Nutrient chapter

L-Methionine

Free sulfur-containing essential amino acid; distinct from protein-bound methionine.

89 recorded mechanisms · 20 availability situations · 12 preserved sources. Draft and verified records are labeled separately.

Read recorded mechanisms Open recursive mind map

The mechanisms

What the sources say this nutrient does, one relationship at a time. Plain wording comes first; the technical statement follows.

Human LAT1 with its SLC3A2 partner transported radiolabeled methionine with an apparent Km of 99 +/- 9 micromolar.
Human L-type amino acid transporter 1 / LAT1 / SLC7A5 → L-Methionine source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human LAT1/SLC3A2 expressed in Xenopus oocytes.
limitations
A transporter assay is not a human intestinal absorption threshold.
nutrient_topic
L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine
plain_language
A shared amino-acid carrier admits methionine.
primary_references
Transport of a neurotoxicant by molecular mimicry: the methylmercury-L-cysteine complex is a substrate for human L-type large neutral amino acid transporter (LAT) 1 and LAT2. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12117417/ · DOI 10.1042/BJ20020841
transport_effect
raises Radiolabelled methionine uptake with an apparent Km of 99 micromolar.
transport_pool
the expressing cell Radiolabelled methionine uptake with an apparent Km of 99 micromolar.
L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 20–26
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human LAT1/SLC3A2 expressed in Xenopus oocytes. · source_derived_draft · unverified_draft
## methionine-lat1-transport A shared amino-acid carrier admits methionine. Human LAT1 with its SLC3A2 partner transported radiolabeled methionine with an apparent Km of 99 +/- 9 micromolar. Model: Human LAT1/SLC3A2 expressed in Xenopus oocytes. Limitations: A transporter assay is not a human intestinal absorption threshold. Evidence access: Primary abstract Transport of a neurotoxicant by molecular mimicry: the methylmercury-L-cysteine complex is a substrate for human L-type large neutral amino acid transporter (LAT) 1 and LAT2. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12117417/ · DOI 10.1042/BJ20020841
Complete structured claim and evidence
Human LAT2/SLC3A2 transported methionine; leucine and phenylalanine stimulated methionine efflux even against an inward methionine gradient.
Human L-type amino acid transporter 2 / LAT2 / SLC7A8 → L-Methionine source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human transporter in Xenopus oocytes; tracer influx and efflux.
limitations
Does not show that ordinary mixed meals deplete methionine.
nutrient_topic
L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine
plain_language
Transport depends on substrates on both sides of the membrane.
primary_references
Transport of a neurotoxicant by molecular mimicry: the methylmercury-L-cysteine complex is a substrate for human L-type large neutral amino acid transporter (LAT) 1 and LAT2. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12117417/ · DOI 10.1042/BJ20020841
L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 28–34
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human transporter in Xenopus oocytes; tracer influx and efflux. · source_derived_draft · unverified_draft
## methionine-lat2-exchange Transport depends on substrates on both sides of the membrane. Human LAT2/SLC3A2 transported methionine; leucine and phenylalanine stimulated methionine efflux even against an inward methionine gradient. Model: Human transporter in Xenopus oocytes; tracer influx and efflux. Limitations: Does not show that ordinary mixed meals deplete methionine. Evidence access: Primary abstract Transport of a neurotoxicant by molecular mimicry: the methylmercury-L-cysteine complex is a substrate for human L-type large neutral amino acid transporter (LAT) 1 and LAT2. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12117417/ · DOI 10.1042/BJ20020841
Complete structured claim and evidence
Methylmercury-L-cysteine used human LAT1/LAT2 in oocyte assays, with substrate exchange characteristics resembling methionine.
Methylmercury-L-cysteine complex → Substrate transport through human LAT1/LAT2 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human carrier expression in Xenopus oocytes.
limitations
Complex identity and chirality matter; this does not demonstrate protection from methionine supplementation.
nutrient_topic
L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine
plain_language
A toxicant complex can exploit nutrient transport machinery.
primary_references
Transport of a neurotoxicant by molecular mimicry: the methylmercury-L-cysteine complex is a substrate for human L-type large neutral amino acid transporter (LAT) 1 and LAT2. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12117417/ · DOI 10.1042/BJ20020841
L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 36–42
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human carrier expression in Xenopus oocytes. · source_derived_draft · unverified_draft
## methionine-toxicant-mimicry A toxicant complex can exploit nutrient transport machinery. Methylmercury-L-cysteine used human LAT1/LAT2 in oocyte assays, with substrate exchange characteristics resembling methionine. Model: Human carrier expression in Xenopus oocytes. Limitations: Complex identity and chirality matter; this does not demonstrate protection from methionine supplementation. Evidence access: Primary abstract Transport of a neurotoxicant by molecular mimicry: the methylmercury-L-cysteine complex is a substrate for human L-type large neutral amino acid transporter (LAT) 1 and LAT2. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12117417/ · DOI 10.1042/BJ20020841
Complete structured claim and evidence
Antigen-receptor activation increased methionine transport; Slc7a5 loss impaired uptake in activated mouse CD4 T cells.
