and its primary-study attribution

experimental_model

Curated human mitochondrial reaction R-HSA-73920; cites human-heart BDH1 work.

limitations

Reversible reaction; redox state and compartment determine net direction.

nutrient_topic

Fasting physiological-state collection; human protocols, cellular deprivation and refeeding are distinguished. · Fasting / abstention from energy intake

plain_language

Ketone interconversion connects to niacin-derived redox chemistry.

primary_references

BDH1: D-beta-hydroxybutyrate + NAD+ ⇌ acetoacetate + NADH + H+ · 2003 · https://reactome.org/content/detail/R-HSA-73920

Fasting: fuel switching, nutrient sensing, ketone signaling, nutrient dependencies and refeeding (2026-09-18) · lines 128–134

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Curated human mitochondrial reaction R-HSA-73920; cites human-heart BDH1 work. · source_derived_draft · unverified_draft

## fast-bdh-reaction Ketone interconversion connects to niacin-derived redox chemistry. BDH1 interconverts D-beta-hydroxybutyrate and acetoacetate using the NAD+/NADH redox pair. Model: Curated human mitochondrial reaction R-HSA-73920; cites human-heart BDH1 work. Limitations: Reversible reaction; redox state and compartment determine net direction. Evidence access: Reactome curated reaction and its primary-study attribution BDH1: D-beta-hydroxybutyrate + NAD+ ⇌ acetoacetate + NADH + H+ · 2003 · https://reactome.org/content/detail/R-HSA-73920

evidence_span

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experimental_model

Product-inhibition kinetics

exposure

Forward and reverse reaction products

limitations

Kinetic mechanism; no evidence here for a dietary detoxification protocol.

nutrient_topic

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

organism

Human

plain_language

Glutathione carries formaldehyde through an enzyme-dependent route.

primary_references

[glutathione-p7213635] Product inhibition studies of human liver formaldehyde dehydrogenase. (1980). https://pubmed.ncbi.nlm.nih.gov/7213635/ DOI: 10.1016/0005-2744(80)90133-3

tissue_or_cell_type

Liver formaldehyde dehydrogenase

Glutathione: metabolism, signaling and nutrient connections (2026-09-17) · lines 1022–1033

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

### glutathione-adh5-formaldehyde Human liver enzyme kinetics supported NAD+-dependent processing of S-hydroxymethylglutathione to the S-formylglutathione/NADH products. Condition category: normal nutrient_topic: Glutathione research collection; topical membership is not evidence of a direct dietary effect. plain_language: Glutathione carries formaldehyde through an enzyme-dependent route. organism: Human tissue_or_cell_type: Liver formaldehyde dehydrogenase experimental_model: Product-inhibition kinetics limitations: Kinetic mechanism; no evidence here for a dietary detoxification protocol. exposure: Forward and reverse reaction products evidence_span: {"source_cache": "artifacts/glutathione-research/7213635.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "dd4cd3715345eebe37dce2f19274529ae09d9c0e5523348eb8fc9b57e854cfa5", "start_char": 0, "end_char": 592, "text_sha256": "dd4cd3715345eebe37dce2f19274529ae09d9c0e5523348eb8fc9b57e854cfa5"} [glutathione-p7213635] Product inhibition studies of human liver formaldehyde dehydrogenase. (1980). https://pubmed.ncbi.nlm.nih.gov/7213635/ DOI: 10.1016/0005-2744(80)90133-3

evidence_span

{"source_cache": "artifacts/molybdenum-research/33355213.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0edb31bff85231dfbde4a99d6858db611c099d2cd00982cad88616aa960b5aa2", "start_char": 0, "end_char": 2211, "text_sha256": "0edb31bff85231dfbde4a99d6858db611c099d2cd00982cad88616aa960b5aa2"}

experimental_model

Recombinant human AOX and human liver S9 kinetics, inhibitors and protein quantification

exposure

Retinaldehyde with/without NAD+; selective inhibitors

limitations

Ex-vivo contribution depends on substrate and NAD+ availability; no dietary molybdenum intervention or universal in-vivo percentage.

nutrient_topic

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

organism

Homo sapiens

plain_language

Different enzymes share vitamin A processing, and their contributions depend on the conditions.

primary_references

[mo-p33355213] Aldehyde Oxidase Contributes to All-Trans-Retinoic Acid Biosynthesis in Human Liver. (2021). https://pubmed.ncbi.nlm.nih.gov/33355213/ DOI: 10.1124/dmd.120.000296

tissue_or_cell_type

Purified enzyme and liver S9 fractions

Molybdenum: cofactor assembly, sulfur metabolism and nutrient interactions (2026-09-17) · lines 911–922

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human AOX and human liver S9 kinetics, inhibitors and protein quantification · source_derived_draft · unverified_draft

### mo-aox-aldh-partition In human liver S9, AOX inhibition reduced retinoic-acid formation by 20-50%, versus 50-80% with ALDH1A1 inhibition; AOX had lower affinity and higher capacity. Condition category: normal nutrient_topic: Molybdenum research collection; topical membership is not evidence of a direct dietary effect. plain_language: Different enzymes share vitamin A processing, and their contributions depend on the conditions. organism: Homo sapiens tissue_or_cell_type: Purified enzyme and liver S9 fractions experimental_model: Recombinant human AOX and human liver S9 kinetics, inhibitors and protein quantification limitations: Ex-vivo contribution depends on substrate and NAD+ availability; no dietary molybdenum intervention or universal in-vivo percentage. exposure: Retinaldehyde with/without NAD+; selective inhibitors evidence_span: {"source_cache": "artifacts/molybdenum-research/33355213.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0edb31bff85231dfbde4a99d6858db611c099d2cd00982cad88616aa960b5aa2", "start_char": 0, "end_char": 2211, "text_sha256": "0edb31bff85231dfbde4a99d6858db611c099d2cd00982cad88616aa960b5aa2"} [mo-p33355213] Aldehyde Oxidase Contributes to All-Trans-Retinoic Acid Biosynthesis in Human Liver. (2021). https://pubmed.ncbi.nlm.nih.gov/33355213/ DOI: 10.1124/dmd.120.000296

evidence_span

{"source_cache": "artifacts/molybdenum-research/10559215.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a0a70e022e9499ca5d0608c1da80afadfad2215ac6cf1219c8ce8da3280a5238", "start_char": 0, "end_char": 1879, "text_sha256": "a0a70e022e9499ca5d0608c1da80afadfad2215ac6cf1219c8ce8da3280a5238"}

experimental_model

Biochemical fractionation of four human livers and three kidneys

exposure

Retinaldehyde and other aldehyde substrate assays

limitations

Biochemical enzyme-fraction identification predates modern isoform assays; does not establish AOX1 as the dominant human retinoic-acid source or mineral-responsive route.

