S-Adenosyl-L-methionine

evidence_span

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experimental_model

Human liver fractionation and recombinant PEMT membrane-topology experiments

exposure

Protein cleavage mapping and methyltransferase localization

limitations

Three methyl transfers make a choline-containing phospholipid; PEMT does not directly synthesize free choline from nothing.

nutrient_topic

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

organism

Human enzyme

plain_language

Membrane PC synthesis and the methyl-donor pool are connected.

primary_references

[choline-p12431977] Membrane topography of human phosphatidylethanolamine N-methyltransferase. (2003). https://pubmed.ncbi.nlm.nih.gov/12431977/ DOI: 10.1074/jbc.m210904200

tissue_or_cell_type

ER and mitochondria-associated membranes

Choline: metabolism, signaling and nutrient connections (2026-09-17) · lines 815–826

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human liver fractionation and recombinant PEMT membrane-topology experiments · source_derived_draft · unverified_draft

### choline-pemt-sam SAM supplies the methyl groups for each of the three PEMT-catalyzed transfers. Condition category: normal nutrient_topic: Choline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Membrane PC synthesis and the methyl-donor pool are connected. organism: Human enzyme tissue_or_cell_type: ER and mitochondria-associated membranes experimental_model: Human liver fractionation and recombinant PEMT membrane-topology experiments limitations: Three methyl transfers make a choline-containing phospholipid; PEMT does not directly synthesize free choline from nothing. exposure: Protein cleavage mapping and methyltransferase localization evidence_span: {"source_cache": "artifacts/choline-research/12431977.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7c299a547408772f2f24bdd77f2f22dc8ea9e5aaf8179150f2d8b59c9713306a", "start_char": 0, "end_char": 1380, "text_sha256": "7c299a547408772f2f24bdd77f2f22dc8ea9e5aaf8179150f2d8b59c9713306a"} [choline-p12431977] Membrane topography of human phosphatidylethanolamine N-methyltransferase. (2003). https://pubmed.ncbi.nlm.nih.gov/12431977/ DOI: 10.1074/jbc.m210904200

evidence_span

{"source_cache": "artifacts/melatonin-research/22775292.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6896e0a7e08f764e1ff8c370601b0477c594e4e1c945df52d0f564e9049a9349", "start_char": 0, "end_char": 1205, "text_sha256": "6896e0a7e08f764e1ff8c370601b0477c594e4e1c945df52d0f564e9049a9349"}

experimental_model

X-ray structure and radioenzymatic variant characterization

exposure

SAM-dependent methyltransferase structure and enzyme activity assays

limitations

Reduced recombinant enzyme activity does not quantify pineal secretion or diagnose a sleep problem in an individual. Variant effects differ; no single universal melatonin-deficiency syndrome.

nutrient_topic

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

organism

Human ASMT and 20 nonsynonymous variants

plain_language

The methyl-donor pool connects this step to methionine and one-carbon metabolism.

primary_references

[melatonin-p22775292] Crystal structure and functional mapping of human ASMT, the last enzyme of the melatonin synthesis pathway. (2013). https://pubmed.ncbi.nlm.nih.gov/22775292/ DOI: 10.1111/j.1600-079x.2012.01020.x

tissue_or_cell_type

Final melatonin synthesis step

Melatonin: synthesis, receptors, circadian timing and nutrient interactions (2026-09-17) · lines 214–225

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · X-ray structure and radioenzymatic variant characterization · source_derived_draft · unverified_draft

### melatonin-asmt-sam Human ASMT has a SAM-dependent O-methyltransferase catalytic domain. Condition category: normal nutrient_topic: Melatonin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The methyl-donor pool connects this step to methionine and one-carbon metabolism. organism: Human ASMT and 20 nonsynonymous variants tissue_or_cell_type: Final melatonin synthesis step experimental_model: X-ray structure and radioenzymatic variant characterization limitations: Reduced recombinant enzyme activity does not quantify pineal secretion or diagnose a sleep problem in an individual. Variant effects differ; no single universal melatonin-deficiency syndrome. exposure: SAM-dependent methyltransferase structure and enzyme activity assays evidence_span: {"source_cache": "artifacts/melatonin-research/22775292.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6896e0a7e08f764e1ff8c370601b0477c594e4e1c945df52d0f564e9049a9349", "start_char": 0, "end_char": 1205, "text_sha256": "6896e0a7e08f764e1ff8c370601b0477c594e4e1c945df52d0f564e9049a9349"} [melatonin-p22775292] Crystal structure and functional mapping of human ASMT, the last enzyme of the melatonin synthesis pathway. (2013). https://pubmed.ncbi.nlm.nih.gov/22775292/ DOI: 10.1111/j.1600-079x.2012.01020.x

evidence_access

Primary abstract

experimental_model

Human CBS structural study with SAM-bound activated conformation.

limitations

Allosteric regulation does not establish in-vivo flux under every nutritional condition.

nutrient_topic

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

plain_language

A plentiful methyl donor can turn up the sulfur-transfer branch.

primary_references

Structural insight into the molecular mechanism of allosteric activation of human cystathionine β-synthase by S-adenosylmethionine. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25197074/ · DOI 10.1073/pnas.1414545111

L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 204–210

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human CBS structural study with SAM-bound activated conformation. · source_derived_draft · unverified_draft

## methionine-cbs-sam-allostery A plentiful methyl donor can turn up the sulfur-transfer branch. SAM binding rearranged the human CBS regulatory domain and relieved autoinhibition, improving access to its catalytic pocket. Model: Human CBS structural study with SAM-bound activated conformation. Limitations: Allosteric regulation does not establish in-vivo flux under every nutritional condition. Evidence access: Primary abstract Structural insight into the molecular mechanism of allosteric activation of human cystathionine β-synthase by S-adenosylmethionine. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25197074/ · DOI 10.1073/pnas.1414545111

evidence_access

Primary abstract

experimental_model

Tumor-cell and mouse experiments; construct species unresolved in accessed abstract.

limitations

Does not mean all methionine methylation suppresses immunity.

nutrient_topic

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

plain_language

The same donor can support an immune-evasion pathway in a different cell.

primary_references

Methionine deficiency facilitates antitumour immunity by altering m6A methylation of immune checkpoint transcripts. · 2023 · https://pubmed.ncbi.nlm.nih.gov/35803704/ · DOI 10.1136/gutjnl-2022-326928

L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 444–450

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Tumor-cell and mouse experiments; construct species unresolved in accessed abstract. · source_derived_draft · unverified_draft

## methionine-checkpoint-rna The same donor can support an immune-evasion pathway in a different cell. Methionine-derived SAM supported m6A modification and YTHDF1-associated translation of PD-L1 and VISTA transcripts in the tumor study. Model: Tumor-cell and mouse experiments; construct species unresolved in accessed abstract. Limitations: Does not mean all methionine methylation suppresses immunity. Evidence access: Primary abstract Methionine deficiency facilitates antitumour immunity by altering m6A methylation of immune checkpoint transcripts. · 2023 · https://pubmed.ncbi.nlm.nih.gov/35803704/ · DOI 10.1136/gutjnl-2022-326928

evidence_access

Primary full text

experimental_model

Human HEK293T and purified-protein binding/interactions.

limitations

Binding affinity is not a plasma target or supplement dose.

nutrient_topic

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

plain_language

The cell senses an activated methionine product rather than only the free amino acid.

primary_references

SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway. · 2017 · https://pubmed.ncbi.nlm.nih.gov/29123071/ · DOI 10.1126/science.aao3265

L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 228–234

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human HEK293T and purified-protein binding/interactions. · source_derived_draft · unverified_draft

## methionine-samtor-binding The cell senses an activated methionine product rather than only the free amino acid. SAM bound human SAMTOR with an approximate dissociation constant of 7 micromolar and disrupted SAMTOR interaction with GATOR1. Model: Human HEK293T and purified-protein binding/interactions. Limitations: Binding affinity is not a plasma target or supplement dose. Evidence access: Primary full text SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway. · 2017 · https://pubmed.ncbi.nlm.nih.gov/29123071/ · DOI 10.1126/science.aao3265

cross_nutrient

Methionine/SAM feedback regulates the B2-dependent folate step.

evidence_location

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

experimental_model

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

exposure

Purified-enzyme assay

limitations

In-vitro regulation; phosphorylation itself did not materially reduce catalytic turnover in this assay.

nutrient_topic

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

organism

Homo sapiens

plain_language

A methionine-cycle product regulates methylfolate production.

primary_references

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

tissue_or_cell_type

Purified recombinant enzyme; no intact tissue

Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1024–1036

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

### b2-mthfr-sam-inhibition SAM inhibited recombinant human MTHFR; phosphorylated protein was more sensitive to this inhibition than phosphatase-treated protein. Condition category: normal nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: A methionine-cycle product regulates methylfolate production. organism: Homo sapiens tissue_or_cell_type: Purified recombinant enzyme; no intact tissue experimental_model: Recombinant human MTHFR expressed in Sf9 cells; mass spectrometry, 2.5-A structure, HPLC activity assays. limitations: In-vitro regulation; phosphorylation itself did not materially reduce catalytic turnover in this assay. exposure: Purified-enzyme assay cross_nutrient: Methionine/SAM feedback regulates the B2-dependent folate step. evidence_location: Results: kinetics, FAD occupancy and SAM inhibition; Table 1; Figs 2-4, 6 [froese2018] Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition. (2018). https://pubmed.ncbi.nlm.nih.gov/29891918/ DOI: 10.1038/s41467-018-04735-2

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

Methionine-cycle feedback affects both folate-enzyme activity and B2-cofactor retention.

evidence_location

Results: FAD loss; Figs 1-3

experimental_model

Baculovirus-produced purified human wild-type, Ala222Val, Glu429Ala and double-mutant MTHFR; dilution/cofactor-release assays.

exposure

Purified-enzyme assay

limitations

In-vitro effects; stabilization is not equivalent to increased reaction flux.

nutrient_topic

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

organism

Homo sapiens

plain_language

Cofactor retention and catalytic speed respond differently to SAM.

primary_references

[yamada2001] Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductase. (2001). https://pubmed.ncbi.nlm.nih.gov/11742092/ DOI: 10.1073/pnas.261469998

tissue_or_cell_type

Purified recombinant enzyme; no intact tissue

trigger_kind

machinery_impairment Imported condition classification; unverified.

Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1066–1078

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Baculovirus-produced purified human wild-type, Ala222Val, Glu429Ala and double-mutant MTHFR; dilution/cofactor-release assays. · source_derived_draft · unverified_draft

### b2-sam-mthfr-retention SAM slowed FAD dissociation after MTHFR dilution, including Ala222Val, despite its separate reversible inhibition of catalytic activity. Condition category: machinery_impairment nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Cofactor retention and catalytic speed respond differently to SAM. organism: Homo sapiens tissue_or_cell_type: Purified recombinant enzyme; no intact tissue experimental_model: Baculovirus-produced purified human wild-type, Ala222Val, Glu429Ala and double-mutant MTHFR; dilution/cofactor-release assays. limitations: In-vitro effects; stabilization is not equivalent to increased reaction flux. exposure: Purified-enzyme assay cross_nutrient: Methionine-cycle feedback affects both folate-enzyme activity and B2-cofactor retention. evidence_location: Results: FAD loss; Figs 1-3 [yamada2001] Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductase. (2001). https://pubmed.ncbi.nlm.nih.gov/11742092/ DOI: 10.1073/pnas.261469998

evidence_access

Primary abstract

experimental_model

Apo and ligand-bound enzyme structures.

limitations

No evidence that human ergothioneine consumption drains SAM; humans lack this established synthesis pathway.

nutrient_topic

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

plain_language

The microbial synthesis branch connects to methyl-donor chemistry.

primary_references

Structural insights into the histidine trimethylation activity of EgtD from Mycobacterium smegmatis. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25251321/ · DOI 10.1016/j.bbrc.2014.09.058

Ergothioneine: transport, redox chemistry and cross-nutrient mechanisms (2026-09-19) · lines 552–558

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Apo and ligand-bound enzyme structures. · source_derived_draft · unverified_draft

## ergothioneine-egtd-sam The microbial synthesis branch connects to methyl-donor chemistry. Mycobacterium smegmatis EgtD uses SAM-dependent methyl transfer to convert histidine into hercynine. Model: Apo and ligand-bound enzyme structures. Limitations: No evidence that human ergothioneine consumption drains SAM; humans lack this established synthesis pathway. Evidence access: Primary abstract Structural insights into the histidine trimethylation activity of EgtD from Mycobacterium smegmatis. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25251321/ · DOI 10.1016/j.bbrc.2014.09.058

evidence_span

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experimental_model

Purified human LIAS turnover and cluster-transfer assays

exposure

LIAS with candidate iron-sulfur cluster donors

limitations

Cell-free transfer distinguishes direct donor activity from upstream functions in intact cells.

nutrient_topic

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

organism

Human recombinant proteins

plain_language

SAM supplies radical chemistry here; this reaction is not methyl-group transfer.

primary_references

[ala-p36281303] In Vitro Demonstration of Human Lipoyl Synthase Catalytic Activity in the Presence of NFU1. (2022). https://pubmed.ncbi.nlm.nih.gov/36281303/ DOI: 10.1021/acsbiomedchemau.2c00020

tissue_or_cell_type

Mitochondrial lipoyl synthesis machinery

Alpha-lipoic acid: cofactor assembly, redox signaling and nutrient interactions (2026-09-17) · lines 286–297

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human LIAS turnover and cluster-transfer assays · source_derived_draft · unverified_draft

### ala-lias-sam-radical LIAS cleaves SAM to generate a 5-deoxyadenosyl radical that initiates hydrogen abstraction from the octanoyl substrate. Condition category: normal nutrient_topic: Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: SAM supplies radical chemistry here; this reaction is not methyl-group transfer. organism: Human recombinant proteins tissue_or_cell_type: Mitochondrial lipoyl synthesis machinery experimental_model: Purified human LIAS turnover and cluster-transfer assays limitations: Cell-free transfer distinguishes direct donor activity from upstream functions in intact cells. exposure: LIAS with candidate iron-sulfur cluster donors evidence_span: {"source_cache": "artifacts/ala-research/36281303.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "29a716d2027786ee1eefa5380aca1ddc035ec330409162f3d4e61db20015780f", "start_char": 0, "end_char": 1732, "text_sha256": "29a716d2027786ee1eefa5380aca1ddc035ec330409162f3d4e61db20015780f"} [ala-p36281303] In Vitro Demonstration of Human Lipoyl Synthase Catalytic Activity in the Presence of NFU1. (2022). https://pubmed.ncbi.nlm.nih.gov/36281303/ DOI: 10.1021/acsbiomedchemau.2c00020

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

Boron can attach to SAM in a test tube; this does not show that it supplies methyl groups or improves methylation.