Mouse LAT1 / Slc7a5 → Methionine uptake in activated mouse T cells source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full text
experimental_model
Mouse T cells; tracer uptake, genetic Slc7a5 loss and antigen/cytokine stimulation.
limitations
Cell activation and genetic loss are distinct from a systemic dietary deficiency.
nutrient_topic
L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine
plain_language
Immune-cell activation requires opening an amino-acid supply route.
primary_references
Antigen receptor control of methionine metabolism in T cells. · 2019 · https://pubmed.ncbi.nlm.nih.gov/30916644/ · DOI 10.7554/eLife.44210
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Methionine: transport, methylation, sulfur 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 · Mouse T cells; tracer uptake, genetic Slc7a5 loss and antigen/cytokine stimulation. · source_derived_draft · unverified_draft
## methionine-tcell-transport Immune-cell activation requires opening an amino-acid supply route. Antigen-receptor activation increased methionine transport; Slc7a5 loss impaired uptake in activated mouse CD4 T cells. Model: Mouse T cells; tracer uptake, genetic Slc7a5 loss and antigen/cytokine stimulation. Limitations: Cell activation and genetic loss are distinct from a systemic dietary deficiency. 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
Complete structured claim and evidence
Methionine availability and induced transport supported protein synthesis, methionine-cycle flux and RNA/histone methylation in activated murine T cells.
L-Methionine → Methionine-cycle flux and RNA/histone methylation in mouse T cells source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Human MARS1 catalyzes methionylation of cognate tRNA; the study compared this activity with stress-induced charging of non-cognate tRNAs.
Human cytosolic methionyl-tRNA synthetase / MARS1 → Human cytosolic methionyl-tRNA source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Human MRS/MARS1 biochemical and HeLa-cell experiments.
limitations
Baseline charging and stress-related mistranslation are separate observations.
nutrient_topic
L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine
plain_language
A dedicated enzyme attaches methionine to the translation machinery.
primary_references
Promiscuous methionyl-tRNA synthetase mediates adaptive mistranslation to protect cells against oxidative stress. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25097229/ · DOI 10.1242/jcs.152470
L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 60–66
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human MRS/MARS1 biochemical and HeLa-cell experiments. · source_derived_draft · unverified_draft
## methionine-mars-charging A dedicated enzyme attaches methionine to the translation machinery. Human MARS1 catalyzes methionylation of cognate tRNA; the study compared this activity with stress-induced charging of non-cognate tRNAs. Model: Human MRS/MARS1 biochemical and HeLa-cell experiments. Limitations: Baseline charging and stress-related mistranslation are separate observations. Evidence access: Primary full text Promiscuous methionyl-tRNA synthetase mediates adaptive mistranslation to protect cells against oxidative stress. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25097229/ · DOI 10.1242/jcs.152470
Complete structured claim and evidence
Oxidative-stress experiments identified ERK-dependent MARS1 phosphorylation at Ser209 and Ser825.
Human ERK1/ERK2 kinases → Human cytosolic methionyl-tRNA synthetase / MARS1 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Human HeLa/HEK293T cells, kinase assays and site-directed mutants.
limitations
Arsenite/peroxide and engineered constructs do not represent routine dietary exposure.
nutrient_topic
L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine
plain_language
Stress signaling changes how the charging enzyme behaves.
primary_references
Promiscuous methionyl-tRNA synthetase mediates adaptive mistranslation to protect cells against oxidative stress. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25097229/ · DOI 10.1242/jcs.152470
L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 68–74
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human HeLa/HEK293T cells, kinase assays and site-directed mutants. · source_derived_draft · unverified_draft
## methionine-mars-phosphorylation Stress signaling changes how the charging enzyme behaves. Oxidative-stress experiments identified ERK-dependent MARS1 phosphorylation at Ser209 and Ser825. Model: Human HeLa/HEK293T cells, kinase assays and site-directed mutants. Limitations: Arsenite/peroxide and engineered constructs do not represent routine dietary exposure. Evidence access: Primary full text Promiscuous methionyl-tRNA synthetase mediates adaptive mistranslation to protect cells against oxidative stress. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25097229/ · DOI 10.1242/jcs.152470
Complete structured claim and evidence
Phosphorylation-mimicking MARS1 favored non-cognate tRNAs and increased methionine incorporation at normally non-methionine positions.
Human cytosolic methionyl-tRNA synthetase / MARS1 → Methionylation of non-cognate human tRNAs source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Human MARS1 mutants and cultured-cell/protein assays.
limitations
Not evidence that all altered proteins retain normal function or that methionine loading is protective.
nutrient_topic
L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine
plain_language
Cells can trade some translation accuracy for a stress response.
primary_references
Promiscuous methionyl-tRNA synthetase mediates adaptive mistranslation to protect cells against oxidative stress. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25097229/ · DOI 10.1242/jcs.152470
L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 76–82
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human MARS1 mutants and cultured-cell/protein assays. · source_derived_draft · unverified_draft
## methionine-mars-mischarging Cells can trade some translation accuracy for a stress response. Phosphorylation-mimicking MARS1 favored non-cognate tRNAs and increased methionine incorporation at normally non-methionine positions. Model: Human MARS1 mutants and cultured-cell/protein assays. Limitations: Not evidence that all altered proteins retain normal function or that methionine loading is protective. Evidence access: Primary full text Promiscuous methionyl-tRNA synthetase mediates adaptive mistranslation to protect cells against oxidative stress. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25097229/ · DOI 10.1242/jcs.152470
Complete structured claim and evidence
Expression of the MARS1 S209D/S825D phosphorylation mimic reduced ROS and cell death in the tested stress conditions.