nutrient_topic

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

organism

Homo sapiens

plain_language

AOX1 intersects vitamin A chemistry, alongside other enzymes.

primary_references

[mo-p10559215] Metabolism of retinaldehyde and other aldehydes in soluble extracts of human liver and kidney. (1999). https://pubmed.ncbi.nlm.nih.gov/10559215/ DOI: 10.1074/jbc.274.47.33366

tissue_or_cell_type

Liver and kidney soluble extracts

Molybdenum: cofactor assembly, sulfur metabolism and nutrient interactions (2026-09-17) · lines 885–896

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Biochemical fractionation of four human livers and three kidneys · source_derived_draft · unverified_draft

### mo-aox-retinal A separable aldehyde-oxidase fraction accounted for some NAD-independent retinaldehyde metabolism in human liver and kidney extracts. Condition category: normal nutrient_topic: Molybdenum research collection; topical membership is not evidence of a direct dietary effect. plain_language: AOX1 intersects vitamin A chemistry, alongside other enzymes. organism: Homo sapiens tissue_or_cell_type: Liver and kidney soluble extracts experimental_model: Biochemical fractionation of four human livers and three kidneys limitations: Biochemical enzyme-fraction identification predates modern isoform assays; does not establish AOX1 as the dominant human retinoic-acid source or mineral-responsive route. exposure: Retinaldehyde and other aldehyde substrate assays evidence_span: {"source_cache": "artifacts/molybdenum-research/10559215.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a0a70e022e9499ca5d0608c1da80afadfad2215ac6cf1219c8ce8da3280a5238", "start_char": 0, "end_char": 1879, "text_sha256": "a0a70e022e9499ca5d0608c1da80afadfad2215ac6cf1219c8ce8da3280a5238"} [mo-p10559215] Metabolism of retinaldehyde and other aldehydes in soluble extracts of human liver and kidney. (1999). https://pubmed.ncbi.nlm.nih.gov/10559215/ DOI: 10.1074/jbc.274.47.33366

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/molybdenum-research/15273247.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d2f73a9ca41e4d51b85d3a66ada08511055ce6ff7462beb0e7eaf21aadf37279", "start_char": 0, "end_char": 1606, "text_sha256": "d2f73a9ca41e4d51b85d3a66ada08511055ce6ff7462beb0e7eaf21aadf37279"}

experimental_model

Rat brain mitochondria/extracts, purified enzyme and Neuro-2a/PC12 cells

exposure

Micromolar sulfite exposure

limitations

Experimental substrate dependence; not a measurement of these effects in people with ordinary low molybdenum intake.

nutrient_topic

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

organism

Rattus norvegicus tissue; rodent cell lines

plain_language

A sulfur-metabolism disturbance can interrupt a separate fuel-processing enzyme.

primary_references

[mo-p15273247] A mechanism of sulfite neurotoxicity: direct inhibition of glutamate dehydrogenase. (2004). https://pubmed.ncbi.nlm.nih.gov/15273247/ DOI: 10.1074/jbc.m402759200

tissue_or_cell_type

Mitochondrial glutamate oxidation

trigger_kind

machinery_impairment Imported condition classification; unverified.

Molybdenum: cofactor assembly, sulfur metabolism and nutrient interactions (2026-09-17) · lines 1366–1377

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat brain mitochondria/extracts, purified enzyme and Neuro-2a/PC12 cells · source_derived_draft · unverified_draft

### mo-sulfite-gdh Sulfite inhibited rat-brain glutamate dehydrogenase and reduced glutamate-supported NADH production. Condition category: machinery_impairment nutrient_topic: Molybdenum research collection; topical membership is not evidence of a direct dietary effect. plain_language: A sulfur-metabolism disturbance can interrupt a separate fuel-processing enzyme. organism: Rattus norvegicus tissue; rodent cell lines tissue_or_cell_type: Mitochondrial glutamate oxidation experimental_model: Rat brain mitochondria/extracts, purified enzyme and Neuro-2a/PC12 cells limitations: Experimental substrate dependence; not a measurement of these effects in people with ordinary low molybdenum intake. exposure: Micromolar sulfite exposure evidence_span: {"source_cache": "artifacts/molybdenum-research/15273247.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d2f73a9ca41e4d51b85d3a66ada08511055ce6ff7462beb0e7eaf21aadf37279", "start_char": 0, "end_char": 1606, "text_sha256": "d2f73a9ca41e4d51b85d3a66ada08511055ce6ff7462beb0e7eaf21aadf37279"} [mo-p15273247] A mechanism of sulfite neurotoxicity: direct inhibition of glutamate dehydrogenase. (2004). https://pubmed.ncbi.nlm.nih.gov/15273247/ DOI: 10.1074/jbc.m402759200

experimental_model

Recombinant p32/RDH5 activity assay

limitations

Cofactor specificity is biochemical; no niacin-deficiency phenotype was tested.

nutrient_topic

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

organism

Bos taurus protein; COS cells

plain_language

RDH5 oxidizes the cis alcohol into the visual chromophore.

primary_references

[simon-1995] The retinal pigment epithelial-specific 11-cis retinol dehydrogenase belongs to the family of short chain alcohol dehydrogenases (1995). https://pubmed.ncbi.nlm.nih.gov/7836368/ DOI: 10.1074/jbc.270.3.1107

tissue_or_cell_type

RPE-derived enzyme

Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 723–732

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant p32/RDH5 activity assay · source_derived_draft · unverified_draft