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 92–103

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-sam-binding S-adenosylmethionine formed a boron complex in capillary-electrophoresis experiments and ranked among the strongest ligands tested. Condition category: normal nutrient_topic: Boron research collection; topical membership is not evidence of a direct dietary effect. plain_language: Boron can attach to SAM in a test tube; this does not show that it supplies methyl groups or improves methylation. 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_access

Primary abstract

experimental_model

Simulation based on purified CBS/CSE kinetics with assumed equimolar enzyme concentrations.

limitations

A modeled 25–70% contribution is not a directly measured universal human tissue fraction.

nutrient_topic

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

plain_language

Methylation-cycle chemistry can influence a sulfur-signaling branch.

primary_references

Relative contributions of cystathionine beta-synthase and gamma-cystathionase to H2S biogenesis via alternative trans-sulfuration reactions. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19531479/ · DOI 10.1074/jbc.M109.010868

L-Cysteine: sulfur allocation, redox supply and cross-nutrient mechanisms (2026-09-19) · lines 292–298

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Simulation based on purified CBS/CSE kinetics with assumed equimolar enzyme concentrations. · source_derived_draft · unverified_draft

## l-cysteine-sam-sulfur-partition Methylation-cycle chemistry can influence a sulfur-signaling branch. Kinetic simulations predicted that SAM-dependent activation changes the relative CBS contribution to H2S generation at specified substrate concentrations. Model: Simulation based on purified CBS/CSE kinetics with assumed equimolar enzyme concentrations. Limitations: A modeled 25–70% contribution is not a directly measured universal human tissue fraction. Evidence access: Primary abstract Relative contributions of cystathionine beta-synthase and gamma-cystathionase to H2S biogenesis via alternative trans-sulfuration reactions. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19531479/ · DOI 10.1074/jbc.M109.010868

experimental_model

Recombinant human MTHFR; cryo-EM and biochemistry.

limitations

Not a whole-body SAM threshold.

nutrient_topic

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

organism

Homo sapiens

plain_language

SAM switches MTHFR into a closed shape.

primary_references

[mthfr-allostery-2024] Dynamic inter-domain transformations mediate the allosteric regulation of human 5, 10-methylenetetrahydrofolate reductase (2024). https://pubmed.ncbi.nlm.nih.gov/38622112/ DOI: 10.1038/s41467-024-47174-y

tissue_or_cell_type

Purified protein

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 460–469

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

### folate-methyl-sam-dual-binding Dual SAM binding rearranged the human MTHFR linker and inserted a loop that blocked catalytic substrate access. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: SAM switches MTHFR into a closed shape. organism: Homo sapiens tissue_or_cell_type: Purified protein experimental_model: Recombinant human MTHFR; cryo-EM and biochemistry. limitations: Not a whole-body SAM threshold. [mthfr-allostery-2024] Dynamic inter-domain transformations mediate the allosteric regulation of human 5, 10-methylenetetrahydrofolate reductase (2024). https://pubmed.ncbi.nlm.nih.gov/38622112/ DOI: 10.1038/s41467-024-47174-y

evidence_access

Primary abstract

experimental_model

Human S-adenosylmethionine decarboxylase biochemical study.

limitations

Do not confuse aminopropyl donation with GAMT methyl transfer.

nutrient_topic

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

plain_language

SAM must be chemically changed before this branch uses it.

primary_references

Structural basis for putrescine activation of human S-adenosylmethionine decarboxylase. · 2008 · https://pubmed.ncbi.nlm.nih.gov/19053272/ · DOI 10.1021/bi801732m

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 150–156

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human S-adenosylmethionine decarboxylase biochemical study. · source_derived_draft · unverified_draft

## arg-amd-reaction SAM must be chemically changed before this branch uses it. AMD1 decarboxylation generates the aminopropyl donor used in polyamine synthesis. Model: Human S-adenosylmethionine decarboxylase biochemical study. Limitations: Do not confuse aminopropyl donation with GAMT methyl transfer. Evidence access: Primary abstract Structural basis for putrescine activation of human S-adenosylmethionine decarboxylase. · 2008 · https://pubmed.ncbi.nlm.nih.gov/19053272/ · DOI 10.1021/bi801732m

evidence_span

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experimental_model

Human soluble COMT crystallography and deposited structure 3BWM

exposure

SAM and 3,5-dinitrocatechol-bound crystals; deposited Mg ion

limitations

Structural cofactor connection, not a CGA-magnesium supplementation trial. Human and rat COMT specificity differs; deposition includes an inhibitor analog rather than CGA.

nutrient_topic

Chlorogenic acid research collection; topical membership is not evidence of a direct dietary effect. · Chlorogenic acid / 5-O-caffeoylquinic acid

organism

Homo sapiens

plain_language

The shared methyl donor links COMT to methionine-cycle metabolism.

primary_references

[chlorogenic_acid-p18486144] Crystal structures of human 108V and 108M catechol O-methyltransferase. (2008). https://pubmed.ncbi.nlm.nih.gov/18486144/ DOI: 10.1016/j.jmb.2008.04.040

tissue_or_cell_type

Purified soluble COMT

Chlorogenic acid: metabolism, signaling and nutrient connections (2026-09-17) · lines 841–852

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human soluble COMT crystallography and deposited structure 3BWM · source_derived_draft · unverified_draft

### chlorogenic_acid-human-comt-sam Human soluble COMT structures resolve bound SAM. Condition category: normal nutrient_topic: Chlorogenic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The shared methyl donor links COMT to methionine-cycle metabolism. organism: Homo sapiens tissue_or_cell_type: Purified soluble COMT experimental_model: Human soluble COMT crystallography and deposited structure 3BWM limitations: Structural cofactor connection, not a CGA-magnesium supplementation trial. Human and rat COMT specificity differs; deposition includes an inhibitor analog rather than CGA. exposure: SAM and 3,5-dinitrocatechol-bound crystals; deposited Mg ion evidence_span: {"source_cache": "artifacts/chlorogenic_acid-research/18486144.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9cafbfc9353f49fab9919bc64608f21f445ace4b190771e44088a5a746e5a6e3", "start_char": 0, "end_char": 1961, "text_sha256": "9cafbfc9353f49fab9919bc64608f21f445ace4b190771e44088a5a746e5a6e3"} [chlorogenic_acid-p18486144] Crystal structures of human 108V and 108M catechol O-methyltransferase. (2008). https://pubmed.ncbi.nlm.nih.gov/18486144/ DOI: 10.1016/j.jmb.2008.04.040

evidence_span

{"source_cache": "artifacts/coq10-research/38425362.fulltext.txt", "locator": "Primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7d25af4ecd7340649536b8fea3b8a0a308a1611bbf8c57f6a79b362f443f1cba", "start_char": 13814, "end_char": 15577, "text_sha256": "c43de1ac5dc6711fad8e37af3a52a8cd9784ed7eeaf77bd2981afe72abaf307f"}

experimental_model

Purified reconstructed COQ metabolon with short-chain substrates

exposure

Enzyme combinations, methyl donors, reductants and metal additions

limitations

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

nutrient_topic

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

organism

Reconstructed ancestral tetrapod proteins

plain_language

CoQ synthesis shares the methyl-donor pool used by other pathways.

primary_references

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

tissue_or_cell_type

Stepwise CoQ head-group assembly

Coenzyme Q10: biosynthesis, electron transfer, antioxidant recycling and nutrient interactions (2026-09-17) · lines 645–656

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

### coq10-coq3-sam COQ3 methylated the tested precursor in the presence of SAM. Condition category: normal nutrient_topic: Coenzyme Q10 research collection; topical membership is not evidence of a direct dietary effect. plain_language: CoQ synthesis shares the methyl-donor pool used by other pathways. organism: Reconstructed ancestral tetrapod proteins tissue_or_cell_type: Stepwise CoQ head-group assembly experimental_model: Purified reconstructed COQ metabolon with short-chain substrates limitations: Ancestral proteins and CoQ1 analogues; no clinical cofactor dose or proof of nutritional rate limitation. Reaction order need not be universal across species. exposure: Enzyme combinations, methyl donors, reductants and metal additions evidence_span: {"source_cache": "artifacts/coq10-research/38425362.fulltext.txt", "locator": "Primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7d25af4ecd7340649536b8fea3b8a0a308a1611bbf8c57f6a79b362f443f1cba", "start_char": 13814, "end_char": 15577, "text_sha256": "c43de1ac5dc6711fad8e37af3a52a8cd9784ed7eeaf77bd2981afe72abaf307f"} [coq10-p38425362] In vitro construction of the COQ metabolon unveils the molecular determinants of coenzyme Q biosynthesis. (2024). https://pubmed.ncbi.nlm.nih.gov/38425362/ DOI: 10.1038/s41929-023-01087-z

evidence_span

{"source_cache": "artifacts/coq10-research/38425362.fulltext.txt", "locator": "Primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7d25af4ecd7340649536b8fea3b8a0a308a1611bbf8c57f6a79b362f443f1cba", "start_char": 23488, "end_char": 27391, "text_sha256": "7147c9d517477cd7bbec4a155e5f13bc733d294380975977eba11b64517047f3"}

experimental_model

Purified reconstructed COQ metabolon with short-chain substrates

exposure

Enzyme combinations, methyl donors, reductants and metal additions

limitations

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

nutrient_topic

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

organism

Reconstructed ancestral tetrapod proteins

plain_language

A second methylating enzyme links CoQ assembly to methyl-donor availability.

primary_references

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

tissue_or_cell_type

Stepwise CoQ head-group assembly

Coenzyme Q10: biosynthesis, electron transfer, antioxidant recycling and nutrient interactions (2026-09-17) · lines 710–721

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

### coq10-coq5-sam Reconstructed COQ5 catalyzed C-methylation with SAM. Condition category: normal nutrient_topic: Coenzyme Q10 research collection; topical membership is not evidence of a direct dietary effect. plain_language: A second methylating enzyme links CoQ assembly to methyl-donor availability. organism: Reconstructed ancestral tetrapod proteins tissue_or_cell_type: Stepwise CoQ head-group assembly experimental_model: Purified reconstructed COQ metabolon with short-chain substrates limitations: Ancestral proteins and CoQ1 analogues; no clinical cofactor dose or proof of nutritional rate limitation. Reaction order need not be universal across species. exposure: Enzyme combinations, methyl donors, reductants and metal additions evidence_span: {"source_cache": "artifacts/coq10-research/38425362.fulltext.txt", "locator": "Primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7d25af4ecd7340649536b8fea3b8a0a308a1611bbf8c57f6a79b362f443f1cba", "start_char": 23488, "end_char": 27391, "text_sha256": "7147c9d517477cd7bbec4a155e5f13bc733d294380975977eba11b64517047f3"} [coq10-p38425362] In vitro construction of the COQ metabolon unveils the molecular determinants of coenzyme Q biosynthesis. (2024). https://pubmed.ncbi.nlm.nih.gov/38425362/ DOI: 10.1038/s41929-023-01087-z

evidence_access

Primary abstract

experimental_model

Human transporter-variant study with functional assays.

limitations

Transporter role and disease consequences are separately recorded.

nutrient_topic

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

plain_language

Making SAM outside mitochondria is not enough; it must reach the organelle.

primary_references

Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26522469/ · DOI 10.1016/j.ajhg.2015.09.013

transport_effect

raises Recorded as import of cytosol-derived SAM into mitochondria.

transport_pool

the mitochondrial matrix Recorded as import of cytosol-derived SAM into mitochondria.

L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 108–114

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human transporter-variant study with functional assays. · source_derived_draft · unverified_draft

## methionine-mitochondrial-sam-entry Making SAM outside mitochondria is not enough; it must reach the organelle. Human SLC25A26 imports cytosol-derived SAM into mitochondria for intramitochondrial methylation. Model: Human transporter-variant study with functional assays. Limitations: Transporter role and disease consequences are separately recorded. Evidence access: Primary abstract Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26522469/ · DOI 10.1016/j.ajhg.2015.09.013

evidence_span

{"source_cache": "artifacts/creatine-research/11595668.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "b195a8b17815bf7d9223831374e2f85ae2f90d8d74117ad7aa8d94af7a9e94b0", "start_char": 0, "end_char": 1687, "text_sha256": "b195a8b17815bf7d9223831374e2f85ae2f90d8d74117ad7aa8d94af7a9e94b0"}

experimental_model

Rat methyl-demand feeding and hepatocyte experiments; reaction context from the primary report

exposure

Guanidinoacetate, creatine and methionine exposures

limitations

The reaction record preserves the biochemical context of this primary experiment; it does not establish a universal fraction of human methylation demand.

nutrient_topic

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

organism

Rats

plain_language

Methionine must first be activated into SAM before its methyl group can finish creatine synthesis.

primary_references

[creatine-p11595668] Methylation demand and homocysteine metabolism: effects of dietary provision of creatine and guanidinoacetate. (2001). https://pubmed.ncbi.nlm.nih.gov/11595668/ DOI: 10.1152/ajpendo.2001.281.5.e1095

tissue_or_cell_type

Liver and isolated hepatocytes

Creatine: synthesis, transport, phosphocreatine energetics and nutrient interactions (2026-09-17) · lines 217–228

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat methyl-demand feeding and hepatocyte experiments; reaction context from the primary report · source_derived_draft · unverified_draft

### creatine-methionine-sam-supply Methionine adenosylation supplies SAM, the methyl donor consumed when guanidinoacetate is converted to creatine. Condition category: normal nutrient_topic: Creatine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Methionine must first be activated into SAM before its methyl group can finish creatine synthesis. organism: Rats tissue_or_cell_type: Liver and isolated hepatocytes experimental_model: Rat methyl-demand feeding and hepatocyte experiments; reaction context from the primary report limitations: The reaction record preserves the biochemical context of this primary experiment; it does not establish a universal fraction of human methylation demand. exposure: Guanidinoacetate, creatine and methionine exposures evidence_span: {"source_cache": "artifacts/creatine-research/11595668.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "b195a8b17815bf7d9223831374e2f85ae2f90d8d74117ad7aa8d94af7a9e94b0", "start_char": 0, "end_char": 1687, "text_sha256": "b195a8b17815bf7d9223831374e2f85ae2f90d8d74117ad7aa8d94af7a9e94b0"} [creatine-p11595668] Methylation demand and homocysteine metabolism: effects of dietary provision of creatine and guanidinoacetate. (2001). https://pubmed.ncbi.nlm.nih.gov/11595668/ DOI: 10.1152/ajpendo.2001.281.5.e1095

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

B2/MTHFR connects folate-dependent remethylation with methionine-cycle biomarkers.

experimental_model

Archived samples from prior BP trials: 115 genotype-characterized adults; TT intervention subset 24 riboflavin and 23 placebo.

exposure

1.6 mg/day riboflavin or placebo for 16 weeks; LC-MS/MS plasma metabolites; secondary analysis, not a new independent trial.

limitations

Secondary sample analysis of prior BP trials; plasma SAM is not tissue SAM flux, DNA methylation, epigenetic silencing or a proved mediator of BP.

nutrient_topic

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

organism

Homo sapiens

plain_language

B2 changed selected circulating methylation-related metabolites; the study did not show that every tissue had been short of methyl groups.

primary_references

[b2-robinson2020] Impact of the MTHFR C677T polymorphism on one-carbon metabolites: Evidence from a randomised trial of riboflavin supplementation (2020). https://pubmed.ncbi.nlm.nih.gov/32330571/ DOI: 10.1016/j.biochi.2020.04.004

tissue_or_cell_type

Human clinical setting

trigger_kind

machinery_impairment Imported condition classification; unverified.

Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1514–1525

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Archived samples from prior BP trials: 115 genotype-characterized adults; TT intervention subset 24 riboflavin and 23 placebo. · source_derived_draft · unverified_draft

### b2-tt-plasma-sam-response In the 47-person TT intervention subset, riboflavin increased plasma SAM and cystathionine; no response was detected in the other measured one-carbon metabolites. Condition category: machinery_impairment nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: B2 changed selected circulating methylation-related metabolites; the study did not show that every tissue had been short of methyl groups. organism: Homo sapiens tissue_or_cell_type: Human clinical setting experimental_model: Archived samples from prior BP trials: 115 genotype-characterized adults; TT intervention subset 24 riboflavin and 23 placebo. limitations: Secondary sample analysis of prior BP trials; plasma SAM is not tissue SAM flux, DNA methylation, epigenetic silencing or a proved mediator of BP. exposure: 1.6 mg/day riboflavin or placebo for 16 weeks; LC-MS/MS plasma metabolites; secondary analysis, not a new independent trial. cross_nutrient: B2/MTHFR connects folate-dependent remethylation with methionine-cycle biomarkers. [b2-robinson2020] Impact of the MTHFR C677T polymorphism on one-carbon metabolites: Evidence from a randomised trial of riboflavin supplementation (2020). https://pubmed.ncbi.nlm.nih.gov/32330571/ DOI: 10.1016/j.biochi.2020.04.004

evidence_span

{"source_cache": "artifacts/molybdenum-research/15180982.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "722c11f1c29a720fb7105f37962af2652ce95b6734afdb59d675dee0b8302097", "start_char": 0, "end_char": 1828, "text_sha256": "722c11f1c29a720fb7105f37962af2652ce95b6734afdb59d675dee0b8302097"}

experimental_model

Recombinant human MOCS1A, cysteine mutagenesis and multiple spectroscopic methods

exposure

Aerobic versus anaerobic purification; iron-sulfur reconstitution

limitations

The human protein study characterized clusters and essential cysteines; no human methylation-cycle depletion or clinical SAM requirement was measured.

nutrient_topic

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

organism

Human protein expressed in Escherichia coli

plain_language

SAM participates in radical chemistry here; this is a different use from donating a methyl group to DNA.

primary_references

[mo-p15180982] Characterization of MOCS1A, an oxygen-sensitive iron-sulfur protein involved in human molybdenum cofactor biosynthesis. (2004). https://pubmed.ncbi.nlm.nih.gov/15180982/ DOI: 10.1074/jbc.m313398200

tissue_or_cell_type

Purified protein and bacterial complementation

Molybdenum: cofactor assembly, sulfur metabolism and nutrient interactions (2026-09-17) · lines 326–337

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human MOCS1A, cysteine mutagenesis and multiple spectroscopic methods · source_derived_draft · unverified_draft

### mo-mocs1a-radical-sam MOCS1A contains a redox-active N-terminal [4Fe-4S] cluster coordinated by the conserved radical-SAM cysteine motif. Condition category: normal nutrient_topic: Molybdenum research collection; topical membership is not evidence of a direct dietary effect. plain_language: SAM participates in radical chemistry here; this is a different use from donating a methyl group to DNA. organism: Human protein expressed in Escherichia coli tissue_or_cell_type: Purified protein and bacterial complementation experimental_model: Recombinant human MOCS1A, cysteine mutagenesis and multiple spectroscopic methods limitations: The human protein study characterized clusters and essential cysteines; no human methylation-cycle depletion or clinical SAM requirement was measured. exposure: Aerobic versus anaerobic purification; iron-sulfur reconstitution evidence_span: {"source_cache": "artifacts/molybdenum-research/15180982.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "722c11f1c29a720fb7105f37962af2652ce95b6734afdb59d675dee0b8302097", "start_char": 0, "end_char": 1828, "text_sha256": "722c11f1c29a720fb7105f37962af2652ce95b6734afdb59d675dee0b8302097"} [mo-p15180982] Characterization of MOCS1A, an oxygen-sensitive iron-sulfur protein involved in human molybdenum cofactor biosynthesis. (2004). https://pubmed.ncbi.nlm.nih.gov/15180982/ DOI: 10.1074/jbc.m313398200

availability_state

machinery_impairment Imported condition classification; unverified.

experimental_model

Bhmt-null mice and wild-type controls.

limitations

Concentration is not methylation flux.

nutrient_topic

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

organism

Mus musculus

plain_language

The hepatic methyl-donor pool fell.

primary_references

[teng-2011] Deletion of betaine-homocysteine S-methyltransferase in mice perturbs choline and 1-carbon metabolism, resulting in fatty liver and hepatocellular carcinomas (2011). https://pubmed.ncbi.nlm.nih.gov/21878621/ DOI: 10.1074/jbc.m111.265348

tissue_or_cell_type

Liver

trigger_kind

machinery_impairment Imported condition classification; unverified.

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 646–655

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Bhmt-null mice and wild-type controls. · source_derived_draft · unverified_draft

### folate-methyl-bhmt-ko-sam Bhmt-null mouse liver contained 43% less SAM than wild type. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The hepatic methyl-donor pool fell. organism: Mus musculus tissue_or_cell_type: Liver experimental_model: Bhmt-null mice and wild-type controls. limitations: Concentration is not methylation flux. [teng-2011] Deletion of betaine-homocysteine S-methyltransferase in mice perturbs choline and 1-carbon metabolism, resulting in fatty liver and hepatocellular carcinomas (2011). https://pubmed.ncbi.nlm.nih.gov/21878621/ DOI: 10.1074/jbc.m111.265348

availability_state

machinery_impairment Imported condition classification; unverified.

experimental_model

Bhmt-null and wild-type mice; four-week folate feeding.

exposure

Four-week feeding

limitations

No proof of restored DNA methylation.

nutrient_topic

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

organism

Mus musculus

plain_language

SAM improved despite persistent high homocysteine.

primary_references

[teng-2012] Homocysteinemia in mice with genetic betaine homocysteine S-methyltransferase deficiency is independent of dietary folate intake (2012). https://pubmed.ncbi.nlm.nih.gov/23014492/ DOI: 10.3945/jn.112.166835

tissue_or_cell_type

Liver

trigger_kind

machinery_impairment Imported condition classification; unverified.

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 681–691

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Bhmt-null and wild-type mice; four-week folate feeding. · source_derived_draft · unverified_draft

### folate-methyl-folate-sam-bhmt The 20 mg folate/kg diet increased hepatic SAM in Bhmt-null mice versus 0 and 2 mg/kg diets. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: SAM improved despite persistent high homocysteine. organism: Mus musculus tissue_or_cell_type: Liver experimental_model: Bhmt-null and wild-type mice; four-week folate feeding. limitations: No proof of restored DNA methylation. exposure: Four-week feeding [teng-2012] Homocysteinemia in mice with genetic betaine homocysteine S-methyltransferase deficiency is independent of dietary folate intake (2012). https://pubmed.ncbi.nlm.nih.gov/23014492/ DOI: 10.3945/jn.112.166835

evidence_span

{"source_cache": "artifacts/phosphorus-research/33656855.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1d45073f7187a06cfb9b2d630f94fa651239f0a9a5ae353b37d9af90750f2f38", "start_char": 0, "end_char": 1520, "text_sha256": "1d45073f7187a06cfb9b2d630f94fa651239f0a9a5ae353b37d9af90750f2f38"}

experimental_model

Human MAT2A kinetics, isotope exchange and inhibitor-bound crystallography

exposure

ATP/methionine reactions and PNPNP ligand complexes

limitations

Phosphoryl chemistry is not evidence that phosphate supplements boost methylation. Metal contacts were resolved with an experimental ATP-site ligand.

nutrient_topic

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

organism

Human recombinant enzyme

plain_language

Making the methyl donor SAM is coupled to ATP-derived phosphate chemistry.

primary_references

[phosphorus-p33656855] Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. (2021). https://pubmed.ncbi.nlm.nih.gov/33656855/ DOI: 10.1021/acs.biochem.0c00998

tissue_or_cell_type

Purified MAT2A active site

Phosphorus: metabolism, signaling and nutrient connections (2026-09-17) · lines 633–644

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human MAT2A kinetics, isotope exchange and inhibitor-bound crystallography · source_derived_draft · unverified_draft

### phosphorus-mat-sam Human MAT2A formed S-adenosylmethionine before rapid triphosphate hydrolysis and product release in the kinetic study. Condition category: normal nutrient_topic: Phosphorus research collection; topical membership is not evidence of a direct dietary effect. plain_language: Making the methyl donor SAM is coupled to ATP-derived phosphate chemistry. organism: Human recombinant enzyme tissue_or_cell_type: Purified MAT2A active site experimental_model: Human MAT2A kinetics, isotope exchange and inhibitor-bound crystallography limitations: Phosphoryl chemistry is not evidence that phosphate supplements boost methylation. Metal contacts were resolved with an experimental ATP-site ligand. exposure: ATP/methionine reactions and PNPNP ligand complexes evidence_span: {"source_cache": "artifacts/phosphorus-research/33656855.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1d45073f7187a06cfb9b2d630f94fa651239f0a9a5ae353b37d9af90750f2f38", "start_char": 0, "end_char": 1520, "text_sha256": "1d45073f7187a06cfb9b2d630f94fa651239f0a9a5ae353b37d9af90750f2f38"} [phosphorus-p33656855] Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. (2021). https://pubmed.ncbi.nlm.nih.gov/33656855/ DOI: 10.1021/acs.biochem.0c00998

evidence_span

{"source_cache": "artifacts/chlorogenic_acid-research/16081510.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e93fafd7946f8a4aea30ff3ee9ef05e303f9154eb947410fca8e63c6521a4170", "start_char": 0, "end_char": 2008, "text_sha256": "e93fafd7946f8a4aea30ff3ee9ef05e303f9154eb947410fca8e63c6521a4170"}

experimental_model

Coupled catechol-methylation/DNA-methylation assays and breast-cancer cell experiments

exposure

CGA DNMT1 IC50 0.9 micromolar in the coupled assay; compounds tested up to 20 micromolar

limitations

These concentrations and coupled-reaction conditions do not establish whole-body methyl-donor depletion, anticancer benefit or vitamin deficiency after food intake. COMT-mediated SAH generation is distinct from direct competitive binding to DNMT1.

nutrient_topic

Chlorogenic acid research collection; topical membership is not evidence of a direct dietary effect. · Chlorogenic acid / 5-O-caffeoylquinic acid

organism

Human DNMT1 and MCF-7/MDA-MB-231 cells; COMT preparation species unresolved in abstract

plain_language

Metabolizing a catechol connects it to methyl-group chemistry.

primary_references

[chlorogenic_acid-p16081510] Inhibition of DNA methylation by caffeic acid and chlorogenic acid, two common catechol-containing coffee polyphenols. (2006). https://pubmed.ncbi.nlm.nih.gov/16081510/ DOI: 10.1093/carcin/bgi206

tissue_or_cell_type

Cell-free methyltransferase reactions and cultured cancer cells

Chlorogenic acid: metabolism, signaling and nutrient connections (2026-09-17) · lines 776–787

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Coupled catechol-methylation/DNA-methylation assays and breast-cancer cell experiments · source_derived_draft · unverified_draft

### chlorogenic_acid-comt-cga COMT-mediated O-methylation of CGA contributed to the coupled-assay response. Condition category: normal nutrient_topic: Chlorogenic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Metabolizing a catechol connects it to methyl-group chemistry. organism: Human DNMT1 and MCF-7/MDA-MB-231 cells; COMT preparation species unresolved in abstract tissue_or_cell_type: Cell-free methyltransferase reactions and cultured cancer cells experimental_model: Coupled catechol-methylation/DNA-methylation assays and breast-cancer cell experiments limitations: These concentrations and coupled-reaction conditions do not establish whole-body methyl-donor depletion, anticancer benefit or vitamin deficiency after food intake. COMT-mediated SAH generation is distinct from direct competitive binding to DNMT1. exposure: CGA DNMT1 IC50 0.9 micromolar in the coupled assay; compounds tested up to 20 micromolar evidence_span: {"source_cache": "artifacts/chlorogenic_acid-research/16081510.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e93fafd7946f8a4aea30ff3ee9ef05e303f9154eb947410fca8e63c6521a4170", "start_char": 0, "end_char": 2008, "text_sha256": "e93fafd7946f8a4aea30ff3ee9ef05e303f9154eb947410fca8e63c6521a4170"} [chlorogenic_acid-p16081510] Inhibition of DNA methylation by caffeic acid and chlorogenic acid, two common catechol-containing coffee polyphenols. (2006). https://pubmed.ncbi.nlm.nih.gov/16081510/ DOI: 10.1093/carcin/bgi206

evidence_span

{"source_cache": "artifacts/chlorogenic_acid-research/16081510.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e93fafd7946f8a4aea30ff3ee9ef05e303f9154eb947410fca8e63c6521a4170", "start_char": 0, "end_char": 2008, "text_sha256": "e93fafd7946f8a4aea30ff3ee9ef05e303f9154eb947410fca8e63c6521a4170"}

experimental_model

Coupled catechol-methylation/DNA-methylation assays and breast-cancer cell experiments

exposure

CGA DNMT1 IC50 0.9 micromolar in the coupled assay; compounds tested up to 20 micromolar

limitations

These concentrations and coupled-reaction conditions do not establish whole-body methyl-donor depletion, anticancer benefit or vitamin deficiency after food intake. COMT-mediated SAH generation is distinct from direct competitive binding to DNMT1.

nutrient_topic

Chlorogenic acid research collection; topical membership is not evidence of a direct dietary effect. · Chlorogenic acid / 5-O-caffeoylquinic acid

organism

Human DNMT1 and MCF-7/MDA-MB-231 cells; COMT preparation species unresolved in abstract

plain_language

Using a methyl donor leaves a product that can restrain other methyltransferases.

primary_references

[chlorogenic_acid-p16081510] Inhibition of DNA methylation by caffeic acid and chlorogenic acid, two common catechol-containing coffee polyphenols. (2006). https://pubmed.ncbi.nlm.nih.gov/16081510/ DOI: 10.1093/carcin/bgi206

tissue_or_cell_type

Cell-free methyltransferase reactions and cultured cancer cells

Chlorogenic acid: metabolism, signaling and nutrient connections (2026-09-17) · lines 789–800

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Coupled catechol-methylation/DNA-methylation assays and breast-cancer cell experiments · source_derived_draft · unverified_draft

### chlorogenic_acid-comt-sah O-methylation of the dietary catechols increased SAH formation. Condition category: normal nutrient_topic: Chlorogenic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Using a methyl donor leaves a product that can restrain other methyltransferases. organism: Human DNMT1 and MCF-7/MDA-MB-231 cells; COMT preparation species unresolved in abstract tissue_or_cell_type: Cell-free methyltransferase reactions and cultured cancer cells experimental_model: Coupled catechol-methylation/DNA-methylation assays and breast-cancer cell experiments limitations: These concentrations and coupled-reaction conditions do not establish whole-body methyl-donor depletion, anticancer benefit or vitamin deficiency after food intake. COMT-mediated SAH generation is distinct from direct competitive binding to DNMT1. exposure: CGA DNMT1 IC50 0.9 micromolar in the coupled assay; compounds tested up to 20 micromolar evidence_span: {"source_cache": "artifacts/chlorogenic_acid-research/16081510.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e93fafd7946f8a4aea30ff3ee9ef05e303f9154eb947410fca8e63c6521a4170", "start_char": 0, "end_char": 2008, "text_sha256": "e93fafd7946f8a4aea30ff3ee9ef05e303f9154eb947410fca8e63c6521a4170"} [chlorogenic_acid-p16081510] Inhibition of DNA methylation by caffeic acid and chlorogenic acid, two common catechol-containing coffee polyphenols. (2006). https://pubmed.ncbi.nlm.nih.gov/16081510/ DOI: 10.1093/carcin/bgi206

evidence_span

{"source_cache": "artifacts/chlorogenic_acid-research/16081510.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e93fafd7946f8a4aea30ff3ee9ef05e303f9154eb947410fca8e63c6521a4170", "start_char": 0, "end_char": 2008, "text_sha256": "e93fafd7946f8a4aea30ff3ee9ef05e303f9154eb947410fca8e63c6521a4170"}

experimental_model

Coupled catechol-methylation/DNA-methylation assays and breast-cancer cell experiments

exposure

CGA DNMT1 IC50 0.9 micromolar in the coupled assay; compounds tested up to 20 micromolar

limitations

These concentrations and coupled-reaction conditions do not establish whole-body methyl-donor depletion, anticancer benefit or vitamin deficiency after food intake. COMT-mediated SAH generation is distinct from direct competitive binding to DNMT1.

nutrient_topic

Chlorogenic acid research collection; topical membership is not evidence of a direct dietary effect. · Chlorogenic acid / 5-O-caffeoylquinic acid

organism

Human DNMT1 and MCF-7/MDA-MB-231 cells; COMT preparation species unresolved in abstract

plain_language

The concentration belongs to this coupled biochemical assay.

primary_references

[chlorogenic_acid-p16081510] Inhibition of DNA methylation by caffeic acid and chlorogenic acid, two common catechol-containing coffee polyphenols. (2006). https://pubmed.ncbi.nlm.nih.gov/16081510/ DOI: 10.1093/carcin/bgi206

tissue_or_cell_type

Cell-free methyltransferase reactions and cultured cancer cells

Chlorogenic acid: metabolism, signaling and nutrient connections (2026-09-17) · lines 815–826

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Coupled catechol-methylation/DNA-methylation assays and breast-cancer cell experiments · source_derived_draft · unverified_draft