Human cytosolic methionyl-tRNA synthetase / MARS1 → ROS and cell death in the MARS1 phosphorylation-mutant experiment source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Human cell experiments with engineered MARS1.
limitations
Not a clinical antioxidant intervention.
nutrient_topic
L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine
plain_language
Changing the enzyme affected stress survival in cultured cells.
primary_references
Promiscuous methionyl-tRNA synthetase mediates adaptive mistranslation to protect cells against oxidative stress. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25097229/ · DOI 10.1242/jcs.152470
L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 84–90
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human cell experiments with engineered MARS1. · source_derived_draft · unverified_draft
## methionine-mars-redox-outcome Changing the enzyme affected stress survival in cultured cells. Expression of the MARS1 S209D/S825D phosphorylation mimic reduced ROS and cell death in the tested stress conditions. Model: Human cell experiments with engineered MARS1. Limitations: Not a clinical antioxidant intervention. Evidence access: Primary full text Promiscuous methionyl-tRNA synthetase mediates adaptive mistranslation to protect cells against oxidative stress. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25097229/ · DOI 10.1242/jcs.152470
Complete structured claim and evidence
MARS2 is the mitochondrial methionyl-tRNA synthetase, connecting methionine to organelle translation.
Human mitochondrial methionyl-tRNA synthetase / MARS2 → Mitochondrial methionyl-tRNA source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Established enzyme role described in the human MARS2 disease study.
limitations
This role statement is distinct from the patient-cell respiratory measurements.
nutrient_topic
L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine
plain_language
Mitochondria need their own charging enzyme.
primary_references
Novel, compound heterozygous, single-nucleotide variants in MARS2 associated with developmental delay, poor growth, and sensorineural hearing loss. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25754315/ · DOI 10.1002/humu.22781
L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 92–98
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Established enzyme role described in the human MARS2 disease study. · source_derived_draft · unverified_draft
## methionine-mars2-charging Mitochondria need their own charging enzyme. MARS2 is the mitochondrial methionyl-tRNA synthetase, connecting methionine to organelle translation. Model: Established enzyme role described in the human MARS2 disease study. Limitations: This role statement is distinct from the patient-cell respiratory measurements. Evidence access: Primary abstract Novel, compound heterozygous, single-nucleotide variants in MARS2 associated with developmental delay, poor growth, and sensorineural hearing loss. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25754315/ · DOI 10.1002/humu.22781
Complete structured claim and evidence
Biallelic MARS2 variants lowered protein abundance; patient cells had complex I/IV defects, and wild-type MARS2 expression increased NDUFB8 and COXII proteins.
Human mitochondrial methionyl-tRNA synthetase / MARS2 → Respiratory-chain protein abundance in human MARS2-deficient cells source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Two affected siblings; human fibroblasts/lymphoblasts and gene-expression rescue.
limitations
Genetic rescue is not proof that methionine supplementation rescues this disorder.
nutrient_topic
L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine
plain_language
A faulty charging enzyme can impair respiratory machinery despite available methionine.
primary_references
Novel, compound heterozygous, single-nucleotide variants in MARS2 associated with developmental delay, poor growth, and sensorineural hearing loss. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25754315/ · DOI 10.1002/humu.22781
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 100–106
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Two affected siblings; human fibroblasts/lymphoblasts and gene-expression rescue. · source_derived_draft · unverified_draft
## methionine-mars2-loss A faulty charging enzyme can impair respiratory machinery despite available methionine. Biallelic MARS2 variants lowered protein abundance; patient cells had complex I/IV defects, and wild-type MARS2 expression increased NDUFB8 and COXII proteins. Model: Two affected siblings; human fibroblasts/lymphoblasts and gene-expression rescue. Limitations: Genetic rescue is not proof that methionine supplementation rescues this disorder. Evidence access: Primary abstract Novel, compound heterozygous, single-nucleotide variants in MARS2 associated with developmental delay, poor growth, and sensorineural hearing loss. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25754315/ · DOI 10.1002/humu.22781
Complete structured claim and evidence
Human SLC25A26 imports cytosol-derived SAM into mitochondria for intramitochondrial methylation.
Human mitochondrial SAM transporter / SLC25A26 → S-Adenosyl-L-methionine source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Recessive SLC25A26 variants impaired mitochondrial methylation with defects in RNA stability, protein modification and translation.
Human mitochondrial SAM transporter / SLC25A26 → Mitochondrial methylation and translation in SLC25A26 disease source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
SLC25A26 mutations were associated with impaired CoQ10 and lipoic-acid biosynthesis in the functional study.
Human mitochondrial SAM transporter / SLC25A26 → CoQ10 and lipoate biosynthesis in the SLC25A26 study source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
The human MAT2A inhibitor-bound structure contained two magnesium ions coordinating phosphate groups at the catalytic site.
Mg2+ → Human methionine adenosyltransferase 2A / MAT2A source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
An essential potassium ion contacted the beta-phosphoryl oxygen in the human MAT2A catalytic-site ligand structure.
Potassium ion → Human methionine adenosyltransferase 2A / MAT2A source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
MAT1A supplies subunits of tetrameric MAT I and dimeric MAT III, which convert methionine and ATP to SAM.
Human methionine adenosyltransferase 1A / MAT1A → Human hepatic MAT I / MAT III isoenzymes source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Reduced MAT I/III function caused persistent hypermethioninemia in patients with biallelic MAT1A variants.
Human methionine adenosyltransferase 1A / MAT1A → Hypermethioninemia in human MAT1A deficiency source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
The cohort contained 32 patients with and 32 without CNS findings; higher mean methionine, often at least 800 micromolar, was associated with abnormalities.