### a-vision-rdh5-oxidation Bovine RDH5 expressed in COS cells oxidized 11-cis-retinol using NAD+; NADP did not support the tested activity. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: RDH5 oxidizes the cis alcohol into the visual chromophore. organism: Bos taurus protein; COS cells tissue_or_cell_type: RPE-derived enzyme experimental_model: Recombinant p32/RDH5 activity assay limitations: Cofactor specificity is biochemical; no niacin-deficiency phenotype was tested. [simon-1995] The retinal pigment epithelial-specific 11-cis retinol dehydrogenase belongs to the family of short chain alcohol dehydrogenases (1995). https://pubmed.ncbi.nlm.nih.gov/7836368/ DOI: 10.1074/jbc.270.3.1107

evidence_location

Abstract

experimental_model

Side-by-side recombinant human ALDH1A1, ALDH1A2 and ALDH1A3 kinetic assays.

exposure

Side-by-side retinaldehyde kinetic measurements by HPLC.

limitations

In vitro catalytic efficiency does not specify its contribution in a particular tissue.

nutrient_topic

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

organism

Homo sapiens recombinant protein

outcome

Human ALDH1A1 oxidized all-trans-retinaldehyde to retinoic acid in comparative enzyme assays.

plain_language

This independently identified enzyme supplies the acid form used for signaling.

primary_references

[va-pequerul-2020] Structural and kinetic features of aldehyde dehydrogenase 1A (ALDH1A) subfamily members, cancer stem cell markers active in retinoic acid biosynthesis (2020). https://pubmed.ncbi.nlm.nih.gov/31923393/ DOI: 10.1016/j.abb.2020.108256

tissue_or_cell_type

Cell-free enzyme

Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 559–571

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Side-by-side recombinant human ALDH1A1, ALDH1A2 and ALDH1A3 kinetic assays. · source_derived_draft · unverified_draft

### va-aldh1a1-retinal-oxidation Human ALDH1A1 oxidized all-trans-retinaldehyde to retinoic acid in comparative enzyme assays. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: This independently identified enzyme supplies the acid form used for signaling. organism: Homo sapiens recombinant protein tissue_or_cell_type: Cell-free enzyme experimental_model: Side-by-side recombinant human ALDH1A1, ALDH1A2 and ALDH1A3 kinetic assays. limitations: In vitro catalytic efficiency does not specify its contribution in a particular tissue. exposure: Side-by-side retinaldehyde kinetic measurements by HPLC. outcome: Human ALDH1A1 oxidized all-trans-retinaldehyde to retinoic acid in comparative enzyme assays. evidence_location: Abstract [va-pequerul-2020] Structural and kinetic features of aldehyde dehydrogenase 1A (ALDH1A) subfamily members, cancer stem cell markers active in retinoic acid biosynthesis (2020). https://pubmed.ncbi.nlm.nih.gov/31923393/ DOI: 10.1016/j.abb.2020.108256

evidence_location

Abstract

experimental_model

Side-by-side recombinant human ALDH1A1, ALDH1A2 and ALDH1A3 kinetic assays.

exposure

Side-by-side retinaldehyde kinetic measurements by HPLC.

limitations

In vitro catalytic efficiency does not specify its contribution in a particular tissue.

nutrient_topic

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

organism

Homo sapiens recombinant protein

outcome

Human ALDH1A2 oxidized all-trans-retinaldehyde to retinoic acid in comparative enzyme assays.

plain_language

This independently identified enzyme supplies the acid form used for signaling.

primary_references

[va-pequerul-2020] Structural and kinetic features of aldehyde dehydrogenase 1A (ALDH1A) subfamily members, cancer stem cell markers active in retinoic acid biosynthesis (2020). https://pubmed.ncbi.nlm.nih.gov/31923393/ DOI: 10.1016/j.abb.2020.108256

tissue_or_cell_type

Cell-free enzyme

Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 573–585

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Side-by-side recombinant human ALDH1A1, ALDH1A2 and ALDH1A3 kinetic assays. · source_derived_draft · unverified_draft

### va-aldh1a2-retinal-oxidation Human ALDH1A2 oxidized all-trans-retinaldehyde to retinoic acid in comparative enzyme assays. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: This independently identified enzyme supplies the acid form used for signaling. organism: Homo sapiens recombinant protein tissue_or_cell_type: Cell-free enzyme experimental_model: Side-by-side recombinant human ALDH1A1, ALDH1A2 and ALDH1A3 kinetic assays. limitations: In vitro catalytic efficiency does not specify its contribution in a particular tissue. exposure: Side-by-side retinaldehyde kinetic measurements by HPLC. outcome: Human ALDH1A2 oxidized all-trans-retinaldehyde to retinoic acid in comparative enzyme assays. evidence_location: Abstract [va-pequerul-2020] Structural and kinetic features of aldehyde dehydrogenase 1A (ALDH1A) subfamily members, cancer stem cell markers active in retinoic acid biosynthesis (2020). https://pubmed.ncbi.nlm.nih.gov/31923393/ DOI: 10.1016/j.abb.2020.108256

evidence_location

Abstract

experimental_model

Side-by-side recombinant human ALDH1A1, ALDH1A2 and ALDH1A3 kinetic assays.

exposure

Side-by-side retinaldehyde kinetic measurements by HPLC.

limitations

In vitro catalytic efficiency does not specify its contribution in a particular tissue.

nutrient_topic

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

organism

Homo sapiens recombinant protein

outcome

Human ALDH1A3 oxidized all-trans-retinaldehyde to retinoic acid in comparative enzyme assays.

plain_language

This independently identified enzyme supplies the acid form used for signaling.