### chlorogenic_acid-dnmt-assay CGA inhibited human DNMT1-mediated methylation with an assay IC50 of 0.9 micromolar. Condition category: normal nutrient_topic: Chlorogenic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The concentration belongs to this coupled biochemical assay. organism: Human DNMT1 and MCF-7/MDA-MB-231 cells; COMT preparation species unresolved in abstract tissue_or_cell_type: Cell-free methyltransferase reactions and cultured cancer cells experimental_model: Coupled catechol-methylation/DNA-methylation assays and breast-cancer cell experiments limitations: These concentrations and coupled-reaction conditions do not establish whole-body methyl-donor depletion, anticancer benefit or vitamin deficiency after food intake. COMT-mediated SAH generation is distinct from direct competitive binding to DNMT1. exposure: CGA DNMT1 IC50 0.9 micromolar in the coupled assay; compounds tested up to 20 micromolar evidence_span: {"source_cache": "artifacts/chlorogenic_acid-research/16081510.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e93fafd7946f8a4aea30ff3ee9ef05e303f9154eb947410fca8e63c6521a4170", "start_char": 0, "end_char": 2008, "text_sha256": "e93fafd7946f8a4aea30ff3ee9ef05e303f9154eb947410fca8e63c6521a4170"} [chlorogenic_acid-p16081510] Inhibition of DNA methylation by caffeic acid and chlorogenic acid, two common catechol-containing coffee polyphenols. (2006). https://pubmed.ncbi.nlm.nih.gov/16081510/ DOI: 10.1093/carcin/bgi206

evidence_span

{"source_cache": "artifacts/chlorogenic_acid-research/16081510.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e93fafd7946f8a4aea30ff3ee9ef05e303f9154eb947410fca8e63c6521a4170", "start_char": 0, "end_char": 2008, "text_sha256": "e93fafd7946f8a4aea30ff3ee9ef05e303f9154eb947410fca8e63c6521a4170"}

experimental_model

Coupled catechol-methylation/DNA-methylation assays and breast-cancer cell experiments

exposure

CGA DNMT1 IC50 0.9 micromolar in the coupled assay; compounds tested up to 20 micromolar

limitations

These concentrations and coupled-reaction conditions do not establish whole-body methyl-donor depletion, anticancer benefit or vitamin deficiency after food intake. COMT-mediated SAH generation is distinct from direct competitive binding to DNMT1.

nutrient_topic

Chlorogenic acid research collection; topical membership is not evidence of a direct dietary effect. · Chlorogenic acid / 5-O-caffeoylquinic acid

organism

Human DNMT1 and MCF-7/MDA-MB-231 cells; COMT preparation species unresolved in abstract

plain_language

One promoter in cancer cells does not describe genome-wide epigenetic health.

primary_references

[chlorogenic_acid-p16081510] Inhibition of DNA methylation by caffeic acid and chlorogenic acid, two common catechol-containing coffee polyphenols. (2006). https://pubmed.ncbi.nlm.nih.gov/16081510/ DOI: 10.1093/carcin/bgi206

tissue_or_cell_type

Cell-free methyltransferase reactions and cultured cancer cells

Chlorogenic acid: metabolism, signaling and nutrient connections (2026-09-17) · lines 828–839

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Coupled catechol-methylation/DNA-methylation assays and breast-cancer cell experiments · source_derived_draft · unverified_draft

### chlorogenic_acid-rarb-methylation The cancer-cell experiments reported partial inhibition of RARB promoter methylation. Condition category: normal nutrient_topic: Chlorogenic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: One promoter in cancer cells does not describe genome-wide epigenetic health. organism: Human DNMT1 and MCF-7/MDA-MB-231 cells; COMT preparation species unresolved in abstract tissue_or_cell_type: Cell-free methyltransferase reactions and cultured cancer cells experimental_model: Coupled catechol-methylation/DNA-methylation assays and breast-cancer cell experiments limitations: These concentrations and coupled-reaction conditions do not establish whole-body methyl-donor depletion, anticancer benefit or vitamin deficiency after food intake. COMT-mediated SAH generation is distinct from direct competitive binding to DNMT1. exposure: CGA DNMT1 IC50 0.9 micromolar in the coupled assay; compounds tested up to 20 micromolar evidence_span: {"source_cache": "artifacts/chlorogenic_acid-research/16081510.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e93fafd7946f8a4aea30ff3ee9ef05e303f9154eb947410fca8e63c6521a4170", "start_char": 0, "end_char": 2008, "text_sha256": "e93fafd7946f8a4aea30ff3ee9ef05e303f9154eb947410fca8e63c6521a4170"} [chlorogenic_acid-p16081510] Inhibition of DNA methylation by caffeic acid and chlorogenic acid, two common catechol-containing coffee polyphenols. (2006). https://pubmed.ncbi.nlm.nih.gov/16081510/ DOI: 10.1093/carcin/bgi206

evidence_span

{"source_cache": "artifacts/chlorogenic_acid-research/16081510.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e93fafd7946f8a4aea30ff3ee9ef05e303f9154eb947410fca8e63c6521a4170", "start_char": 0, "end_char": 2008, "text_sha256": "e93fafd7946f8a4aea30ff3ee9ef05e303f9154eb947410fca8e63c6521a4170"}

experimental_model

Coupled catechol-methylation/DNA-methylation assays and breast-cancer cell experiments

exposure

CGA DNMT1 IC50 0.9 micromolar in the coupled assay; compounds tested up to 20 micromolar

limitations

These concentrations and coupled-reaction conditions do not establish whole-body methyl-donor depletion, anticancer benefit or vitamin deficiency after food intake. COMT-mediated SAH generation is distinct from direct competitive binding to DNMT1.

nutrient_topic

Chlorogenic acid research collection; topical membership is not evidence of a direct dietary effect. · Chlorogenic acid / 5-O-caffeoylquinic acid

organism

Human DNMT1 and MCF-7/MDA-MB-231 cells; COMT preparation species unresolved in abstract

plain_language

An indirect metabolite-mediated effect differs from a direct DNMT1 inhibitor.

primary_references

[chlorogenic_acid-p16081510] Inhibition of DNA methylation by caffeic acid and chlorogenic acid, two common catechol-containing coffee polyphenols. (2006). https://pubmed.ncbi.nlm.nih.gov/16081510/ DOI: 10.1093/carcin/bgi206

tissue_or_cell_type

Cell-free methyltransferase reactions and cultured cancer cells

Chlorogenic acid: metabolism, signaling and nutrient connections (2026-09-17) · lines 802–813

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Coupled catechol-methylation/DNA-methylation assays and breast-cancer cell experiments · source_derived_draft · unverified_draft

### chlorogenic_acid-sah-dnmt Increased SAH largely explained the observed inhibition of DNA methylation. Condition category: normal nutrient_topic: Chlorogenic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: An indirect metabolite-mediated effect differs from a direct DNMT1 inhibitor. organism: Human DNMT1 and MCF-7/MDA-MB-231 cells; COMT preparation species unresolved in abstract tissue_or_cell_type: Cell-free methyltransferase reactions and cultured cancer cells experimental_model: Coupled catechol-methylation/DNA-methylation assays and breast-cancer cell experiments limitations: These concentrations and coupled-reaction conditions do not establish whole-body methyl-donor depletion, anticancer benefit or vitamin deficiency after food intake. COMT-mediated SAH generation is distinct from direct competitive binding to DNMT1. exposure: CGA DNMT1 IC50 0.9 micromolar in the coupled assay; compounds tested up to 20 micromolar evidence_span: {"source_cache": "artifacts/chlorogenic_acid-research/16081510.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e93fafd7946f8a4aea30ff3ee9ef05e303f9154eb947410fca8e63c6521a4170", "start_char": 0, "end_char": 2008, "text_sha256": "e93fafd7946f8a4aea30ff3ee9ef05e303f9154eb947410fca8e63c6521a4170"} [chlorogenic_acid-p16081510] Inhibition of DNA methylation by caffeic acid and chlorogenic acid, two common catechol-containing coffee polyphenols. (2006). https://pubmed.ncbi.nlm.nih.gov/16081510/ DOI: 10.1093/carcin/bgi206

evidence_access

Primary abstract

experimental_model

Human enzyme and liver-S9 kinetics.

limitations

Product formation is not identical to accumulation after further metabolism.

nutrient_topic

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

plain_language

The enzyme initially favored the diosmetin branch.

primary_references

Luteolin is a rare substrate of human catechol-O-methyltransferase favoring a para-methylation. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23386290/ · DOI 10.1002/mnfr.201200584

Luteolin: metabolism, immune signaling, redox chemistry and cross-nutrient mechanisms (2026-09-19) · lines 92–98

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human enzyme and liver-S9 kinetics. · source_derived_draft · unverified_draft

## luteolin-comt-para The enzyme initially favored the diosmetin branch. Human recombinant COMT and liver S9 favored 4′- over 3′-O-methylation of luteolin. Model: Human enzyme and liver-S9 kinetics. Limitations: Product formation is not identical to accumulation after further metabolism. Evidence access: Primary abstract Luteolin is a rare substrate of human catechol-O-methyltransferase favoring a para-methylation. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23386290/ · DOI 10.1002/mnfr.201200584

evidence_span

{"source_cache": "artifacts/choline-research/12431977.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7c299a547408772f2f24bdd77f2f22dc8ea9e5aaf8179150f2d8b59c9713306a", "start_char": 0, "end_char": 1380, "text_sha256": "7c299a547408772f2f24bdd77f2f22dc8ea9e5aaf8179150f2d8b59c9713306a"}

experimental_model

Human liver fractionation and recombinant PEMT membrane-topology experiments

exposure

Protein cleavage mapping and methyltransferase localization

limitations

Three methyl transfers make a choline-containing phospholipid; PEMT does not directly synthesize free choline from nothing.

nutrient_topic

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

organism

Human enzyme

plain_language

The body can build a choline headgroup in a membrane lipid by spending methyl groups.

primary_references

[choline-p12431977] Membrane topography of human phosphatidylethanolamine N-methyltransferase. (2003). https://pubmed.ncbi.nlm.nih.gov/12431977/ DOI: 10.1074/jbc.m210904200

tissue_or_cell_type

ER and mitochondria-associated membranes

Choline: metabolism, signaling and nutrient connections (2026-09-17) · lines 802–813

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human liver fractionation and recombinant PEMT membrane-topology experiments · source_derived_draft · unverified_draft

### choline-pemt-pc PEMT converts PE to PC through three sequential SAM-dependent methylation reactions. Condition category: normal nutrient_topic: Choline research collection; topical membership is not evidence of a direct dietary effect. plain_language: The body can build a choline headgroup in a membrane lipid by spending methyl groups. organism: Human enzyme tissue_or_cell_type: ER and mitochondria-associated membranes experimental_model: Human liver fractionation and recombinant PEMT membrane-topology experiments limitations: Three methyl transfers make a choline-containing phospholipid; PEMT does not directly synthesize free choline from nothing. exposure: Protein cleavage mapping and methyltransferase localization evidence_span: {"source_cache": "artifacts/choline-research/12431977.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7c299a547408772f2f24bdd77f2f22dc8ea9e5aaf8179150f2d8b59c9713306a", "start_char": 0, "end_char": 1380, "text_sha256": "7c299a547408772f2f24bdd77f2f22dc8ea9e5aaf8179150f2d8b59c9713306a"} [choline-p12431977] Membrane topography of human phosphatidylethanolamine N-methyltransferase. (2003). https://pubmed.ncbi.nlm.nih.gov/12431977/ DOI: 10.1074/jbc.m210904200

evidence_span

{"source_cache": "artifacts/melatonin-research/22775292.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6896e0a7e08f764e1ff8c370601b0477c594e4e1c945df52d0f564e9049a9349", "start_char": 0, "end_char": 1205, "text_sha256": "6896e0a7e08f764e1ff8c370601b0477c594e4e1c945df52d0f564e9049a9349"}

experimental_model

X-ray structure and radioenzymatic variant characterization

exposure

SAM-dependent methyltransferase structure and enzyme activity assays

limitations

Reduced recombinant enzyme activity does not quantify pineal secretion or diagnose a sleep problem in an individual. Variant effects differ; no single universal melatonin-deficiency syndrome.

nutrient_topic

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

organism

Human ASMT and 20 nonsynonymous variants

plain_language

A methyl group completes the molecule.

primary_references

[melatonin-p22775292] Crystal structure and functional mapping of human ASMT, the last enzyme of the melatonin synthesis pathway. (2013). https://pubmed.ncbi.nlm.nih.gov/22775292/ DOI: 10.1111/j.1600-079x.2012.01020.x

tissue_or_cell_type

Final melatonin synthesis step

Melatonin: synthesis, receptors, circadian timing and nutrient interactions (2026-09-17) · lines 201–212

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · X-ray structure and radioenzymatic variant characterization · source_derived_draft · unverified_draft

### melatonin-asmt-methylation Human ASMT catalyzes the terminal methylation step converting N-acetylserotonin to melatonin using SAM. Condition category: normal nutrient_topic: Melatonin research collection; topical membership is not evidence of a direct dietary effect. plain_language: A methyl group completes the molecule. organism: Human ASMT and 20 nonsynonymous variants tissue_or_cell_type: Final melatonin synthesis step experimental_model: X-ray structure and radioenzymatic variant characterization limitations: Reduced recombinant enzyme activity does not quantify pineal secretion or diagnose a sleep problem in an individual. Variant effects differ; no single universal melatonin-deficiency syndrome. exposure: SAM-dependent methyltransferase structure and enzyme activity assays evidence_span: {"source_cache": "artifacts/melatonin-research/22775292.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6896e0a7e08f764e1ff8c370601b0477c594e4e1c945df52d0f564e9049a9349", "start_char": 0, "end_char": 1205, "text_sha256": "6896e0a7e08f764e1ff8c370601b0477c594e4e1c945df52d0f564e9049a9349"} [melatonin-p22775292] Crystal structure and functional mapping of human ASMT, the last enzyme of the melatonin synthesis pathway. (2013). https://pubmed.ncbi.nlm.nih.gov/22775292/ DOI: 10.1111/j.1600-079x.2012.01020.x

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Six affected individuals from three families; exome sequencing and recombinant variant assays.

limitations

A functional block of SAH hydrolysis from adenosine accumulation is the mechanistic interpretation; this is not primary AHCY deficiency.

nutrient_topic

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

plain_language

Removing one reaction product helps keep the recycling pathway moving.

primary_references

Adenosine kinase deficiency disrupts the methionine cycle and causes hypermethioninemia, encephalopathy, and abnormal liver function. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21963049/ · DOI 10.1016/j.ajhg.2011.09.004

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 196–202

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Six affected individuals from three families; exome sequencing and recombinant variant assays. · source_derived_draft · unverified_draft

## methionine-adk-product-removal Removing one reaction product helps keep the recycling pathway moving. ADK variants impaired recombinant enzyme activity and were linked to increased adenosine excretion and SAM/SAH/methionine accumulation. Model: Six affected individuals from three families; exome sequencing and recombinant variant assays. Limitations: A functional block of SAH hydrolysis from adenosine accumulation is the mechanistic interpretation; this is not primary AHCY deficiency. Evidence access: Primary abstract Adenosine kinase deficiency disrupts the methionine cycle and causes hypermethioninemia, encephalopathy, and abnormal liver function. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21963049/ · DOI 10.1016/j.ajhg.2011.09.004

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human infant, liver/red-cell/fibroblast assays and genetic analysis.

limitations

Single rare-disease case; not evidence of the same block in ordinary dietary variation.

nutrient_topic

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

plain_language

Abundant methyl-donor substrate can coexist with blocked recycling.

primary_references

S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism. · 2004 · https://pubmed.ncbi.nlm.nih.gov/15024124/ · DOI 10.1073/pnas.0400658101

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 180–186

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human infant, liver/red-cell/fibroblast assays and genetic analysis. · source_derived_draft · unverified_draft

## methionine-ahcy-loss Abundant methyl-donor substrate can coexist with blocked recycling. The index AHCY-deficient patient had very low enzyme activity and markedly elevated plasma SAH, SAM and methionine. Model: Human infant, liver/red-cell/fibroblast assays and genetic analysis. Limitations: Single rare-disease case; not evidence of the same block in ordinary dietary variation. Evidence access: Primary abstract S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism. · 2004 · https://pubmed.ncbi.nlm.nih.gov/15024124/ · DOI 10.1073/pnas.0400658101

availability_state

biomarker_context Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human AHCY-deficiency case; different tissues and biochemical readouts.

limitations

No universal high-SAH-to-all-DNA-hypomethylation rule is inferred.

nutrient_topic

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

plain_language

A blood metabolite pattern does not predict every methylation endpoint in one direction.

primary_references

S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism. · 2004 · https://pubmed.ncbi.nlm.nih.gov/15024124/ · DOI 10.1073/pnas.0400658101

trigger_kind

biomarker_context Imported condition classification; unverified.