Hypermethioninemia in human MAT1A deficiency → CNS abnormalities in the MAT1A cohort source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Retrospective international human case aggregation; MRI and clinical data.
limitations
Association in a rare disease is not a universal toxicity threshold or a controlled dietary experiment.
nutrient_topic
L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine
plain_language
The same diagnosis had variable neurologic outcomes.
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
biomarker_context Imported condition classification; unverified.
L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 164–170
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Retrospective international human case aggregation; MRI and clinical data. · source_derived_draft · unverified_draft
## methionine-mat1-neurologic-context The same diagnosis had variable neurologic outcomes. The cohort contained 32 patients with and 32 without CNS findings; higher mean methionine, often at least 800 micromolar, was associated with abnormalities. Model: Retrospective international human case aggregation; MRI and clinical data. Limitations: Association in a rare disease is not a universal toxicity threshold or a controlled dietary experiment. 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
Complete structured claim and evidence
AHCY catalyzes reversible conversion between SAH and adenosine plus homocysteine; product clearance favors net SAH removal.
Human adenosylhomocysteinase / AHCY → S-Adenosyl-L-homocysteine source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Established reaction in the human AHCY-deficiency investigation.
limitations
Reaction equilibrium and cellular product removal matter; plasma concentrations do not uniquely define tissue flux.
nutrient_topic
L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine
plain_language
After methyl transfer, the spent donor must be processed.
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
L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 172–178
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Established reaction in the human AHCY-deficiency investigation. · source_derived_draft · unverified_draft
## methionine-ahcy-reaction After methyl transfer, the spent donor must be processed. AHCY catalyzes reversible conversion between SAH and adenosine plus homocysteine; product clearance favors net SAH removal. Model: Established reaction in the human AHCY-deficiency investigation. Limitations: Reaction equilibrium and cellular product removal matter; plasma concentrations do not uniquely define tissue flux. 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
Complete structured claim and evidence
The index AHCY-deficient patient had very low enzyme activity and markedly elevated plasma SAH, SAM and methionine.
Human adenosylhomocysteinase / AHCY → SAM/SAH accumulation in human AHCY deficiency source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Despite SAH accumulation, the index case showed leukocyte DNA hypermethylation, along with low plasma choline/phosphatidylcholine and high guanidinoacetate.
SAM/SAH accumulation in human AHCY deficiency → Leukocyte DNA hypermethylation in the AHCY index case source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
ADK variants impaired recombinant enzyme activity and were linked to increased adenosine excretion and SAM/SAH/methionine accumulation.
Human adenosine kinase / ADK → Adenosine removal coupled to the human methionine cycle source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
SAM binding rearranged the human CBS regulatory domain and relieved autoinhibition, improving access to its catalytic pocket.
S-Adenosyl-L-methionine → Human cystathionine beta-synthase / CBS source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Rat GNMT structures located two folate-binding sites between subunits; occupancy restricts the N-terminal movements needed for substrate access.
5-Methyltetrahydrofolate → Glycine N-methyltransferase (Rattus norvegicus) source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Feedback-insensitive yeast MTHFR mutants underwent excessive methionine/SAM cycling with ATP and nucleotide depletion and poor growth in methionine-containing medium.
Engineered feedback-insensitive yeast MTHFR → Futile SAM synthesis/recycling in engineered yeast source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
SAM bound human SAMTOR with an approximate dissociation constant of 7 micromolar and disrupted SAMTOR interaction with GATOR1.
S-Adenosyl-L-methionine → Human SAM sensor / SAMTOR source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Two-hour methionine starvation lowered cellular SAM, promoted SAMTOR-GATOR1 association and inhibited mTORC1 signaling.
Human SAM sensor / SAMTOR → Human GATOR1 complex source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
SAMTOR loss made mTORC1 resistant to methionine starvation while leaving leucine- and arginine-starvation sensitivity intact.
Human SAM sensor / SAMTOR → L-Methionine source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full text
experimental_model
Human HEK293T knockout and re-expression experiments.
limitations
Loss of one sensor does not make methionine dispensable for proteins or methylation.
nutrient_topic
L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine
plain_language
Different amino acids enter the growth-control network through different sensors.
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 244–250
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human HEK293T knockout and re-expression experiments. · source_derived_draft · unverified_draft
## methionine-samtor-specificity Different amino acids enter the growth-control network through different sensors. SAMTOR loss made mTORC1 resistant to methionine starvation while leaving leucine- and arginine-starvation sensitivity intact. Model: Human HEK293T knockout and re-expression experiments. Limitations: Loss of one sensor does not make methionine dispensable for proteins or methylation. 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
Complete structured claim and evidence
Acute MAT2A depletion reduced mTORC1 responsiveness to methionine while largely preserving responsiveness to supplied SAM.
Human methionine adenosyltransferase 2A / MAT2A → Methionine-to-mTORC1 coupling in human HEK293T cells source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Methionine-starvation-induced SAM depletion increased MAT2A expression through METTL16-dependent splicing involving a conserved 3-prime-UTR hairpin.
Human RNA methyltransferase / METTL16 → Splicing of the retained human MAT2A intron source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
METTL16 was identified as a SAM-dependent U6 snRNA m6A methyltransferase.
Human RNA methyltransferase / METTL16 → Human U6 small nuclear RNA source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Methionine restriction changed SAM/SAH pools and rapidly reduced H3K4me3; restoring methionine restored the metabolic and methylation response.
L-Methionine → H3K4 trimethylation in human HCT116 cells source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
MTAP loss caused methylthioadenosine accumulation in the study cancer-cell systems, identifying salvage failure as a change in the intracellular metabolite environment.