primary_references

[va-pequerul-2020] Structural and kinetic features of aldehyde dehydrogenase 1A (ALDH1A) subfamily members, cancer stem cell markers active in retinoic acid biosynthesis (2020). https://pubmed.ncbi.nlm.nih.gov/31923393/ DOI: 10.1016/j.abb.2020.108256

tissue_or_cell_type

Cell-free enzyme

Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 587–599

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Side-by-side recombinant human ALDH1A1, ALDH1A2 and ALDH1A3 kinetic assays. · source_derived_draft · unverified_draft

### va-aldh1a3-retinal-oxidation Human ALDH1A3 oxidized all-trans-retinaldehyde to retinoic acid in comparative enzyme assays. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: This independently identified enzyme supplies the acid form used for signaling. organism: Homo sapiens recombinant protein tissue_or_cell_type: Cell-free enzyme experimental_model: Side-by-side recombinant human ALDH1A1, ALDH1A2 and ALDH1A3 kinetic assays. limitations: In vitro catalytic efficiency does not specify its contribution in a particular tissue. exposure: Side-by-side retinaldehyde kinetic measurements by HPLC. outcome: Human ALDH1A3 oxidized all-trans-retinaldehyde to retinoic acid in comparative enzyme assays. evidence_location: Abstract [va-pequerul-2020] Structural and kinetic features of aldehyde dehydrogenase 1A (ALDH1A) subfamily members, cancer stem cell markers active in retinoic acid biosynthesis (2020). https://pubmed.ncbi.nlm.nih.gov/31923393/ DOI: 10.1016/j.abb.2020.108256

cross_nutrient

NAD-dependent retinol oxidation connects vitamin A metabolism to nicotinamide redox-cofactor availability.

evidence_location

Results: cofactor preference

experimental_model

Human RDH10 in Sf9 microsomes and siRNA perturbation in human cells.

exposure

1 micromolar retinol and 1 millimolar NAD+ versus NADP+.

limitations

Cofactor specificity does not establish an effect of dietary niacin deficiency.

nutrient_topic

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

organism

Homo sapiens protein in Spodoptera frugiperda Sf9 cells

outcome

Recombinant human RDH10 oxidized all-trans-retinol with NAD+ in microsomal assays.

plain_language

RDH10 uses the oxidized nicotinamide cofactor to make retinal.

primary_references

[va-belyaeva-2008] Kinetic Analysis of Human Enzyme RDH10 Defines the Characteristics of a Physiologically Relevant Retinol Dehydrogenase (2008). https://pmc.ncbi.nlm.nih.gov/articles/PMC2459273/ DOI: 10.1074/jbc.M800019200

tissue_or_cell_type

Microsomes

Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 487–500

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human RDH10 in Sf9 microsomes and siRNA perturbation in human cells. · source_derived_draft · unverified_draft

### va-rdh10-retinol-oxidation Recombinant human RDH10 oxidized all-trans-retinol with NAD+ in microsomal assays. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: RDH10 uses the oxidized nicotinamide cofactor to make retinal. organism: Homo sapiens protein in Spodoptera frugiperda Sf9 cells tissue_or_cell_type: Microsomes experimental_model: Human RDH10 in Sf9 microsomes and siRNA perturbation in human cells. limitations: Cofactor specificity does not establish an effect of dietary niacin deficiency. exposure: 1 micromolar retinol and 1 millimolar NAD+ versus NADP+. outcome: Recombinant human RDH10 oxidized all-trans-retinol with NAD+ in microsomal assays. evidence_location: Results: cofactor preference cross_nutrient: NAD-dependent retinol oxidation connects vitamin A metabolism to nicotinamide redox-cofactor availability. [va-belyaeva-2008] Kinetic Analysis of Human Enzyme RDH10 Defines the Characteristics of a Physiologically Relevant Retinol Dehydrogenase (2008). https://pmc.ncbi.nlm.nih.gov/articles/PMC2459273/ DOI: 10.1074/jbc.M800019200

evidence_access

Primary full text

experimental_model

Mouse C57BL/6J brown-fat mitochondria and reconstituted enzyme system.

limitations

An isolated-organelle assay does not prove that oral aspartate increases thermogenesis.

nutrient_topic

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

plain_language

The transport cycle linked a cytosolic redox pool to mitochondrial machinery.

primary_references

The malate-aspartate shuttle supports thermogenic lipid mobilization in brown adipocytes. · 2026 · https://pubmed.ncbi.nlm.nih.gov/41704162/ · DOI 10.1111/febs.70461

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 322–328

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse C57BL/6J brown-fat mitochondria and reconstituted enzyme system. · source_derived_draft · unverified_draft

## l-aspartate-brown-shuttle-redox The transport cycle linked a cytosolic redox pool to mitochondrial machinery. Isolated mouse brown-fat mitochondria reconstituted with cytosolic shuttle enzymes oxidized extramitochondrial NADH in a glutamate-dependent manner. Model: Mouse C57BL/6J brown-fat mitochondria and reconstituted enzyme system. Limitations: An isolated-organelle assay does not prove that oral aspartate increases thermogenesis. Evidence access: Primary full text The malate-aspartate shuttle supports thermogenic lipid mobilization in brown adipocytes. · 2026 · https://pubmed.ncbi.nlm.nih.gov/41704162/ · DOI 10.1111/febs.70461

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Mouse Slc25a13-null hepatocytes with exogenous aralar expression.

limitations

Gene-expression rescue is not proof that oral aspartate or calcium corrects human citrin deficiency.

nutrient_topic

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

plain_language

A related carrier can substitute for part of the missing transport function in this model.

primary_references

Exogenous aralar/slc25a12 can replace citrin/slc25a13 as malate aspartate shuttle component in liver. · 2023 · https://pubmed.ncbi.nlm.nih.gov/36967723/ · DOI 10.1016/j.ymgmr.2023.100967

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 122–128

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse Slc25a13-null hepatocytes with exogenous aralar expression. · source_derived_draft · unverified_draft