L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 188–194

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human AHCY-deficiency case; different tissues and biochemical readouts. · source_derived_draft · unverified_draft

## methionine-ahcy-methylation-boundary A blood metabolite pattern does not predict every methylation endpoint in one direction. Despite SAH accumulation, the index case showed leukocyte DNA hypermethylation, along with low plasma choline/phosphatidylcholine and high guanidinoacetate. Model: Human AHCY-deficiency case; different tissues and biochemical readouts. Limitations: No universal high-SAH-to-all-DNA-hypomethylation rule is inferred. Evidence access: Primary abstract S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism. · 2004 · https://pubmed.ncbi.nlm.nih.gov/15024124/ · DOI 10.1073/pnas.0400658101

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Conditional mouse T-cell Dot1l knockout and culture add-back experiments.

limitations

Not a claim that dietary methionine deficiency causes DOT1L loss; gene loss and substrate shortage are distinct. Correction record: Author correction published online 12 December 2025 (2026 issue): Extended Data Fig. 1j originally duplicated the A375-supernatant flow-cytometry plot in the Sup+Ser condition; publisher replaced the representative image. This is a figure correction, not an opposing scientific finding. https://www.nature.com/articles/s41586-025-09845-8

nutrient_topic

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

plain_language

Supplying the nutrient failed when the downstream methyltransferase was absent.

primary_references

Cancer SLC43A2 alters T cell methionine metabolism and histone methylation. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32879489/ · DOI 10.1038/s41586-020-2682-1

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Methionine: transport, methylation, sulfur metabolism 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 · Conditional mouse T-cell Dot1l knockout and culture add-back experiments. · source_derived_draft · unverified_draft

## methionine-dot1l-gate Supplying the nutrient failed when the downstream methyltransferase was absent. T-cell Dot1l deletion removed H3K79me2 and prevented methionine supplementation from rescuing tumor-medium-induced apoptosis and impaired cytokine production. Model: Conditional mouse T-cell Dot1l knockout and culture add-back experiments. Limitations: Not a claim that dietary methionine deficiency causes DOT1L loss; gene loss and substrate shortage are distinct. Correction record: Author correction published online 12 December 2025 (2026 issue): Extended Data Fig. 1j originally duplicated the A375-supernatant flow-cytometry plot in the Sup+Ser condition; publisher replaced the representative image. This is a figure correction, not an opposing scientific finding. https://www.nature.com/articles/s41586-025-09845-8 Evidence access: Primary full text Cancer SLC43A2 alters T cell methionine metabolism and histone methylation. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32879489/ · DOI 10.1038/s41586-020-2682-1

evidence_access

Primary abstract

experimental_model

Rat liver GNMT crystallography and binding experiments.

limitations

Rat enzyme and defined ligand conditions; not a demonstrated human supplement interaction.

nutrient_topic

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

plain_language

Folate can regulate methyl-group disposal through glycine.

primary_references

5-methyltetrahydrofolate is bound in intersubunit areas of rat liver folate-binding protein glycine N-methyltransferase. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17158459/ · DOI 10.1074/jbc.M610384200

L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 212–218

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

## methionine-gnmt-folate-structure Folate can regulate methyl-group disposal through glycine. Rat GNMT structures located two folate-binding sites between subunits; occupancy restricts the N-terminal movements needed for substrate access. Model: Rat liver GNMT crystallography and binding experiments. Limitations: Rat enzyme and defined ligand conditions; not a demonstrated human supplement interaction. Evidence access: Primary abstract 5-methyltetrahydrofolate is bound in intersubunit areas of rat liver folate-binding protein glycine N-methyltransferase. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17158459/ · DOI 10.1074/jbc.M610384200

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary abstract and primary figure legends

experimental_model

Human HCT116 and additional cultured-cell experiments; restriction/recovery.

limitations

H3K4me3 is not interchangeable with DNA methylation or all histone marks.

nutrient_topic

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

plain_language

Availability changed a specific chromatin mark, reversibly.

primary_references

Histone Methylation Dynamics and Gene Regulation Occur through the Sensing of One-Carbon Metabolism. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26411344/ · DOI 10.1016/j.cmet.2015.08.024

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Methionine: transport, methylation, sulfur metabolism 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 · Human HCT116 and additional cultured-cell experiments; restriction/recovery. · source_derived_draft · unverified_draft

## methionine-histone-response Availability changed a specific chromatin mark, reversibly. Methionine restriction changed SAM/SAH pools and rapidly reduced H3K4me3; restoring methionine restored the metabolic and methylation response. Model: Human HCT116 and additional cultured-cell experiments; restriction/recovery. Limitations: H3K4me3 is not interchangeable with DNA methylation or all histone marks. Evidence access: Primary abstract and primary figure legends Histone Methylation Dynamics and Gene Regulation Occur through the Sensing of One-Carbon Metabolism. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26411344/ · DOI 10.1016/j.cmet.2015.08.024

evidence_access

Primary abstract

experimental_model

Human MAT2A structure with nonhydrolyzable imidotriphosphate and methylthioadenosine.

limitations

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

nutrient_topic

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

plain_language

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

primary_references

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

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

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

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

evidence_access

Primary abstract

experimental_model

Purified human MAT2A crystallography and kinetic study.

limitations

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

nutrient_topic

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

plain_language

Potassium participates directly in the enzyme chemistry.

primary_references

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

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

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

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

evidence_access

Primary abstract

experimental_model

Human MAT1A disease cohort; established isoenzyme chemistry.

limitations

MAT1A and MAT2A retain separate identities.

nutrient_topic

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

plain_language

The liver has distinct enzyme assemblies for activating methionine.

primary_references

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

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

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

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

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Aggregated clinical data from 64 homozygous/compound-heterozygous patients.

limitations

Does not imply that high methionine always means this genetic disorder.

nutrient_topic

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

plain_language

High substrate can signal failure to process it.

primary_references

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

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Methionine: transport, methylation, sulfur metabolism 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 · Aggregated clinical data from 64 homozygous/compound-heterozygous patients. · source_derived_draft · unverified_draft

## methionine-mat1-loss High substrate can signal failure to process it. Reduced MAT I/III function caused persistent hypermethioninemia in patients with biallelic MAT1A variants. Model: Aggregated clinical data from 64 homozygous/compound-heterozygous patients. Limitations: Does not imply that high methionine always means this genetic disorder. Evidence access: Primary abstract Mudd's disease (MAT I/III deficiency): a survey of data for MAT1A homozygotes and compound heterozygotes. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26289392/ · DOI 10.1186/s13023-015-0321-y

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human cancer-cell genetic depletion experiments.

limitations

This genetic interaction is not proof of efficacy for methionine restriction or a particular drug in patients.

nutrient_topic

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

plain_language

Loss of a recycling enzyme can make cells more sensitive to reduced donor synthesis.

primary_references

MTAP Deletions in Cancer Create Vulnerability to Targeting of the MAT2A/PRMT5/RIOK1 Axis. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27068473/ · DOI 10.1016/j.celrep.2016.03.043

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 300–306

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

## methionine-mat2a-prmt5-vulnerability Loss of a recycling enzyme can make cells more sensitive to reduced donor synthesis. MAT2A depletion preferentially reduced growth and PRMT5 methylation activity in MTAP-deleted cells. Model: Human cancer-cell genetic depletion experiments. Limitations: This genetic interaction is not proof of efficacy for methionine restriction or a particular drug in patients. Evidence access: Primary abstract MTAP Deletions in Cancer Create Vulnerability to Targeting of the MAT2A/PRMT5/RIOK1 Axis. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27068473/ · DOI 10.1016/j.celrep.2016.03.043

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human doxycycline-regulated MAT2A cells; starvation and repletion.

limitations

Cellular SAM addition is not evidence for equivalent oral delivery.

nutrient_topic

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

plain_language

The amino acid must be converted before this sensor route works.

primary_references

SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway. · 2017 · https://pubmed.ncbi.nlm.nih.gov/29123071/ · DOI 10.1126/science.aao3265

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Methionine: transport, methylation, sulfur metabolism 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 doxycycline-regulated MAT2A cells; starvation and repletion. · source_derived_draft · unverified_draft

## methionine-mat2a-sensor-coupling The amino acid must be converted before this sensor route works. Acute MAT2A depletion reduced mTORC1 responsiveness to methionine while largely preserving responsiveness to supplied SAM. Model: Human doxycycline-regulated MAT2A cells; starvation and repletion. Limitations: Cellular SAM addition is not evidence for equivalent oral delivery. Evidence access: Primary full text SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway. · 2017 · https://pubmed.ncbi.nlm.nih.gov/29123071/ · DOI 10.1126/science.aao3265

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human MAT2A reporter/cell and RNA-biochemistry experiments.

limitations

Increased transcript processing does not replace the missing methionine substrate.

nutrient_topic

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

plain_language

Low methyl-donor availability can increase production capacity through RNA processing.

primary_references

The U6 snRNA m6A Methyltransferase METTL16 Regulates SAM Synthetase Intron Retention. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28525753/ · DOI 10.1016/j.cell.2017.05.003

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Methionine: transport, methylation, sulfur metabolism 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 MAT2A reporter/cell and RNA-biochemistry experiments. · source_derived_draft · unverified_draft

## methionine-mettl16-feedback Low methyl-donor availability can increase production capacity through RNA processing. Methionine-starvation-induced SAM depletion increased MAT2A expression through METTL16-dependent splicing involving a conserved 3-prime-UTR hairpin. Model: Human MAT2A reporter/cell and RNA-biochemistry experiments. Limitations: Increased transcript processing does not replace the missing methionine substrate. Evidence access: Primary abstract The U6 snRNA m6A Methyltransferase METTL16 Regulates SAM Synthetase Intron Retention. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28525753/ · DOI 10.1016/j.cell.2017.05.003

evidence_access

Primary abstract

experimental_model

Human RNA methylation/biochemical study.

limitations

No claim that every splicing event is controlled by dietary methionine.

nutrient_topic

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

plain_language

The same enzyme also modifies RNA used in splicing.

primary_references

The U6 snRNA m6A Methyltransferase METTL16 Regulates SAM Synthetase Intron Retention. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28525753/ · DOI 10.1016/j.cell.2017.05.003

L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 268–274

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human RNA methylation/biochemical study. · source_derived_draft · unverified_draft

## methionine-mettl16-u6 The same enzyme also modifies RNA used in splicing. METTL16 was identified as a SAM-dependent U6 snRNA m6A methyltransferase. Model: Human RNA methylation/biochemical study. Limitations: No claim that every splicing event is controlled by dietary methionine. Evidence access: Primary abstract The U6 snRNA m6A Methyltransferase METTL16 Regulates SAM Synthetase Intron Retention. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28525753/ · DOI 10.1016/j.cell.2017.05.003

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human mitochondrial disease study and functional models.

limitations

This does not demonstrate that oral methionine, SAM, CoQ10 or lipoate repairs the transporter.

nutrient_topic

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

plain_language

One transport gate connects methyl-donor supply with other cofactors.

primary_references

Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26522469/ · DOI 10.1016/j.ajhg.2015.09.013

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 124–130

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human mitochondrial disease study and functional models. · source_derived_draft · unverified_draft

## methionine-mitochondrial-cofactor-products One transport gate connects methyl-donor supply with other cofactors. SLC25A26 mutations were associated with impaired CoQ10 and lipoic-acid biosynthesis in the functional study. Model: Human mitochondrial disease study and functional models. Limitations: This does not demonstrate that oral methionine, SAM, CoQ10 or lipoate repairs the transporter. Evidence access: Primary abstract Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26522469/ · DOI 10.1016/j.ajhg.2015.09.013

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human families and cellular/functional variant studies.

limitations

Phenotypes varied; no general SAM or methionine supplement rescue is established.

nutrient_topic

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

plain_language

A compartment-specific shortage can occur without proving a dietary shortage.

primary_references

Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26522469/ · DOI 10.1016/j.ajhg.2015.09.013

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 116–122

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human families and cellular/functional variant studies. · source_derived_draft · unverified_draft

## methionine-mitochondrial-sam-loss A compartment-specific shortage can occur without proving a dietary shortage. Recessive SLC25A26 variants impaired mitochondrial methylation with defects in RNA stability, protein modification and translation. Model: Human families and cellular/functional variant studies. Limitations: Phenotypes varied; no general SAM or methionine supplement rescue is established. Evidence access: Primary abstract Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26522469/ · DOI 10.1016/j.ajhg.2015.09.013

evidence_access

Primary abstract

experimental_model

Human cancer-cell and purified-enzyme study.

limitations

Selectivity applies to the tested panel and conditions; not all methyltransferases.

nutrient_topic

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

plain_language

A recycling product can inhibit another methylation enzyme.

primary_references

MTAP Deletions in Cancer Create Vulnerability to Targeting of the MAT2A/PRMT5/RIOK1 Axis. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27068473/ · DOI 10.1016/j.celrep.2016.03.043

L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 292–298

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

## methionine-mta-prmt5 A recycling product can inhibit another methylation enzyme. Biochemical methyltransferase profiling identified MTA as a potent selective PRMT5 inhibitor; MTAP-deleted cells had reduced PRMT5 methylation activity. Model: Human cancer-cell and purified-enzyme study. Limitations: Selectivity applies to the tested panel and conditions; not all methyltransferases. Evidence access: Primary abstract MTAP Deletions in Cancer Create Vulnerability to Targeting of the MAT2A/PRMT5/RIOK1 Axis. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27068473/ · DOI 10.1016/j.celrep.2016.03.043

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

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

limitations

Not a phenotype demonstrated for common human MTHFR polymorphisms.

nutrient_topic

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

plain_language

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

primary_references

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

trigger_kind

machinery_impairment Imported condition classification; unverified.