Human methylthioadenosine phosphorylase / MTAP → 5′-Methylthioadenosine source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Human cancer-cell shRNA/metabolomics and biochemical profiling.
limitations
Extracellular stromal clearance and in-vivo exposure can differ from isolated culture.
nutrient_topic
L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine
plain_language
A product of polyamine synthesis must be recycled or removed.
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 284–290
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human cancer-cell shRNA/metabolomics and biochemical profiling. · source_derived_draft · unverified_draft
## methionine-mtap-salvage A product of polyamine synthesis must be recycled or removed. MTAP loss caused methylthioadenosine accumulation in the study cancer-cell systems, identifying salvage failure as a change in the intracellular metabolite environment. Model: Human cancer-cell shRNA/metabolomics and biochemical profiling. Limitations: Extracellular stromal clearance and in-vivo exposure can differ from isolated culture. 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
Complete structured claim and evidence
Biochemical methyltransferase profiling identified MTA as a potent selective PRMT5 inhibitor; MTAP-deleted cells had reduced PRMT5 methylation activity.
5′-Methylthioadenosine → Human protein arginine methyltransferase 5 / PRMT5 source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
MAT2A depletion preferentially reduced growth and PRMT5 methylation activity in MTAP-deleted cells.
Human methionine adenosyltransferase 2A / MAT2A → Human protein arginine methyltransferase 5 / PRMT5 source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
APIP depletion impaired HeLa growth when methionine was replaced by MTA, supporting its role in the salvage pathway.
Human methylthioribulose-1-phosphate dehydratase / APIP → Growth of human cells supplied MTA instead of methionine source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Human HeLa knockdown with supporting microbial reporter assays.
limitations
Alternative-substrate culture does not establish the fraction of dietary requirements normally met by salvage.
nutrient_topic
L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine
plain_language
Recycling sulfur back to methionine needs additional enzymes beyond MTAP.
primary_references
Functional identification of APIP as human mtnB, a key enzyme in the methionine salvage pathway. · 2012 · https://pubmed.ncbi.nlm.nih.gov/23285211/ · DOI 10.1371/journal.pone.0052877
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 308–314
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human HeLa knockdown with supporting microbial reporter assays. · source_derived_draft · unverified_draft
## methionine-apip-salvage Recycling sulfur back to methionine needs additional enzymes beyond MTAP. APIP depletion impaired HeLa growth when methionine was replaced by MTA, supporting its role in the salvage pathway. Model: Human HeLa knockdown with supporting microbial reporter assays. Limitations: Alternative-substrate culture does not establish the fraction of dietary requirements normally met by salvage. Evidence access: Primary abstract Functional identification of APIP as human mtnB, a key enzyme in the methionine salvage pathway. · 2012 · https://pubmed.ncbi.nlm.nih.gov/23285211/ · DOI 10.1371/journal.pone.0052877
Complete structured claim and evidence
Mutation of the predicted zinc-binding site abolished APIP salvage function, whereas three tested potential phosphorylation-site mutations did not.
Human methylthioribulose-1-phosphate dehydratase / APIP → Putative zinc-binding site of human APIP source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Human APIP mutant-function study.
limitations
Mutating a metal-binding site is not the same experiment as dietary zinc deficiency or zinc rescue.
nutrient_topic
L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine
plain_language
A metal-binding site can be a separate gate in nutrient recycling.
primary_references
Functional identification of APIP as human mtnB, a key enzyme in the methionine salvage pathway. · 2012 · https://pubmed.ncbi.nlm.nih.gov/23285211/ · DOI 10.1371/journal.pone.0052877
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 316–322
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human APIP mutant-function study. · source_derived_draft · unverified_draft
## methionine-apip-zinc-site A metal-binding site can be a separate gate in nutrient recycling. Mutation of the predicted zinc-binding site abolished APIP salvage function, whereas three tested potential phosphorylation-site mutations did not. Model: Human APIP mutant-function study. Limitations: Mutating a metal-binding site is not the same experiment as dietary zinc deficiency or zinc rescue. Evidence access: Primary abstract Functional identification of APIP as human mtnB, a key enzyme in the methionine salvage pathway. · 2012 · https://pubmed.ncbi.nlm.nih.gov/23285211/ · DOI 10.1371/journal.pone.0052877
Complete structured claim and evidence
Reduced APIP expression or added MTA increased Salmonella-induced cell death in the human-cell study.
Human methylthioribulose-1-phosphate dehydratase / APIP → Salmonella-induced caspase-1 cell death in human-cell assays source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Human genetic association and cellular expression/metabolite experiments.
limitations
Cell-death programs and infection context matter; not a dietary immunity claim.
nutrient_topic
L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine
plain_language
A salvage pathway also intersected with inflammatory cell death.
primary_references
Functional genetic screen of human diversity reveals that a methionine salvage enzyme regulates inflammatory cell death. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22837397/ · DOI 10.1073/pnas.1206701109
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 324–330
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human genetic association and cellular expression/metabolite experiments. · source_derived_draft · unverified_draft
## methionine-apip-inflammatory-death A salvage pathway also intersected with inflammatory cell death. Reduced APIP expression or added MTA increased Salmonella-induced cell death in the human-cell study. Model: Human genetic association and cellular expression/metabolite experiments. Limitations: Cell-death programs and infection context matter; not a dietary immunity claim. Evidence access: Primary abstract Functional genetic screen of human diversity reveals that a methionine salvage enzyme regulates inflammatory cell death. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22837397/ · DOI 10.1073/pnas.1206701109
Complete structured claim and evidence
Oxidation of paired CaMKII regulatory methionines sustained kinase activity after calcium/calmodulin was removed.