## l-aspartate-citrin-aralar-rescue A related carrier can substitute for part of the missing transport function in this model. Exogenous aralar expression reversed the increased NADH/NAD+ ratio in hepatocytes from citrin-null mice. Model: Mouse Slc25a13-null hepatocytes with exogenous aralar expression. Limitations: Gene-expression rescue is not proof that oral aspartate or calcium corrects human citrin deficiency. Evidence access: Primary full text Exogenous aralar/slc25a12 can replace citrin/slc25a13 as malate aspartate shuttle component in liver. · 2023 · https://pubmed.ncbi.nlm.nih.gov/36967723/ · DOI 10.1016/j.ymgmr.2023.100967

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Isolated liver mitochondria from genetically modified mice.

limitations

Small ex vivo flux increment; not human therapeutic efficacy.

nutrient_topic

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

plain_language

A measurable transport rescue did not amount to proof of complete disease correction.

primary_references

Exogenous aralar/slc25a12 can replace citrin/slc25a13 as malate aspartate shuttle component in liver. · 2023 · https://pubmed.ncbi.nlm.nih.gov/36967723/ · DOI 10.1016/j.ymgmr.2023.100967

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 130–136

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Isolated liver mitochondria from genetically modified mice. · source_derived_draft · unverified_draft

## l-aspartate-citrin-shuttle-rescue A measurable transport rescue did not amount to proof of complete disease correction. Liver-specific transgenic aralar expression increased residual shuttle activity in citrin-null mouse mitochondria by approximately 4–6 nmol per mg protein per minute. Model: Isolated liver mitochondria from genetically modified mice. Limitations: Small ex vivo flux increment; not human therapeutic efficacy. Evidence access: Primary full text Exogenous aralar/slc25a12 can replace citrin/slc25a13 as malate aspartate shuttle component in liver. · 2023 · https://pubmed.ncbi.nlm.nih.gov/36967723/ · DOI 10.1016/j.ymgmr.2023.100967

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human proliferating cell models; genetic screen and metabolic tracing during ETC inhibition.

limitations

Direction is conditional, not an intrinsic one-way label for GOT1.

nutrient_topic

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

plain_language

A reversible enzyme can run in a different direction when the cell’s redox state changes.

primary_references

An Essential Role of the Mitochondrial Electron Transport Chain in Cell Proliferation Is to Enable Aspartate Synthesis. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26232224/ · DOI 10.1016/j.cell.2015.07.016

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 50–56

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human proliferating cell models; genetic screen and metabolic tracing during ETC inhibition. · source_derived_draft · unverified_draft

## l-aspartate-got1-reversal A reversible enzyme can run in a different direction when the cell’s redox state changes. Under electron-transport-chain inhibition, human GOT1 supported cytosolic aspartate synthesis rather than its usual aspartate-consuming shuttle direction. Model: Human proliferating cell models; genetic screen and metabolic tracing during ETC inhibition. Limitations: Direction is conditional, not an intrinsic one-way label for GOT1. Evidence access: Primary full text An Essential Role of the Mitochondrial Electron Transport Chain in Cell Proliferation Is to Enable Aspartate Synthesis. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26232224/ · DOI 10.1016/j.cell.2015.07.016

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human 143B cytochrome-b-mutant cells; metabolomics after high extracellular aspartate.

limitations

The GMP branch also depends on redox chemistry; high culture supplementation does not establish oral delivery.

nutrient_topic

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

plain_language

Restoring one substrate repaired some nucleotide steps without repairing all of them.

primary_references

Supporting Aspartate Biosynthesis Is an Essential Function of Respiration in Proliferating Cells. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26232225/ · DOI 10.1016/j.cell.2015.07.017

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 66–72

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human 143B cytochrome-b-mutant cells; metabolomics after high extracellular aspartate. · source_derived_draft · unverified_draft

## l-aspartate-purine-rescue Restoring one substrate repaired some nucleotide steps without repairing all of them. Aspartate supplementation relieved IMP accumulation and restored AMP and SAICAR pools in respiration-impaired 143B cells, while GMP did not similarly recover. Model: Human 143B cytochrome-b-mutant cells; metabolomics after high extracellular aspartate. Limitations: The GMP branch also depends on redox chemistry; high culture supplementation does not establish oral delivery. Evidence access: Primary full text Supporting Aspartate Biosynthesis Is an Essential Function of Respiration in Proliferating Cells. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26232225/ · DOI 10.1016/j.cell.2015.07.017

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human Jurkat-centered genetic and metabolic experiments.

limitations

Pyruvate is not a universally effective rescue for every respiratory or transaminase defect.

nutrient_topic

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

plain_language

Providing an electron acceptor did not bypass the need for functioning synthesis machinery.

primary_references

An Essential Role of the Mitochondrial Electron Transport Chain in Cell Proliferation Is to Enable Aspartate Synthesis. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26232224/ · DOI 10.1016/j.cell.2015.07.016

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 58–64

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human Jurkat-centered genetic and metabolic experiments. · source_derived_draft · unverified_draft

## l-aspartate-pyruvate-got1-gate Providing an electron acceptor did not bypass the need for functioning synthesis machinery. GOT1 loss prevented pyruvate from rescuing aspartate synthesis and proliferation during ETC dysfunction. Model: Human Jurkat-centered genetic and metabolic experiments. Limitations: Pyruvate is not a universally effective rescue for every respiratory or transaminase defect. Evidence access: Primary full text An Essential Role of the Mitochondrial Electron Transport Chain in Cell Proliferation Is to Enable Aspartate Synthesis. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26232224/ · DOI 10.1016/j.cell.2015.07.016

evidence_access

Primary abstract and primary figure descriptions

experimental_model

Proliferating-cell perturbation and tracer study, including human NSCLC models.

limitations

Substrate availability in cell models is not evidence for benefits of oral L-aspartate.

nutrient_topic

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

plain_language

Aspartate demand for building material can compete with its participation in redox transfer.

primary_references

Aspartate availability drives differential engagement of the malate-aspartate shuttle. · 2026 · https://pubmed.ncbi.nlm.nih.gov/41759528/ · DOI 10.1016/j.molcel.2026.02.004

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 226–232

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Proliferating-cell perturbation and tracer study, including human NSCLC models. · source_derived_draft · unverified_draft