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

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

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

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human HEK293T starvation/repletion experiments.

limitations

Specific acute culture context; mTORC1 integrates other nutrients and signals too.

nutrient_topic

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

plain_language

A shortage signal can pause growth signaling.

primary_references

SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway. · 2017 · https://pubmed.ncbi.nlm.nih.gov/29123071/ · DOI 10.1126/science.aao3265

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 236–242

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human HEK293T starvation/repletion experiments. · source_derived_draft · unverified_draft

## methionine-samtor-shortage A shortage signal can pause growth signaling. Two-hour methionine starvation lowered cellular SAM, promoted SAMTOR-GATOR1 association and inhibited mTORC1 signaling. Model: Human HEK293T starvation/repletion experiments. Limitations: Specific acute culture context; mTORC1 integrates other nutrients and signals too. Evidence access: Primary full text SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway. · 2017 · https://pubmed.ncbi.nlm.nih.gov/29123071/ · DOI 10.1126/science.aao3265

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human A375-conditioned T cells and colorectal tumor-infiltrating T cells ex vivo; Extended Data Figs. 2k and 4j-m.

limitations

A defined histone mark is not a global DNA methylation readout; not a validated oral cancer treatment. Correction record: Author correction published online 12 December 2025 (2026 issue): Extended Data Fig. 1j originally duplicated the A375-supernatant flow-cytometry plot in the Sup+Ser condition; publisher replaced the representative image. This is a figure correction, not an opposing scientific finding. https://www.nature.com/articles/s41586-025-09845-8

nutrient_topic

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

plain_language

Nutrient competition reached a specific chromatin and signaling program.

primary_references

Cancer SLC43A2 alters T cell methionine metabolism and histone methylation. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32879489/ · DOI 10.1038/s41586-020-2682-1

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 436–442

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human A375-conditioned T cells and colorectal tumor-infiltrating T cells ex vivo; Extended Data Figs. 2k and 4j-m. · source_derived_draft · unverified_draft

## methionine-tcell-histone-stat5 Nutrient competition reached a specific chromatin and signaling program. Human T cells exposed to tumor supernatants lost H3K79 methylation; adding methionine to human colorectal tumor-infiltrating T-cell cultures improved H3K79me2 and STAT5 readouts. Model: Human A375-conditioned T cells and colorectal tumor-infiltrating T cells ex vivo; Extended Data Figs. 2k and 4j-m. Limitations: A defined histone mark is not a global DNA methylation readout; not a validated oral cancer treatment. Correction record: Author correction published online 12 December 2025 (2026 issue): Extended Data Fig. 1j originally duplicated the A375-supernatant flow-cytometry plot in the Sup+Ser condition; publisher replaced the representative image. This is a figure correction, not an opposing scientific finding. https://www.nature.com/articles/s41586-025-09845-8 Evidence access: Primary full text Cancer SLC43A2 alters T cell methionine metabolism and histone methylation. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32879489/ · DOI 10.1038/s41586-020-2682-1

evidence_access

Primary full text

experimental_model

Murine T-cell proteomics and metabolic labeling.

limitations

Does not establish that more dietary methionine improves immunity in adequately nourished people.

nutrient_topic

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

plain_language

The imported amino acid feeds both proteins and regulatory methyl marks.

primary_references

Antigen receptor control of methionine metabolism in T cells. · 2019 · https://pubmed.ncbi.nlm.nih.gov/30916644/ · DOI 10.7554/eLife.44210

L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 52–58

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Murine T-cell proteomics and metabolic labeling. · source_derived_draft · unverified_draft

## methionine-tcell-methylation The imported amino acid feeds both proteins and regulatory methyl marks. Methionine availability and induced transport supported protein synthesis, methionine-cycle flux and RNA/histone methylation in activated murine T cells. Model: Murine T-cell proteomics and metabolic labeling. Limitations: Does not establish that more dietary methionine improves immunity in adequately nourished people. Evidence access: Primary full text Antigen receptor control of methionine metabolism in T cells. · 2019 · https://pubmed.ncbi.nlm.nih.gov/30916644/ · DOI 10.7554/eLife.44210

evidence_access

Primary abstract

experimental_model

Mouse B16F10/ID8 transporter-knockdown and T-cell coculture experiments; human expression correlations are distinct.

limitations

Local competition cannot be inferred from plasma methionine alone. Correction record: Author correction published online 12 December 2025 (2026 issue): Extended Data Fig. 1j originally duplicated the A375-supernatant flow-cytometry plot in the Sup+Ser condition; publisher replaced the representative image. This is a figure correction, not an opposing scientific finding. https://www.nature.com/articles/s41586-025-09845-8

nutrient_topic

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

plain_language

A neighboring cell can change supply without a dietary deficiency.

primary_references

Cancer SLC43A2 alters T cell methionine metabolism and histone methylation. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32879489/ · DOI 10.1038/s41586-020-2682-1

L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 428–434

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse B16F10/ID8 transporter-knockdown and T-cell coculture experiments; human expression correlations are distinct. · source_derived_draft · unverified_draft

## methionine-tumor-transporter A neighboring cell can change supply without a dietary deficiency. Slc43a2 knockdown in B16F10/ID8 mouse tumor cells reduced methionine consumption and improved T-cell supply/function in coculture experiments. Model: Mouse B16F10/ID8 transporter-knockdown and T-cell coculture experiments; human expression correlations are distinct. Limitations: Local competition cannot be inferred from plasma methionine alone. Correction record: Author correction published online 12 December 2025 (2026 issue): Extended Data Fig. 1j originally duplicated the A375-supernatant flow-cytometry plot in the Sup+Ser condition; publisher replaced the representative image. This is a figure correction, not an opposing scientific finding. https://www.nature.com/articles/s41586-025-09845-8 Evidence access: Primary abstract Cancer SLC43A2 alters T cell methionine metabolism and histone methylation. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32879489/ · DOI 10.1038/s41586-020-2682-1

evidence_span

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experimental_model

Two-week feeding and isolated hepatocyte experiments

exposure

Guanidinoacetate or creatine feeding; guanidinoacetate plus methionine in hepatocytes

limitations

Animal methyl-demand experiment; effect sizes do not predict human homocysteine responses.

nutrient_topic

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

organism

Rats

plain_language

Providing more precursor increased the load on the methylation step in these rats.

primary_references

[creatine-p11595668] Methylation demand and homocysteine metabolism: effects of dietary provision of creatine and guanidinoacetate. (2001). https://pubmed.ncbi.nlm.nih.gov/11595668/ DOI: 10.1152/ajpendo.2001.281.5.e1095

tissue_or_cell_type

Plasma and liver cells

Creatine: synthesis, transport, phosphocreatine energetics and nutrient interactions (2026-09-17) · lines 685–696

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Two-week feeding and isolated hepatocyte experiments · source_derived_draft · unverified_draft

### creatine-gaa-homocysteine Guanidinoacetate feeding raised plasma homocysteine by approximately 50% in the rat experiment. Condition category: normal nutrient_topic: Creatine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Providing more precursor increased the load on the methylation step in these rats. organism: Rats tissue_or_cell_type: Plasma and liver cells experimental_model: Two-week feeding and isolated hepatocyte experiments limitations: Animal methyl-demand experiment; effect sizes do not predict human homocysteine responses. exposure: Guanidinoacetate or creatine feeding; guanidinoacetate plus methionine in hepatocytes evidence_span: {"source_cache": "artifacts/creatine-research/11595668.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "b195a8b17815bf7d9223831374e2f85ae2f90d8d74117ad7aa8d94af7a9e94b0", "start_char": 0, "end_char": 1687, "text_sha256": "b195a8b17815bf7d9223831374e2f85ae2f90d8d74117ad7aa8d94af7a9e94b0"} [creatine-p11595668] Methylation demand and homocysteine metabolism: effects of dietary provision of creatine and guanidinoacetate. (2001). https://pubmed.ncbi.nlm.nih.gov/11595668/ DOI: 10.1152/ajpendo.2001.281.5.e1095

evidence_span

{"source_cache": "artifacts/creatine-research/12079381.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "4f63981cbaa4b7614a24f0a637893d05f9eff2c2143991404b0a7af1ea6667c6", "start_char": 0, "end_char": 1161, "text_sha256": "4f63981cbaa4b7614a24f0a637893d05f9eff2c2143991404b0a7af1ea6667c6"}

experimental_model

SAH-bound crystal structure and mutagenesis

exposure

SAH-bound structure at 2.5 angstrom resolution

limitations

The crystallized construct lacks 36 N-terminal residues; its dimer arrangement is not assigned universally to native human GAMT.

nutrient_topic

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

organism

Rat GAMT

plain_language

The second synthesis step spends one SAM methyl group to finish each creatine molecule.

primary_references

[creatine-p12079381] Crystal structure of guanidinoacetate methyltransferase from rat liver: a model structure of protein arginine methyltransferase. (2002). https://pubmed.ncbi.nlm.nih.gov/12079381/ DOI: 10.1016/s0022-2836(02)00448-5 [creatine-p11595668] Methylation demand and homocysteine metabolism: effects of dietary provision of creatine and guanidinoacetate. (2001). https://pubmed.ncbi.nlm.nih.gov/11595668/ DOI: 10.1152/ajpendo.2001.281.5.e1095

tissue_or_cell_type

Purified, N-terminally truncated enzyme

Creatine: synthesis, transport, phosphocreatine energetics and nutrient interactions (2026-09-17) · lines 203–215

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

### creatine-gamt-methyl-transfer GAMT transfers a methyl group from S-adenosylmethionine to guanidinoacetate, producing creatine and S-adenosylhomocysteine. Condition category: normal nutrient_topic: Creatine research collection; topical membership is not evidence of a direct dietary effect. plain_language: The second synthesis step spends one SAM methyl group to finish each creatine molecule. organism: Rat GAMT tissue_or_cell_type: Purified, N-terminally truncated enzyme experimental_model: SAH-bound crystal structure and mutagenesis limitations: The crystallized construct lacks 36 N-terminal residues; its dimer arrangement is not assigned universally to native human GAMT. exposure: SAH-bound structure at 2.5 angstrom resolution evidence_span: {"source_cache": "artifacts/creatine-research/12079381.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "4f63981cbaa4b7614a24f0a637893d05f9eff2c2143991404b0a7af1ea6667c6", "start_char": 0, "end_char": 1161, "text_sha256": "4f63981cbaa4b7614a24f0a637893d05f9eff2c2143991404b0a7af1ea6667c6"} [creatine-p12079381] Crystal structure of guanidinoacetate methyltransferase from rat liver: a model structure of protein arginine methyltransferase. (2002). https://pubmed.ncbi.nlm.nih.gov/12079381/ DOI: 10.1016/s0022-2836(02)00448-5 [creatine-p11595668] Methylation demand and homocysteine metabolism: effects of dietary provision of creatine and guanidinoacetate. (2001). https://pubmed.ncbi.nlm.nih.gov/11595668/ DOI: 10.1152/ajpendo.2001.281.5.e1095

evidence_span

{"source_cache": "artifacts/creatine-research/19017728.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8394bd0e01991356b47a2e57593a5054e565b4020d50226b1331dbb290fc0cee", "start_char": 0, "end_char": 1599, "text_sha256": "8394bd0e01991356b47a2e57593a5054e565b4020d50226b1331dbb290fc0cee"}

experimental_model

Rat feeding, isolated hepatocytes and in-vivo hepatic balance

exposure

Creatine-fed versus creatine-free conditions; guanidinoacetate and methionine substrate experiments

limitations

Interorgan division of synthesis is established here in rats; this is not proof that human tissues never synthesize both steps locally.

nutrient_topic

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

organism

Rats

plain_language

Methionine helped supply the methyl donor needed to finish creatine.

primary_references

[creatine-p19017728] Creatine synthesis: hepatic metabolism of guanidinoacetate and creatine in the rat in vitro and in vivo. (2009). https://pubmed.ncbi.nlm.nih.gov/19017728/ DOI: 10.1152/ajpendo.90547.2008

tissue_or_cell_type

Kidney, liver, plasma and isolated hepatocytes

Creatine: synthesis, transport, phosphocreatine energetics and nutrient interactions (2026-09-17) · lines 282–293

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat feeding, isolated hepatocytes and in-vivo hepatic balance · source_derived_draft · unverified_draft

### creatine-methionine-hepatic-synthesis Adding methionine increased hepatocyte SAM and creatine synthesis from guanidinoacetate. Condition category: normal nutrient_topic: Creatine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Methionine helped supply the methyl donor needed to finish creatine. organism: Rats tissue_or_cell_type: Kidney, liver, plasma and isolated hepatocytes experimental_model: Rat feeding, isolated hepatocytes and in-vivo hepatic balance limitations: Interorgan division of synthesis is established here in rats; this is not proof that human tissues never synthesize both steps locally. exposure: Creatine-fed versus creatine-free conditions; guanidinoacetate and methionine substrate experiments evidence_span: {"source_cache": "artifacts/creatine-research/19017728.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8394bd0e01991356b47a2e57593a5054e565b4020d50226b1331dbb290fc0cee", "start_char": 0, "end_char": 1599, "text_sha256": "8394bd0e01991356b47a2e57593a5054e565b4020d50226b1331dbb290fc0cee"} [creatine-p19017728] Creatine synthesis: hepatic metabolism of guanidinoacetate and creatine in the rat in vitro and in vivo. (2009). https://pubmed.ncbi.nlm.nih.gov/19017728/ DOI: 10.1152/ajpendo.90547.2008

evidence_access

Primary abstract

experimental_model

Recombinant bacterial enzyme pathway.

limitations

Humans have no established equivalent ergothioneine biosynthetic pathway.

nutrient_topic

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

plain_language

Microbes first modify histidine before adding sulfur.

primary_references

In vitro reconstitution of Mycobacterial ergothioneine biosynthesis. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20420449/ · DOI 10.1021/ja101721e

Ergothioneine: transport, redox chemistry and cross-nutrient mechanisms (2026-09-19) · lines 168–174

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Recombinant bacterial enzyme pathway. · source_derived_draft · unverified_draft

## ergothioneine-histidine-methylation Microbes first modify histidine before adding sulfur. Reconstituted Mycobacterium smegmatis biosynthesis used a methyltransferase to add three methyl groups to the histidine alpha-amino group, producing hercynine. Model: Recombinant bacterial enzyme pathway. Limitations: Humans have no established equivalent ergothioneine biosynthetic pathway. Evidence access: Primary abstract In vitro reconstitution of Mycobacterial ergothioneine biosynthesis. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20420449/ · DOI 10.1021/ja101721e

evidence_access

Primary abstract

experimental_model

Human enzyme transition-state and inhibitor kinetics; structural analysis.

limitations

Shared SAM use does not prove that tyrosine supplementation drains folate, B12 or methionine.

nutrient_topic

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

plain_language

A downstream branch uses a methyl donor from methionine metabolism.

primary_references

Transition-State Analogues of Phenylethanolamine N-Methyltransferase. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32702980/ · DOI 10.1021/jacs.0c05446

L-Tyrosine: catecholamines, thyroid chemistry, pigment, metabolism 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 enzyme transition-state and inhibitor kinetics; structural analysis. · source_derived_draft · unverified_draft

## l-tyrosine-pnmt-methyl A downstream branch uses a methyl donor from methionine metabolism. Human PNMT transfers a methyl group from SAM to norepinephrine during epinephrine synthesis. Model: Human enzyme transition-state and inhibitor kinetics; structural analysis. Limitations: Shared SAM use does not prove that tyrosine supplementation drains folate, B12 or methionine. Evidence access: Primary abstract Transition-State Analogues of Phenylethanolamine N-Methyltransferase. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32702980/ · DOI 10.1021/jacs.0c05446

evidence_access

Primary abstract

experimental_model

Human cancer-cell metabolic tracing and nutrient manipulation.

limitations

This is not proof that adding serine increases methylation in every tissue.

nutrient_topic

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

plain_language

Methylation needs the ATP-making side of serine metabolism as well as one-carbon donation.

primary_references

Serine Metabolism Supports the Methionine Cycle and DNA/RNA Methylation through De Novo ATP Synthesis in Cancer Cells. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26774282/ · DOI 10.1016/j.molcel.2015.12.014

L-Serine: synthesis, one-carbon metabolism, lipids and cross-nutrient mechanisms (2026-09-19) · lines 182–188

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

## l-serine-serine-atp-methylation Methylation needs the ATP-making side of serine metabolism as well as one-carbon donation. Serine metabolism supported the methionine cycle through de novo ATP synthesis both with and without extracellular methionine in the tested cancer cells. Model: Human cancer-cell metabolic tracing and nutrient manipulation. Limitations: This is not proof that adding serine increases methylation in every tissue. Evidence access: Primary abstract Serine Metabolism Supports the Methionine Cycle and DNA/RNA Methylation through De Novo ATP Synthesis in Cancer Cells. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26774282/ · DOI 10.1016/j.molcel.2015.12.014

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human cancer-cell starvation experiments.

limitations

No universal oncogene activation, whole-body methylation collapse or dietary threshold is established.

nutrient_topic

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

plain_language

A shortage can alter methylation without a simple energy-sensor response.

primary_references

Serine Metabolism Supports the Methionine Cycle and DNA/RNA Methylation through De Novo ATP Synthesis in Cancer Cells. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26774282/ · DOI 10.1016/j.molcel.2015.12.014