Protein-bound methionine → Oxidized regulatory methionines in the CaMKII study source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Biochemical kinase assays with cardiomyocyte and mouse experiments; exact purified construct species not resolved here.
limitations
Initial calcium/calmodulin exposure and sustained autonomous activity are distinct; not a dietary methionine effect.
nutrient_topic
L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine
plain_language
Oxidation can leave a signaling protein switched on.
primary_references
A dynamic pathway for calcium-independent activation of CaMKII by methionine oxidation. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18455987/ · DOI 10.1016/j.cell.2008.02.048
L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 332–338
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Biochemical kinase assays with cardiomyocyte and mouse experiments; exact purified construct species not resolved here. · source_derived_draft · unverified_draft
## methionine-camkii-oxidation Oxidation can leave a signaling protein switched on. Oxidation of paired CaMKII regulatory methionines sustained kinase activity after calcium/calmodulin was removed. Model: Biochemical kinase assays with cardiomyocyte and mouse experiments; exact purified construct species not resolved here. Limitations: Initial calcium/calmodulin exposure and sustained autonomous activity are distinct; not a dietary methionine effect. Evidence access: Primary abstract A dynamic pathway for calcium-independent activation of CaMKII by methionine oxidation. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18455987/ · DOI 10.1016/j.cell.2008.02.048
Complete structured claim and evidence
Msra-null mice had greater CaMKII oxidation, myocardial apoptosis and post-infarction dysfunction; methionine-sulfoxide reduction reversed oxidation-dependent activation in supporting assays.
Mouse methionine sulfoxide reductase A / Msra → Oxidized CaMKII and cardiac injury in mice source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Msra-knockout mice with biochemical support.
limitations
MSRA and selenium-dependent MSRB1 differ in substrate stereochemistry; they are not interchangeable.
nutrient_topic
L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine
plain_language
Repairing an oxidized residue can reset a signaling switch.
primary_references
A dynamic pathway for calcium-independent activation of CaMKII by methionine oxidation. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18455987/ · DOI 10.1016/j.cell.2008.02.048
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 340–346
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Msra-knockout mice with biochemical support. · source_derived_draft · unverified_draft
## methionine-msra-camkii-repair Repairing an oxidized residue can reset a signaling switch. Msra-null mice had greater CaMKII oxidation, myocardial apoptosis and post-infarction dysfunction; methionine-sulfoxide reduction reversed oxidation-dependent activation in supporting assays. Model: Msra-knockout mice with biochemical support. Limitations: MSRA and selenium-dependent MSRB1 differ in substrate stereochemistry; they are not interchangeable. Evidence access: Primary abstract A dynamic pathway for calcium-independent activation of CaMKII by methionine oxidation. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18455987/ · DOI 10.1016/j.cell.2008.02.048
Complete structured claim and evidence
T-cell Dot1l deletion removed H3K79me2 and prevented methionine supplementation from rescuing tumor-medium-induced apoptosis and impaired cytokine production.
Mouse histone H3K79 methyltransferase / Dot1l → Methionine rescue of mouse T-cell survival and function source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Reducing dietary methionine from 0.86% to 0.17% extended male F344 rat lifespan by about 30% while abolishing growth in the original experiment.
Experimentally methionine-restricted diet → Lifespan and growth in methionine-restricted male F344 rats source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Lifelong controlled feeding of male Fischer 344 rats.
limitations
Not human lifespan evidence or a nutritionally appropriate target for children.
nutrient_topic
L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine
plain_language
The longevity observation came with a substantial growth cost.
primary_references
Low methionine ingestion by rats extends life span. · 1993 · https://pubmed.ncbi.nlm.nih.gov/8429371/ · DOI 10.1093/jn/123.2.269
L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 356–362
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Lifelong controlled feeding of male Fischer 344 rats. · source_derived_draft · unverified_draft
## methionine-rat-lifespan-growth The longevity observation came with a substantial growth cost. Reducing dietary methionine from 0.86% to 0.17% extended male F344 rat lifespan by about 30% while abolishing growth in the original experiment. Model: Lifelong controlled feeding of male Fischer 344 rats. Limitations: Not human lifespan evidence or a nutritionally appropriate target for children. Evidence access: Primary abstract Low methionine ingestion by rats extends life span. · 1993 · https://pubmed.ncbi.nlm.nih.gov/8429371/ · DOI 10.1093/jn/123.2.269
Complete structured claim and evidence
Adding 0.5% cysteine for twelve weeks largely reversed the low-adiposity and related metabolic phenotype of methionine restriction without restoring serum methionine.