## l-aspartate-shuttle-aspartate-availability Aspartate demand for building material can compete with its participation in redox transfer. Increasing aspartate availability enhanced malate–aspartate shuttle use and mitochondrial metabolism of glucose-derived pyruvate in proliferating cell experiments. Model: Proliferating-cell perturbation and tracer study, including human NSCLC models. Limitations: Substrate availability in cell models is not evidence for benefits of oral L-aspartate. Evidence access: Primary abstract and primary figure descriptions Aspartate availability drives differential engagement of the malate-aspartate shuttle. · 2026 · https://pubmed.ncbi.nlm.nih.gov/41759528/ · DOI 10.1016/j.molcel.2026.02.004

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract and primary figure descriptions

experimental_model

Human lung-cancer cell gene editing, metabolite ratios and carbon tracing.

limitations

A ratio is a redox proxy, and no dietary serine/aspartate deficiency threshold was measured.

nutrient_topic

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

plain_language

Redox handling connects aspartate machinery to synthesis of another amino acid.

primary_references

Aspartate availability drives differential engagement of the malate-aspartate shuttle. · 2026 · https://pubmed.ncbi.nlm.nih.gov/41759528/ · DOI 10.1016/j.molcel.2026.02.004

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 234–240

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human lung-cancer cell gene editing, metabolite ratios and carbon tracing. · source_derived_draft · unverified_draft

## l-aspartate-shuttle-serine-link Redox handling connects aspartate machinery to synthesis of another amino acid. Loss of shuttle components reduced pyruvate/lactate ratios and glucose-derived serine synthesis in the studied human A549 models. Model: Human lung-cancer cell gene editing, metabolite ratios and carbon tracing. Limitations: A ratio is a redox proxy, and no dietary serine/aspartate deficiency threshold was measured. Evidence access: Primary abstract and primary figure descriptions Aspartate availability drives differential engagement of the malate-aspartate shuttle. · 2026 · https://pubmed.ncbi.nlm.nih.gov/41759528/ · DOI 10.1016/j.molcel.2026.02.004

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Mouse T-cell genetic and redox-restoration experiments.

limitations

Not evidence that NAD metabolism is irrelevant in other cell states.

nutrient_topic

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

plain_language

Correcting one metabolic measurement did not fix the nitrogen-handling problem.

primary_references

The malate shuttle detoxifies ammonia in exhausted T cells by producing 2-ketoglutarate. · 2023 · https://pubmed.ncbi.nlm.nih.gov/37813964/ · DOI 10.1038/s41590-023-01636-5

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 314–320

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse T-cell genetic and redox-restoration experiments. · source_derived_draft · unverified_draft

## l-aspartate-tcell-redox-insufficient Correcting one metabolic measurement did not fix the nitrogen-handling problem. Increasing the NAD+/NADH ratio did not restore the impaired antiviral T-cell response after Got1 loss in the tested chronic-infection setting. Model: Mouse T-cell genetic and redox-restoration experiments. Limitations: Not evidence that NAD metabolism is irrelevant in other cell states. Evidence access: Primary abstract The malate shuttle detoxifies ammonia in exhausted T cells by producing 2-ketoglutarate. · 2023 · https://pubmed.ncbi.nlm.nih.gov/37813964/ · DOI 10.1038/s41590-023-01636-5

cross_nutrient

Nicotinamide cofactors connect folate chemistry to redox metabolism.

experimental_model

Purified recombinant enzyme

exposure

Assay conditions described in the linked primary study.

limitations

Cellular cofactor partition is not quantified.

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

This mitochondrial enzyme extracts electrons from folate-bound carbon.

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 812–823

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-nad-oxidation Purified human MTHFD2 oxidizes 5,10-methylene-THF using NAD+ to form methenyl-THF and NADH. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: This mitochondrial enzyme extracts electrons from folate-bound carbon. organism: Homo sapiens tissue_or_cell_type: Cell-free experimental_model: Purified recombinant enzyme limitations: Cellular cofactor partition is not quantified. exposure: Assay conditions described in the linked primary study. cross_nutrient: Nicotinamide cofactors connect folate chemistry to redox metabolism. [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

cross_nutrient

Direct magnesium/phosphate requirement in folate oxidation.

experimental_model

Cofactor omission/addition assays

exposure

Assay conditions described in the linked primary study.

limitations

No dietary magnesium threshold follows from these assays.

nutrient_topic

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

organism

Rattus norvegicus

plain_language

Magnesium supports this NAD-linked folate reaction.

primary_references

[shin-2014] Mitochondrial MTHFD2L is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase expressed in both adult and embryonic tissues (2014). https://pubmed.ncbi.nlm.nih.gov/24733394/ DOI: 10.1074/jbc.m114.555573

tissue_or_cell_type

Cell-free

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 862–873

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

### rat-mthfd2l-magnesium-phosphate The NAD+-dependent rat MTHFD2L dehydrogenase assay requires magnesium in the presence of phosphate. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Magnesium supports this NAD-linked folate reaction. organism: Rattus norvegicus tissue_or_cell_type: Cell-free experimental_model: Cofactor omission/addition assays limitations: No dietary magnesium threshold follows from these assays. exposure: Assay conditions described in the linked primary study. cross_nutrient: Direct magnesium/phosphate requirement in folate oxidation. [shin-2014] Mitochondrial MTHFD2L is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase expressed in both adult and embryonic tissues (2014). https://pubmed.ncbi.nlm.nih.gov/24733394/ DOI: 10.1074/jbc.m114.555573

experimental_model

Purified recombinant rat protein

exposure

Assay conditions described in the linked primary study.

limitations

Human ortholog flux was not measured.

nutrient_topic

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

organism

Rattus norvegicus

plain_language

A second mitochondrial enzyme can use either electron carrier.