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Serine: synthesis, one-carbon metabolism, lipids and cross-nutrient mechanisms (2026-09-19) · lines 190–196

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

## l-serine-serine-starvation-methylation A shortage can alter methylation without a simple energy-sensor response. Serine starvation increased the methionine/SAM ratio and reduced methyl-group transfer to DNA and RNA; ATP and AMP fell without AMPK activation. Model: Human cancer-cell starvation experiments. Limitations: No universal oncogene activation, whole-body methylation collapse or dietary threshold is established. Evidence access: Primary abstract Serine Metabolism Supports the Methionine Cycle and DNA/RNA Methylation through De Novo ATP Synthesis in Cancer Cells. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26774282/ · DOI 10.1016/j.molcel.2015.12.014

evidence_access

Primary abstract

experimental_model

Purified recombinant human enzyme; ternary structures and steady-state kinetics.

limitations

A shared SAM requirement does not prove clinically important methyl depletion from histamine turnover.

nutrient_topic

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

plain_language

Histamine disposal connects to the cellular methyl-donor system.

primary_references

Two polymorphic forms of human histamine methyltransferase: structural, thermal, and kinetic comparisons. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11566133/ · DOI 10.1016/s0969-2126(01)00643-8

L-Histidine: supply, catabolism, histamine, receptors 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 · Purified recombinant human enzyme; ternary structures and steady-state kinetics. · source_derived_draft · unverified_draft

## histidine-hnmt-methylation Histamine disposal connects to the cellular methyl-donor system. Human HNMT methylates histamine using SAM; structural complexes locate histamine and the reaction product SAH at the enzyme. Model: Purified recombinant human enzyme; ternary structures and steady-state kinetics. Limitations: A shared SAM requirement does not prove clinically important methyl depletion from histamine turnover. Evidence access: Primary abstract Two polymorphic forms of human histamine methyltransferase: structural, thermal, and kinetic comparisons. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11566133/ · DOI 10.1016/s0969-2126(01)00643-8

evidence_access

Primary abstract

experimental_model

Human recombinant enzyme comparison.

limitations

Results paragraph reports increased Km; the abstract conclusion says lowered Km. Numerical results are retained as a source wording discrepancy, not two independent experiments. No clinical symptom prediction.

nutrient_topic

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

plain_language

A common enzyme variant changed the measured reaction kinetics.

primary_references

Two polymorphic forms of human histamine methyltransferase: structural, thermal, and kinetic comparisons. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11566133/ · DOI 10.1016/s0969-2126(01)00643-8

L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 218–224

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

## histidine-hnmt-variant A common enzyme variant changed the measured reaction kinetics. Recombinant Ile105 HNMT had about 16 percent lower specific activity and higher apparent Km for SAM and histamine than Thr105 across 25-45 degrees C. Model: Human recombinant enzyme comparison. Limitations: Results paragraph reports increased Km; the abstract conclusion says lowered Km. Numerical results are retained as a source wording discrepancy, not two independent experiments. No clinical symptom prediction. Evidence access: Primary abstract Two polymorphic forms of human histamine methyltransferase: structural, thermal, and kinetic comparisons. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11566133/ · DOI 10.1016/s0969-2126(01)00643-8

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Mouse embryonic stem-cell Tdh depletion, alongside dietary-substrate tracing in the same study.

limitations

The experiment and threonine withdrawal are complementary tests from one paper, not independent laboratories.

nutrient_topic

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

plain_language

The precursor requires an active metabolic pathway to affect the downstream mark.

primary_references

Influence of threonine metabolism on S-adenosylmethionine and histone methylation. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23118012/ · DOI 10.1126/science.1226603

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Threonine: translation, intestinal barrier, metabolism and cross-nutrient mechanisms (2026-09-19) · lines 338–344

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse embryonic stem-cell Tdh depletion, alongside dietary-substrate tracing in the same study. · source_derived_draft · unverified_draft

## l-threonine-mouse-tdh-methylation The precursor requires an active metabolic pathway to affect the downstream mark. Depleting Tdh also lowered SAM and H3K4 trimethylation in the mouse stem-cell experiments. Model: Mouse embryonic stem-cell Tdh depletion, alongside dietary-substrate tracing in the same study. Limitations: The experiment and threonine withdrawal are complementary tests from one paper, not independent laboratories. Evidence access: Primary abstract Influence of threonine metabolism on S-adenosylmethionine and histone methylation. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23118012/ · DOI 10.1126/science.1226603

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Mouse stem-cell isotope tracing and culture-medium withdrawal.

limitations

Do not generalize to all methylation marks, adult human tissues or a threonine treatment for methylation problems.

nutrient_topic

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

plain_language

A nutrient supply change altered a specific epigenetic mark in this cell model.

primary_references

Influence of threonine metabolism on S-adenosylmethionine and histone methylation. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23118012/ · DOI 10.1126/science.1226603

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Threonine: translation, intestinal barrier, metabolism and cross-nutrient mechanisms (2026-09-19) · lines 330–336

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

## l-threonine-mouse-threonine-methylation A nutrient supply change altered a specific epigenetic mark in this cell model. Threonine withdrawal reduced SAM accumulation and H3K4 trimethylation in mouse embryonic stem cells, with slower growth and increased differentiation. Model: Mouse stem-cell isotope tracing and culture-medium withdrawal. Limitations: Do not generalize to all methylation marks, adult human tissues or a threonine treatment for methylation problems. Evidence access: Primary abstract Influence of threonine metabolism on S-adenosylmethionine and histone methylation. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23118012/ · DOI 10.1126/science.1226603

cross_nutrient

true

evidence_span

{"source_cache": "artifacts/niacin-consumption-sources/nnmt2013.txt", "locator": "Full text, normalized paragraph 35", "start_char": 19327, "end_char": 21089, "file_sha256": "7d88fd656ba772962185234a9bd021e40a9b83f9156db836f723eba06b68acca", "text_sha256": "5b6ea17ec741ecc064f97de9d83d49809db5e62588ffc1164e6e771fc9fc50c3"}

experimental_model

Immunoblotting of histone methylation in engineered cells

exposure

NNMT overexpression; 10 or 20 micromolar methionine; GFP and inactive NNMT controls

limitations

Engineered human cancer-cell culture, not healthy-human niacin repletion. SAM consumption does not establish systemic methyl depletion or a need for folate/B12 supplements. Not every histone mark changed; this does not establish global DNA hypomethylation.

nutrient_topic

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

organism

Human

plain_language

NNMT changed several histone methylation marks in this culture model.

primary_references

[b3-cons-nnmt2013] NNMT promotes epigenetic remodeling in cancer by creating a metabolic methylation sink. (2013). https://pubmed.ncbi.nlm.nih.gov/23455543/ DOI: 10.1038/nchembio.1204

tissue_or_cell_type

Human 769P renal carcinoma cells

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 803–815

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Immunoblotting of histone methylation in engineered cells · source_derived_draft · unverified_draft

### b3-cons-nnmt-histone-methylation At 10–20 micromolar medium methionine, NNMT-overexpressing 769P cells had reduced methylation of several histone lysine marks compared with controls. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: NNMT changed several histone methylation marks in this culture model. organism: Human tissue_or_cell_type: Human 769P renal carcinoma cells experimental_model: Immunoblotting of histone methylation in engineered cells limitations: Engineered human cancer-cell culture, not healthy-human niacin repletion. SAM consumption does not establish systemic methyl depletion or a need for folate/B12 supplements. Not every histone mark changed; this does not establish global DNA hypomethylation. exposure: NNMT overexpression; 10 or 20 micromolar methionine; GFP and inactive NNMT controls cross_nutrient: true evidence_span: {"source_cache": "artifacts/niacin-consumption-sources/nnmt2013.txt", "locator": "Full text, normalized paragraph 35", "start_char": 19327, "end_char": 21089, "file_sha256": "7d88fd656ba772962185234a9bd021e40a9b83f9156db836f723eba06b68acca", "text_sha256": "5b6ea17ec741ecc064f97de9d83d49809db5e62588ffc1164e6e771fc9fc50c3"} [b3-cons-nnmt2013] NNMT promotes epigenetic remodeling in cancer by creating a metabolic methylation sink. (2013). https://pubmed.ncbi.nlm.nih.gov/23455543/ DOI: 10.1038/nchembio.1204

cross_nutrient

true

evidence_span

{"source_cache": "artifacts/niacin-consumption-sources/nnmt2013.txt", "locator": "Full text, normalized paragraph 8", "start_char": 2396, "end_char": 4508, "file_sha256": "7d88fd656ba772962185234a9bd021e40a9b83f9156db836f723eba06b68acca", "text_sha256": "fc5cdd48751fa59656f5c16e70c31ab3f36788c265267d7cb57f269bb1848fc6"}

experimental_model

Human cancer-cell enzyme activity and metabolomics study

exposure

Nicotinamide substrate and NNMT expression/activity comparisons

limitations

Engineered human cancer-cell culture, not healthy-human niacin repletion. SAM consumption does not establish systemic methyl depletion or a need for folate/B12 supplements.

nutrient_topic

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

organism

Human

plain_language

Nicotinamide methylation uses a methyl group from SAM.

primary_references

[b3-cons-nnmt2013] NNMT promotes epigenetic remodeling in cancer by creating a metabolic methylation sink. (2013). https://pubmed.ncbi.nlm.nih.gov/23455543/ DOI: 10.1038/nchembio.1204

tissue_or_cell_type

769P, OVCAR3, MUM2C and comparison cell models

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 747–759

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

### b3-cons-nnmt-methyl-transfer NNMT transfers a methyl group from SAM to nicotinamide, yielding N1-methylnicotinamide and S-adenosylhomocysteine. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Nicotinamide methylation uses a methyl group from SAM. organism: Human tissue_or_cell_type: 769P, OVCAR3, MUM2C and comparison cell models experimental_model: Human cancer-cell enzyme activity and metabolomics study limitations: Engineered human cancer-cell culture, not healthy-human niacin repletion. SAM consumption does not establish systemic methyl depletion or a need for folate/B12 supplements. exposure: Nicotinamide substrate and NNMT expression/activity comparisons cross_nutrient: true evidence_span: {"source_cache": "artifacts/niacin-consumption-sources/nnmt2013.txt", "locator": "Full text, normalized paragraph 8", "start_char": 2396, "end_char": 4508, "file_sha256": "7d88fd656ba772962185234a9bd021e40a9b83f9156db836f723eba06b68acca", "text_sha256": "fc5cdd48751fa59656f5c16e70c31ab3f36788c265267d7cb57f269bb1848fc6"} [b3-cons-nnmt2013] NNMT promotes epigenetic remodeling in cancer by creating a metabolic methylation sink. (2013). https://pubmed.ncbi.nlm.nih.gov/23455543/ DOI: 10.1038/nchembio.1204

cross_nutrient

true

evidence_span

{"source_cache": "artifacts/niacin-consumption-sources/nnmt2013.txt", "locator": "Full text, normalized paragraph 24", "start_char": 12788, "end_char": 14928, "file_sha256": "7d88fd656ba772962185234a9bd021e40a9b83f9156db836f723eba06b68acca", "text_sha256": "760641ee47babbc4c1261afe881ea4baa14ae9032d0538bd467c9957224059f7"}

experimental_model

Targeted LC-MS metabolomics

exposure

Stable NNMT overexpression; 100 micromolar methionine medium and lower-methionine comparisons

limitations

Engineered human cancer-cell culture, not healthy-human niacin repletion. SAM consumption does not establish systemic methyl depletion or a need for folate/B12 supplements.

nutrient_topic

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

organism

Human

plain_language

Extra NNMT activity increased the methyl-transfer coproduct SAH.

primary_references

[b3-cons-nnmt2013] NNMT promotes epigenetic remodeling in cancer by creating a metabolic methylation sink. (2013). https://pubmed.ncbi.nlm.nih.gov/23455543/ DOI: 10.1038/nchembio.1204

tissue_or_cell_type

769P renal carcinoma; MUM2C and OVCAR3 comparisons

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 761–773

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

### b3-cons-nnmt-sah-increase NNMT overexpression raised cellular SAH relative to GFP or inactive-NNMT controls in the tested human cancer-cell models. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Extra NNMT activity increased the methyl-transfer coproduct SAH. organism: Human tissue_or_cell_type: 769P renal carcinoma; MUM2C and OVCAR3 comparisons experimental_model: Targeted LC-MS metabolomics limitations: Engineered human cancer-cell culture, not healthy-human niacin repletion. SAM consumption does not establish systemic methyl depletion or a need for folate/B12 supplements. exposure: Stable NNMT overexpression; 100 micromolar methionine medium and lower-methionine comparisons cross_nutrient: true evidence_span: {"source_cache": "artifacts/niacin-consumption-sources/nnmt2013.txt", "locator": "Full text, normalized paragraph 24", "start_char": 12788, "end_char": 14928, "file_sha256": "7d88fd656ba772962185234a9bd021e40a9b83f9156db836f723eba06b68acca", "text_sha256": "760641ee47babbc4c1261afe881ea4baa14ae9032d0538bd467c9957224059f7"} [b3-cons-nnmt2013] NNMT promotes epigenetic remodeling in cancer by creating a metabolic methylation sink. (2013). https://pubmed.ncbi.nlm.nih.gov/23455543/ DOI: 10.1038/nchembio.1204

cross_nutrient

true

evidence_span

{"source_cache": "artifacts/niacin-consumption-sources/nnmt2013.txt", "locator": "Full text, normalized paragraph 24", "start_char": 12788, "end_char": 14928, "file_sha256": "7d88fd656ba772962185234a9bd021e40a9b83f9156db836f723eba06b68acca", "text_sha256": "760641ee47babbc4c1261afe881ea4baa14ae9032d0538bd467c9957224059f7"}

experimental_model

Targeted LC-MS metabolomics

exposure

NNMT overexpression versus GFP/inactive Y20A controls in 10 micromolar methionine medium

limitations

Engineered human cancer-cell culture, not healthy-human niacin repletion. SAM consumption does not establish systemic methyl depletion or a need for folate/B12 supplements. Low medium methionine is an experimental exposure, not diagnosed human methionine or niacin deficiency.

nutrient_topic

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

organism

Human

plain_language

SAM fell when these NNMT-rich cancer cells were cultured with less methionine.

primary_references

[b3-cons-nnmt2013] NNMT promotes epigenetic remodeling in cancer by creating a metabolic methylation sink. (2013). https://pubmed.ncbi.nlm.nih.gov/23455543/ DOI: 10.1038/nchembio.1204

tissue_or_cell_type

Human 769P renal carcinoma cells

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 789–801

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

### b3-cons-nnmt-sam-low-methionine In 769P cells cultured with 10 micromolar methionine, NNMT overexpression significantly lowered SAM relative to control cells. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: SAM fell when these NNMT-rich cancer cells were cultured with less methionine. organism: Human tissue_or_cell_type: Human 769P renal carcinoma cells experimental_model: Targeted LC-MS metabolomics limitations: Engineered human cancer-cell culture, not healthy-human niacin repletion. SAM consumption does not establish systemic methyl depletion or a need for folate/B12 supplements. Low medium methionine is an experimental exposure, not diagnosed human methionine or niacin deficiency. exposure: NNMT overexpression versus GFP/inactive Y20A controls in 10 micromolar methionine medium cross_nutrient: true evidence_span: {"source_cache": "artifacts/niacin-consumption-sources/nnmt2013.txt", "locator": "Full text, normalized paragraph 24", "start_char": 12788, "end_char": 14928, "file_sha256": "7d88fd656ba772962185234a9bd021e40a9b83f9156db836f723eba06b68acca", "text_sha256": "760641ee47babbc4c1261afe881ea4baa14ae9032d0538bd467c9957224059f7"} [b3-cons-nnmt2013] NNMT promotes epigenetic remodeling in cancer by creating a metabolic methylation sink. (2013). https://pubmed.ncbi.nlm.nih.gov/23455543/ DOI: 10.1038/nchembio.1204

cross_nutrient

true

evidence_span

{"source_cache": "artifacts/niacin-consumption-sources/nnmt2013.txt", "locator": "Full text, normalized paragraph 24", "start_char": 12788, "end_char": 14928, "file_sha256": "7d88fd656ba772962185234a9bd021e40a9b83f9156db836f723eba06b68acca", "text_sha256": "760641ee47babbc4c1261afe881ea4baa14ae9032d0538bd467c9957224059f7"}

experimental_model

Targeted LC-MS metabolomics

exposure

100 micromolar methionine culture medium; NNMT overexpression

limitations

Engineered human cancer-cell culture, not healthy-human niacin repletion. SAM consumption does not establish systemic methyl depletion or a need for folate/B12 supplements.