L-Cysteine → Adiposity and metabolic responses to methionine restriction in rats source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Four-group rat feeding study.
limitations
Does not imply all restriction effects are exclusively due to cysteine in every species.
nutrient_topic
L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine
plain_language
Changing the downstream sulfur supply changed the dietary response.
primary_references
Cysteine supplementation reverses methionine restriction effects on rat adiposity: significance of stearoyl-coenzyme A desaturase. · 2011 · https://pubmed.ncbi.nlm.nih.gov/20871132/ · DOI 10.1194/jlr.M010215
L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 364–370
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Four-group rat feeding study. · source_derived_draft · unverified_draft
## methionine-rat-cysteine-reversal Changing the downstream sulfur supply changed the dietary response. Adding 0.5% cysteine for twelve weeks largely reversed the low-adiposity and related metabolic phenotype of methionine restriction without restoring serum methionine. Model: Four-group rat feeding study. Limitations: Does not imply all restriction effects are exclusively due to cysteine in every species. Evidence access: Primary abstract Cysteine supplementation reverses methionine restriction effects on rat adiposity: significance of stearoyl-coenzyme A desaturase. · 2011 · https://pubmed.ncbi.nlm.nih.gov/20871132/ · DOI 10.1194/jlr.M010215
Complete structured claim and evidence
Methionine restriction reduced hepatic Scd1 expression and serum fatty-acid desaturation indices; cysteine supplementation reversed these changes.
Experimentally methionine-restricted diet → Rat stearoyl-CoA desaturase 1 / Scd1 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Rat liver RNA/protein and serum lipid profiling.
limitations
Desaturation indices are indirect activity readouts; no isolated human enzyme effect is established.
nutrient_topic
L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine
plain_language
Sulfur-amino-acid composition influenced a lipid-metabolism enzyme.
primary_references
Cysteine supplementation reverses methionine restriction effects on rat adiposity: significance of stearoyl-coenzyme A desaturase. · 2011 · https://pubmed.ncbi.nlm.nih.gov/20871132/ · DOI 10.1194/jlr.M010215
L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 372–378
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat liver RNA/protein and serum lipid profiling. · source_derived_draft · unverified_draft
## methionine-rat-scd1-response Sulfur-amino-acid composition influenced a lipid-metabolism enzyme. Methionine restriction reduced hepatic Scd1 expression and serum fatty-acid desaturation indices; cysteine supplementation reversed these changes. Model: Rat liver RNA/protein and serum lipid profiling. Limitations: Desaturation indices are indirect activity readouts; no isolated human enzyme effect is established. Evidence access: Primary abstract Cysteine supplementation reverses methionine restriction effects on rat adiposity: significance of stearoyl-coenzyme A desaturase. · 2011 · https://pubmed.ncbi.nlm.nih.gov/20871132/ · DOI 10.1194/jlr.M010215
Complete structured claim and evidence
Gcn2-null mice retained the methionine-restriction changes in adiposity, energy expenditure, insulin sensitivity and FGF21 induction.
Experimentally methionine-restricted diet → Mouse GCN2 / Eif2ak4 source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Wild-type and Gcn2-knockout mice under the study diet.
limitations
Not a universal statement about GCN2 during total starvation or other amino-acid deficiencies.
nutrient_topic
L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine
plain_language
This dietary response did not require the usual amino-acid stress sensor.
primary_references
Role of GCN2-Independent Signaling Through a Noncanonical PERK/NRF2 Pathway in the Physiological Responses to Dietary Methionine Restriction. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26936965/ · DOI 10.2337/db15-1324
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 380–386
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Wild-type and Gcn2-knockout mice under the study diet. · source_derived_draft · unverified_draft
## methionine-gcn2-dispensability This dietary response did not require the usual amino-acid stress sensor. Gcn2-null mice retained the methionine-restriction changes in adiposity, energy expenditure, insulin sensitivity and FGF21 induction. Model: Wild-type and Gcn2-knockout mice under the study diet. Limitations: Not a universal statement about GCN2 during total starvation or other amino-acid deficiencies. Evidence access: Primary abstract Role of GCN2-Independent Signaling Through a Noncanonical PERK/NRF2 Pathway in the Physiological Responses to Dietary Methionine Restriction. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26936965/ · DOI 10.2337/db15-1324
Complete structured claim and evidence
Methionine restriction activated hepatic PERK and an antioxidant/ISR program in wild-type and Gcn2-null mice, without the measured ER-stress pattern.
Experimentally methionine-restricted diet → Mouse PERK / Eif2ak3 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Mouse liver signaling and dietary experiments.
limitations
The proposed glutathione-sensing mechanism is not evidence of direct methionine binding to PERK.
nutrient_topic
L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine
plain_language
Dietary sulfur status engaged an alternative stress-response route.
primary_references
Role of GCN2-Independent Signaling Through a Noncanonical PERK/NRF2 Pathway in the Physiological Responses to Dietary Methionine Restriction. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26936965/ · DOI 10.2337/db15-1324
L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 388–394
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse liver signaling and dietary experiments. · source_derived_draft · unverified_draft
## methionine-perk-redox-response Dietary sulfur status engaged an alternative stress-response route. Methionine restriction activated hepatic PERK and an antioxidant/ISR program in wild-type and Gcn2-null mice, without the measured ER-stress pattern. Model: Mouse liver signaling and dietary experiments. Limitations: The proposed glutathione-sensing mechanism is not evidence of direct methionine binding to PERK. Evidence access: Primary abstract Role of GCN2-Independent Signaling Through a Noncanonical PERK/NRF2 Pathway in the Physiological Responses to Dietary Methionine Restriction. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26936965/ · DOI 10.2337/db15-1324
Complete structured claim and evidence
In twenty adults, four-week methionine-only restriction changed fewer metabolic markers than combined methionine/cysteine restriction; both increased FGF21 in the reported comparisons.