primary_references

[shin-2014] Mitochondrial MTHFD2L is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase expressed in both adult and embryonic tissues (2014). https://pubmed.ncbi.nlm.nih.gov/24733394/ DOI: 10.1074/jbc.m114.555573

tissue_or_cell_type

Cell-free

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 838–848

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

### rat-mthfd2l-oxidation Rat MTHFD2L catalyzes methylene-THF oxidation with either NAD+ or NADP+. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: A second mitochondrial enzyme can use either electron carrier. organism: Rattus norvegicus tissue_or_cell_type: Cell-free experimental_model: Purified recombinant rat protein limitations: Human ortholog flux was not measured. exposure: Assay conditions described in the linked primary study. [shin-2014] Mitochondrial MTHFD2L is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase expressed in both adult and embryonic tissues (2014). https://pubmed.ncbi.nlm.nih.gov/24733394/ DOI: 10.1074/jbc.m114.555573

cross_nutrient

Direct magnesium/phosphate requirement in folate oxidation.

experimental_model

Cofactor omission/addition assays

exposure

Assay conditions described in the linked primary study.

limitations

No dietary magnesium threshold follows from these assays.

nutrient_topic

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

organism

Rattus norvegicus

plain_language

Phosphate is another required partner in the NAD-linked reaction.

primary_references

[shin-2014] Mitochondrial MTHFD2L is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase expressed in both adult and embryonic tissues (2014). https://pubmed.ncbi.nlm.nih.gov/24733394/ DOI: 10.1074/jbc.m114.555573

tissue_or_cell_type

Cell-free

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1321–1332

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

### rat-mthfd2l-phosphate-nad-requirement The NAD+-dependent rat MTHFD2L assay also requires phosphate in the presence of magnesium. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Phosphate is another required partner in the NAD-linked reaction. organism: Rattus norvegicus tissue_or_cell_type: Cell-free experimental_model: Cofactor omission/addition assays limitations: No dietary magnesium threshold follows from these assays. exposure: Assay conditions described in the linked primary study. cross_nutrient: Direct magnesium/phosphate requirement in folate oxidation. [shin-2014] Mitochondrial MTHFD2L is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase expressed in both adult and embryonic tissues (2014). https://pubmed.ncbi.nlm.nih.gov/24733394/ DOI: 10.1074/jbc.m114.555573

cross_nutrient

Direct magnesium/phosphate requirement in folate oxidation.

experimental_model

Cofactor omission/addition assays

exposure

Assay conditions described in the linked primary study.

limitations

No dietary magnesium threshold follows from these assays.

nutrient_topic

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

organism

Rattus norvegicus

plain_language

The same phosphate has the opposite effect with the alternative electron carrier.

primary_references

[shin-2014] Mitochondrial MTHFD2L is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase expressed in both adult and embryonic tissues (2014). https://pubmed.ncbi.nlm.nih.gov/24733394/ DOI: 10.1074/jbc.m114.555573

tissue_or_cell_type

Cell-free

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1334–1345

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

### rat-mthfd2l-phosphate-nadp-inhibition Inorganic phosphate inhibits the NADP+-dependent dehydrogenase activity of rat MTHFD2L. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The same phosphate has the opposite effect with the alternative electron carrier. organism: Rattus norvegicus tissue_or_cell_type: Cell-free experimental_model: Cofactor omission/addition assays limitations: No dietary magnesium threshold follows from these assays. exposure: Assay conditions described in the linked primary study. cross_nutrient: Direct magnesium/phosphate requirement in folate oxidation. [shin-2014] Mitochondrial MTHFD2L is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase expressed in both adult and embryonic tissues (2014). https://pubmed.ncbi.nlm.nih.gov/24733394/ DOI: 10.1074/jbc.m114.555573

evidence_span

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experimental_model

X-ray crystallography of horse liver alcohol dehydrogenase at 2.9 angstrom

exposure

Inhibitor-bound and coenzyme-bound states

limitations

The founding structure of the enzyme family, in horse liver enzyme. It establishes where the zinc and the coenzyme sit; it is not a human kinetic measurement.

nutrient_topic

Alcohol research collection; topical membership is not evidence of a direct clinical effect, and ethanol is recorded separately from the acetaldehyde it becomes. · Ethanol

organism

Horse enzyme

plain_language

The zinc that does the chemistry sits at the bottom of a deep slot, far from the surface.

primary_references

[alcohol-p4365379] Structure of liver alcohol dehydrogenase at 2.9-angstrom resolution. (1973). https://pubmed.ncbi.nlm.nih.gov/4365379/ DOI: 10.1073/pnas.70.8.2439

tissue_or_cell_type

Purified dimeric enzyme

Alcohol: ethanol clearance, acetaldehyde, the channels it binds, organ injury and nutrient collisions (2026-09-21) · lines 59–70

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · X-ray crystallography of horse liver alcohol dehydrogenase at 2.9 angstrom · source_derived_draft · unverified_draft

### alcohol-adh-catalytic-zinc-position Each subunit of the dimeric enzyme is organised into two unequal parts separated by a wide deep active-site cleft, with the catalytic zinc atoms bound at the bottom of the clefts about 20 angstrom from the molecular surface, and the adenosine moiety of the coenzyme bound within the smaller region. Condition category: normal nutrient_topic: Alcohol research collection; topical membership is not evidence of a direct clinical effect, and ethanol is recorded separately from the acetaldehyde it becomes. plain_language: The zinc that does the chemistry sits at the bottom of a deep slot, far from the surface. organism: Horse enzyme tissue_or_cell_type: Purified dimeric enzyme experimental_model: X-ray crystallography of horse liver alcohol dehydrogenase at 2.9 angstrom limitations: The founding structure of the enzyme family, in horse liver enzyme. It establishes where the zinc and the coenzyme sit; it is not a human kinetic measurement. exposure: Inhibitor-bound and coenzyme-bound states evidence_span: {"source_cache": "artifacts/alcohol-research/4365379.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "857dc9a65cac403f6591e0f33ea1bd3295f4a997274a26c362a3f392dbe9c987", "start_char": 0, "end_char": 912, "text_sha256": "857dc9a65cac403f6591e0f33ea1bd3295f4a997274a26c362a3f392dbe9c987"} [alcohol-p4365379] Structure of liver alcohol dehydrogenase at 2.9-angstrom resolution. (1973). https://pubmed.ncbi.nlm.nih.gov/4365379/ DOI: 10.1073/pnas.70.8.2439

evidence_span

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experimental_model

Freeze-clamped liver metabolite measurement in starved rats after ethanol

exposure

Single ethanol dose, sampled over 30 minutes in fed and starved animals

limitations

The classic redox measurement. Metabolite ratios are calculated from near-equilibrium assumptions rather than measured directly, which the authors state.