nutrient_topic

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

organism

Human

plain_language

A higher methyl-transfer product did not necessarily mean a large fall in SAM.

primary_references

[b3-cons-nnmt2013] NNMT promotes epigenetic remodeling in cancer by creating a metabolic methylation sink. (2013). https://pubmed.ncbi.nlm.nih.gov/23455543/ DOI: 10.1038/nchembio.1204

tissue_or_cell_type

Human cancer-cell overexpression models

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 775–787

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

### b3-cons-nnmt-sam-standard At standard 100 micromolar medium methionine, NNMT overexpression changed SAM by less than 1.5-fold despite increased SAH. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: A higher methyl-transfer product did not necessarily mean a large fall in SAM. organism: Human tissue_or_cell_type: Human cancer-cell overexpression models experimental_model: Targeted LC-MS metabolomics limitations: Engineered human cancer-cell culture, not healthy-human niacin repletion. SAM consumption does not establish systemic methyl depletion or a need for folate/B12 supplements. exposure: 100 micromolar methionine culture medium; NNMT overexpression cross_nutrient: true evidence_span: {"source_cache": "artifacts/niacin-consumption-sources/nnmt2013.txt", "locator": "Full text, normalized paragraph 24", "start_char": 12788, "end_char": 14928, "file_sha256": "7d88fd656ba772962185234a9bd021e40a9b83f9156db836f723eba06b68acca", "text_sha256": "760641ee47babbc4c1261afe881ea4baa14ae9032d0538bd467c9957224059f7"} [b3-cons-nnmt2013] NNMT promotes epigenetic remodeling in cancer by creating a metabolic methylation sink. (2013). https://pubmed.ncbi.nlm.nih.gov/23455543/ DOI: 10.1038/nchembio.1204

evidence_access

Primary abstract plus Reactome reaction R-HSA-8876789

experimental_model

Purified human enzyme; reaction identity also curated in Reactome R-HSA-8876789.

limitations

Does not establish methyl-donor depletion or benefit from folate/B12 supplements.

nutrient_topic

Carnosine collection; isomer, preparation, species, exposure and manipulation remain explicit. · L-Carnosine / beta-alanyl-L-histidine

plain_language

A methyl group turns carnosine into a distinct peptide.

primary_references

UPF0586 Protein C9orf41 Homolog Is Anserine-producing Methyltransferase. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26001783/ · DOI 10.1074/jbc.M115.640037

Carnosine: synthesis, transport, carbonyl chemistry and nutrient interactions (2026-09-19) · lines 148–154

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Purified human enzyme; reaction identity also curated in Reactome R-HSA-8876789. · source_derived_draft · unverified_draft

## carnosine-methylation A methyl group turns carnosine into a distinct peptide. Recombinant human CARNMT1 methylated carnosine to anserine; the reaction uses S-adenosylmethionine as methyl donor. Model: Purified human enzyme; reaction identity also curated in Reactome R-HSA-8876789. Limitations: Does not establish methyl-donor depletion or benefit from folate/B12 supplements. Evidence access: Primary abstract plus Reactome reaction R-HSA-8876789 UPF0586 Protein C9orf41 Homolog Is Anserine-producing Methyltransferase. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26001783/ · DOI 10.1074/jbc.M115.640037

experimental_model

Purified human SET7/9 structure and H3-peptide assays.

limitations

Peptide activity does not establish SETD7 as the dominant H3K4 writer in every chromatin context. 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

SAM provides the methyl group; the protein-bound lysine receives it.

primary_references

[setd7-2002] Crystal structure and functional analysis of the histone methyltransferase SET7/9 (2002). https://pubmed.ncbi.nlm.nih.gov/12372304/ DOI: 10.1016/s0092-8674(02)00964-9

tissue_or_cell_type

Not specified as a whole tissue; see experimental model.

L-Lysine: mechanism-first literature curation (2026-09-17) · lines 547–555

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human SET7/9 structure and H3-peptide assays. · source_derived_draft · unverified_draft

### setd7-h3k4-methylation SETD7 transfers a methyl group from SAM to histone H3 Lys4 in peptide assays. Plain language: SAM provides the methyl group; the protein-bound lysine receives it. Condition category: normal organism: Human tissue_or_cell_type: Not specified as a whole tissue; see experimental model. experimental_model: Purified human SET7/9 structure and H3-peptide assays. limitations: Peptide activity does not establish SETD7 as the dominant H3K4 writer in every chromatin context. This reaction modifies lysine already in a protein. It does not show that extra oral lysine increases the reaction or improves a clinical outcome. [setd7-2002] Crystal structure and functional analysis of the histone methyltransferase SET7/9 (2002). https://pubmed.ncbi.nlm.nih.gov/12372304/ DOI: 10.1016/s0092-8674(02)00964-9

evidence_span

{"source_cache": "artifacts/molybdenum-research/15180982.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "722c11f1c29a720fb7105f37962af2652ce95b6734afdb59d675dee0b8302097", "start_char": 0, "end_char": 1828, "text_sha256": "722c11f1c29a720fb7105f37962af2652ce95b6734afdb59d675dee0b8302097"}

experimental_model

Recombinant human MOCS1A, cysteine mutagenesis and multiple spectroscopic methods

exposure

Aerobic versus anaerobic purification; iron-sulfur reconstitution

limitations

Cluster states depend on preparation and oxygen exposure; the paper does not demonstrate a dietary iron or methyl-donor threshold.

nutrient_topic

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

organism

Human protein expressed in Escherichia coli

plain_language

Molybdenum-cofactor assembly itself requires iron-sulfur machinery.

primary_references

[mo-p15180982] Characterization of MOCS1A, an oxygen-sensitive iron-sulfur protein involved in human molybdenum cofactor biosynthesis. (2004). https://pubmed.ncbi.nlm.nih.gov/15180982/ DOI: 10.1074/jbc.m313398200

tissue_or_cell_type

Purified protein and bacterial complementation

Molybdenum: cofactor assembly, sulfur metabolism and nutrient interactions (2026-09-17) · lines 313–324

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human MOCS1A, cysteine mutagenesis and multiple spectroscopic methods · source_derived_draft · unverified_draft

### mo-mocs1a-fes Anaerobic reconstitution yielded human MOCS1A containing two [4Fe-4S] clusters. Condition category: normal nutrient_topic: Molybdenum research collection; topical membership is not evidence of a direct dietary effect. plain_language: Molybdenum-cofactor assembly itself requires iron-sulfur machinery. organism: Human protein expressed in Escherichia coli tissue_or_cell_type: Purified protein and bacterial complementation experimental_model: Recombinant human MOCS1A, cysteine mutagenesis and multiple spectroscopic methods limitations: Cluster states depend on preparation and oxygen exposure; the paper does not demonstrate a dietary iron or methyl-donor threshold. exposure: Aerobic versus anaerobic purification; iron-sulfur reconstitution evidence_span: {"source_cache": "artifacts/molybdenum-research/15180982.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "722c11f1c29a720fb7105f37962af2652ce95b6734afdb59d675dee0b8302097", "start_char": 0, "end_char": 1828, "text_sha256": "722c11f1c29a720fb7105f37962af2652ce95b6734afdb59d675dee0b8302097"} [mo-p15180982] Characterization of MOCS1A, an oxygen-sensitive iron-sulfur protein involved in human molybdenum cofactor biosynthesis. (2004). https://pubmed.ncbi.nlm.nih.gov/15180982/ DOI: 10.1074/jbc.m313398200

availability_state

nutrient_deficiency Imported condition classification; unverified.

experimental_model

Thirty-three women aged 60–85 in depletion, thirty in four repletion groups.

exposure

Seven weeks 118 micrograms/day folate, followed by seven weeks 200 or 415 micrograms/day with different food/supplement combinations.

limitations

The assay interpretation is distinct from measuring intracellular SAM or methylation at specific genes.

nutrient_topic

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

organism

Homo sapiens

plain_language

The assay found more available sites for adding methyl groups to the extracted DNA.

primary_references

[fol-rampersaud2000] Genomic DNA methylation decreases in response to moderate folate depletion in elderly women (2000). https://pubmed.ncbi.nlm.nih.gov/11010943/ DOI: 10.1093/ajcn/72.4.998

tissue_or_cell_type

Human leukocyte DNA, ex-vivo assay

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1445–1455

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Thirty-three women aged 60–85 in depletion, thirty in four repletion groups. · source_derived_draft · unverified_draft

### fol-elderly-dna-methyl-acceptance In vitro incorporation of labeled SAM methyl groups into extracted leukocyte DNA increased after depletion (P=0.0025), consistent with lower pre-existing methylation. Condition category: nutrient_deficiency nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The assay found more available sites for adding methyl groups to the extracted DNA. organism: Homo sapiens tissue_or_cell_type: Human leukocyte DNA, ex-vivo assay experimental_model: Thirty-three women aged 60–85 in depletion, thirty in four repletion groups. limitations: The assay interpretation is distinct from measuring intracellular SAM or methylation at specific genes. exposure: Seven weeks 118 micrograms/day folate, followed by seven weeks 200 or 415 micrograms/day with different food/supplement combinations. [fol-rampersaud2000] Genomic DNA methylation decreases in response to moderate folate depletion in elderly women (2000). https://pubmed.ncbi.nlm.nih.gov/11010943/ DOI: 10.1093/ajcn/72.4.998

experimental_model

Native rat liver and bacterially expressed rat GNMT.

limitations

Not a human circulating threshold.

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 folate form restrains SAM use by GNMT.

primary_references

[luka-2008] Acetylation of N-terminal valine of glycine N-methyltransferase affects enzyme inhibition by folate (2008). https://pubmed.ncbi.nlm.nih.gov/18501206/ DOI: 10.1016/j.bbapap.2008.04.016

tissue_or_cell_type

Purified liver enzyme

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 767–776

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Native rat liver and bacterially expressed rat GNMT. · source_derived_draft · unverified_draft

### folate-methyl-gnmt-folate-inhibition Folate pentaglutamate produced 50% inhibition of native rat GNMT at 1.3 micromolar. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: A folate form restrains SAM use by GNMT. organism: Rattus norvegicus tissue_or_cell_type: Purified liver enzyme experimental_model: Native rat liver and bacterially expressed rat GNMT. limitations: Not a human circulating threshold. [luka-2008] Acetylation of N-terminal valine of glycine N-methyltransferase affects enzyme inhibition by folate (2008). https://pubmed.ncbi.nlm.nih.gov/18501206/ DOI: 10.1016/j.bbapap.2008.04.016

experimental_model

Native rat liver and bacterially expressed rat GNMT.

limitations

Does not quantify whole-body methyl demand.

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

GNMT spends a SAM methyl group on glycine.

primary_references

[luka-2008] Acetylation of N-terminal valine of glycine N-methyltransferase affects enzyme inhibition by folate (2008). https://pubmed.ncbi.nlm.nih.gov/18501206/ DOI: 10.1016/j.bbapap.2008.04.016

tissue_or_cell_type

Native/recombinant rat enzyme

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 756–765

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Native rat liver and bacterially expressed rat GNMT. · source_derived_draft · unverified_draft

### folate-methyl-gnmt-methyl-use Rat GNMT activity assays measured SAM-dependent glycine methylation to sarcosine. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: GNMT spends a SAM methyl group on glycine. organism: Rattus norvegicus tissue_or_cell_type: Native/recombinant rat enzyme experimental_model: Native rat liver and bacterially expressed rat GNMT. limitations: Does not quantify whole-body methyl demand. [luka-2008] Acetylation of N-terminal valine of glycine N-methyltransferase affects enzyme inhibition by folate (2008). https://pubmed.ncbi.nlm.nih.gov/18501206/ DOI: 10.1016/j.bbapap.2008.04.016

availability_state

machinery_impairment Imported condition classification; unverified.

experimental_model

Mtrr gene-trap hypomorphic mice and controls.

limitations

Ratio is not DNA methylation.

nutrient_topic

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

organism

Mus musculus

plain_language

The ratio did not fall uniformly.

primary_references

[elmore-2007] Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase (2007). https://pubmed.ncbi.nlm.nih.gov/17369066/ DOI: 10.1016/j.ymgme.2007.02.001

tissue_or_cell_type

Assayed tissue panel

trigger_kind

machinery_impairment Imported condition classification; unverified.

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 588–597

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mtrr gene-trap hypomorphic mice and controls. · source_derived_draft · unverified_draft

### folate-methyl-mtrr-mouse-ratio Mtrr gene-trap mice did not show decreased SAM:SAH ratios in most tissues despite disturbed remethylation. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The ratio did not fall uniformly. organism: Mus musculus tissue_or_cell_type: Assayed tissue panel experimental_model: Mtrr gene-trap hypomorphic mice and controls. limitations: Ratio is not DNA methylation. [elmore-2007] Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase (2007). https://pubmed.ncbi.nlm.nih.gov/17369066/ DOI: 10.1016/j.ymgme.2007.02.001

experimental_model

Human liver cytosol and metabolite comparisons.

limitations

Assay potency does not establish brain, liver or whole-body inhibition after ingestion.

nutrient_topic

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

plain_language

A liver preparation showed inhibition of a methyl-transfer enzyme.

primary_references

Inhibition of human liver catechol-O-methyltransferase by tea catechins and their metabolites: structure-activity relationship and molecular-modeling studies. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15857617/ · DOI 10.1016/j.bcp.2005.01.024

EGCG: receptor signaling, metabolism, nutrient interactions and discovery questions (2026-09-18) · lines 164–170

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human liver cytosol and metabolite comparisons. · source_derived_draft · unverified_draft

## egcg-comt-invitro A liver preparation showed inhibition of a methyl-transfer enzyme. EGCG inhibited human liver cytosolic COMT-mediated catechol-estrogen methylation, IC50 0.07 micromolar, with mixed inhibition. Model: Human liver cytosol and metabolite comparisons. Limitations: Assay potency does not establish brain, liver or whole-body inhibition after ingestion. Evidence access: primary abstract. Inhibition of human liver catechol-O-methyltransferase by tea catechins and their metabolites: structure-activity relationship and molecular-modeling studies. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15857617/ · DOI 10.1016/j.bcp.2005.01.024

evidence_access

Primary abstract

experimental_model

Human AMD1 structures, binding measurements and targeted mutants.

limitations

Feedback demonstrated at enzyme level; not a measured systemic methyl-donor drain.

nutrient_topic

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

plain_language

A pathway product helps activate production of the next branch’s donor.

primary_references

Structural basis for putrescine activation of human S-adenosylmethionine decarboxylase. · 2008 · https://pubmed.ncbi.nlm.nih.gov/19053272/ · DOI 10.1021/bi801732m

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 142–148

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human AMD1 structures, binding measurements and targeted mutants. · source_derived_draft · unverified_draft

## arg-amd-feedback A pathway product helps activate production of the next branch’s donor. Putrescine stimulated human AMD1 autoprocessing and decarboxylation through a binding pocket separate from the active site. Model: Human AMD1 structures, binding measurements and targeted mutants. Limitations: Feedback demonstrated at enzyme level; not a measured systemic methyl-donor drain. Evidence access: Primary abstract Structural basis for putrescine activation of human S-adenosylmethionine decarboxylase. · 2008 · https://pubmed.ncbi.nlm.nih.gov/19053272/ · DOI 10.1021/bi801732m