nutrient_topic

Alcohol research collection; topical membership is not evidence of a direct clinical effect, and ethanol is recorded separately from the acetaldehyde it becomes. · Ethanol

organism

Rat

plain_language

Burning alcohol floods the cell with the reduced form of the carrier that every other pathway needs oxidised.

primary_references

[alcohol-p4342558] The time-course of the effects of ethanol on the redox and phosphorylation states of rat liver. (1972). https://pubmed.ncbi.nlm.nih.gov/4342558/ DOI: 10.1042/bj1270387

tissue_or_cell_type

Liver

Alcohol: ethanol clearance, acetaldehyde, the channels it binds, organ injury and nutrient collisions (2026-09-21) · lines 98–109

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Freeze-clamped liver metabolite measurement in starved rats after ethanol · source_derived_draft · unverified_draft

### alcohol-redox-shift Ethanol administration caused an immediate decrease in the NAD+/NADH ratio of both cytoplasm and mitochondria, which persisted over the 30 minutes studied. Condition category: normal nutrient_topic: Alcohol research collection; topical membership is not evidence of a direct clinical effect, and ethanol is recorded separately from the acetaldehyde it becomes. plain_language: Burning alcohol floods the cell with the reduced form of the carrier that every other pathway needs oxidised. organism: Rat tissue_or_cell_type: Liver experimental_model: Freeze-clamped liver metabolite measurement in starved rats after ethanol limitations: The classic redox measurement. Metabolite ratios are calculated from near-equilibrium assumptions rather than measured directly, which the authors state. exposure: Single ethanol dose, sampled over 30 minutes in fed and starved animals evidence_span: {"source_cache": "artifacts/alcohol-research/4342558.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "dce57aa8128b432a841f087e3c4e70963b8fe318e462df980e6cdd66ed4af79d", "start_char": 0, "end_char": 959, "text_sha256": "dce57aa8128b432a841f087e3c4e70963b8fe318e462df980e6cdd66ed4af79d"} [alcohol-p4342558] The time-course of the effects of ethanol on the redox and phosphorylation states of rat liver. (1972). https://pubmed.ncbi.nlm.nih.gov/4342558/ DOI: 10.1042/bj1270387

evidence_span

{"source_cache": "artifacts/phosphorus-research/4042545.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "474d2b2722565fa0e4c2f0ddf4a332715ce176f9325b9af5c22027bd6ac93e43", "start_char": 0, "end_char": 1711, "text_sha256": "474d2b2722565fa0e4c2f0ddf4a332715ce176f9325b9af5c22027bd6ac93e43"}

experimental_model

ICU erythrocyte measurements and normal-donor cell incubation

exposure

Plasma Pi 0.1–4.2 mmol/L in patients; normal-donor cells incubated at 1 or 5 mmol/L Pi

limitations

Observed ranges are not universal thresholds; ATP concentration, ATP synthetic flux and 2,3-DPG are separate endpoints.

nutrient_topic

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

organism

Human

plain_language

More phosphate accelerated the measured glycolytic output in this cell preparation.

primary_references

[phosphorus-p4042545] Phosphate metabolism in erythrocytes of critically ill patients. (1985). https://pubmed.ncbi.nlm.nih.gov/4042545/ DOI: 10.1042/cs0690435

tissue_or_cell_type

Red blood cells

Phosphorus: metabolism, signaling and nutrient connections (2026-09-17) · lines 1089–1100

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · ICU erythrocyte measurements and normal-donor cell incubation · source_derived_draft · unverified_draft

### phosphorus-rbc-lactate Raising incubation Pi from 1 to 5 mmol/L increased normal-donor erythrocyte lactate production from 2.09 to 3.11 mmol/hour/L cells. Condition category: normal nutrient_topic: Phosphorus research collection; topical membership is not evidence of a direct dietary effect. plain_language: More phosphate accelerated the measured glycolytic output in this cell preparation. organism: Human tissue_or_cell_type: Red blood cells experimental_model: ICU erythrocyte measurements and normal-donor cell incubation limitations: Observed ranges are not universal thresholds; ATP concentration, ATP synthetic flux and 2,3-DPG are separate endpoints. exposure: Plasma Pi 0.1–4.2 mmol/L in patients; normal-donor cells incubated at 1 or 5 mmol/L Pi evidence_span: {"source_cache": "artifacts/phosphorus-research/4042545.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "474d2b2722565fa0e4c2f0ddf4a332715ce176f9325b9af5c22027bd6ac93e43", "start_char": 0, "end_char": 1711, "text_sha256": "474d2b2722565fa0e4c2f0ddf4a332715ce176f9325b9af5c22027bd6ac93e43"} [phosphorus-p4042545] Phosphate metabolism in erythrocytes of critically ill patients. (1985). https://pubmed.ncbi.nlm.nih.gov/4042545/ DOI: 10.1042/cs0690435

cell_type

experimental cells

experimental_model

Metal-dependent enzyme assays

limitations

Cofactor dependence does not establish nutritional limitation.

organism

mammalian

Selenium: literature corrections and mechanism additions · lines 450–460

Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Metal-dependent enzyme assays · secondary_verified · secondary_verified

## manganese-supports-selenoo-nadase Manganese acts as a cofactor in this reaction. Mn2+ supports the reported SELENOO NAD-hydrolysis activity. Organism: mammalian Cell type: experimental cells Experimental model: Metal-dependent enzyme assays Limitations: Cofactor dependence does not establish nutritional limitation. Primary reference: [NAD+ hydrolysis catalyzed by SelO is required for mitochondrial homeostasis](https://pubmed.ncbi.nlm.nih.gov/41806834/)