Experimentally methionine-restricted diet → Human metabolic responses to methionine-only versus total sulfur restriction source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Controlled feeding; sequential control, moderate and greater restriction periods separated by washouts.
limitations
Small short-term study with fixed diet-period ordering; no lifespan or cancer outcomes.
nutrient_topic
L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine
plain_language
Restricting one sulfur amino acid is not the same intervention as restricting both.
primary_references
Dietary Methionine and Total Sulfur Amino Acid Restriction in Healthy Adults. · 2023 · https://pubmed.ncbi.nlm.nih.gov/36806866/ · DOI 10.1007/s12603-023-1883-3
L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 396–402
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Controlled feeding; sequential control, moderate and greater restriction periods separated by washouts. · source_derived_draft · unverified_draft
## methionine-human-metr-saar Restricting one sulfur amino acid is not the same intervention as restricting both. In twenty adults, four-week methionine-only restriction changed fewer metabolic markers than combined methionine/cysteine restriction; both increased FGF21 in the reported comparisons. Model: Controlled feeding; sequential control, moderate and greater restriction periods separated by washouts. Limitations: Small short-term study with fixed diet-period ordering; no lifespan or cancer outcomes. Evidence access: Primary abstract Dietary Methionine and Total Sulfur Amino Acid Restriction in Healthy Adults. · 2023 · https://pubmed.ncbi.nlm.nih.gov/36806866/ · DOI 10.1007/s12603-023-1883-3
Complete structured claim and evidence
An eight-week randomized study of 59 adults found 1.14 kg greater weight loss with lower versus higher sulfur-amino-acid intake; resting metabolic rate did not differ.
Combined methionine/cysteine-restricted human study diet → Body-weight change in the eight-week SAAR trial source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Fully supplied plant-based diets, approximately 2 versus 5.6 g/day sulfur amino acids; baseline/sex-adjusted model.
limitations
Combined methionine/cysteine intervention; not proof of isolated methionine causality or long-term safety.
nutrient_topic
L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine
plain_language
Human evidence includes a short-term weight outcome, not just animal experiments.
primary_references
Dietary sulfur amino acid restriction in humans with overweight and obesity: a translational randomized controlled trial. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38195568/ · DOI 10.1186/s12967-023-04833-w
L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 404–410
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Fully supplied plant-based diets, approximately 2 versus 5.6 g/day sulfur amino acids; baseline/sex-adjusted model. · source_derived_draft · unverified_draft
## methionine-human-saar-weight Human evidence includes a short-term weight outcome, not just animal experiments. An eight-week randomized study of 59 adults found 1.14 kg greater weight loss with lower versus higher sulfur-amino-acid intake; resting metabolic rate did not differ. Model: Fully supplied plant-based diets, approximately 2 versus 5.6 g/day sulfur amino acids; baseline/sex-adjusted model. Limitations: Combined methionine/cysteine intervention; not proof of isolated methionine causality or long-term safety. Evidence access: Primary abstract Dietary sulfur amino acid restriction in humans with overweight and obesity: a translational randomized controlled trial. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38195568/ · DOI 10.1186/s12967-023-04833-w
Complete structured claim and evidence
A 0.1 g/kg oral methionine load increased mean plasma homocysteine from 7.9 to 23.1 micromolar at four hours in 24 healthy volunteers.
L-Methionine → Human post-methionine-load plasma total homocysteine response source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Randomized crossover human loading study.
limitations
Challenge dose is not ordinary food intake; response depends on metabolism and context.
nutrient_topic
L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine
plain_language
A large acute load challenges recycling and sulfur disposal.
primary_references
Hyperhomocysteinemia after an oral methionine load acutely impairs endothelial function in healthy adults. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9799203/ · DOI 10.1161/01.cir.98.18.1848
trigger_kind
biomarker_context Imported condition classification; unverified.
L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 412–418
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Randomized crossover human loading study. · source_derived_draft · unverified_draft
## methionine-load-homocysteine A large acute load challenges recycling and sulfur disposal. A 0.1 g/kg oral methionine load increased mean plasma homocysteine from 7.9 to 23.1 micromolar at four hours in 24 healthy volunteers. Model: Randomized crossover human loading study. Limitations: Challenge dose is not ordinary food intake; response depends on metabolism and context. Evidence access: Primary abstract Hyperhomocysteinemia after an oral methionine load acutely impairs endothelial function in healthy adults. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9799203/ · DOI 10.1161/01.cir.98.18.1848
Complete structured claim and evidence
The methionine-loading visit showed reduced flow-mediated dilation alongside higher homocysteine; the time courses were similar in a smaller follow-up group.
L-Methionine → Flow-mediated brachial dilation after methionine loading source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Healthy adults; 0.1 g/kg oral load and brachial-artery measurements.
limitations
Does not isolate homocysteine as the sole mediator or demonstrate long-term cardiovascular events.
nutrient_topic
L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine
plain_language
The loading experiment also measured a vascular response.
primary_references
Hyperhomocysteinemia after an oral methionine load acutely impairs endothelial function in healthy adults. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9799203/ · DOI 10.1161/01.cir.98.18.1848
trigger_kind
biomarker_context Imported condition classification; unverified.
L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 420–426
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Healthy adults; 0.1 g/kg oral load and brachial-artery measurements. · source_derived_draft · unverified_draft
## methionine-load-vascular The loading experiment also measured a vascular response. The methionine-loading visit showed reduced flow-mediated dilation alongside higher homocysteine; the time courses were similar in a smaller follow-up group. Model: Healthy adults; 0.1 g/kg oral load and brachial-artery measurements. Limitations: Does not isolate homocysteine as the sole mediator or demonstrate long-term cardiovascular events. Evidence access: Primary abstract Hyperhomocysteinemia after an oral methionine load acutely impairs endothelial function in healthy adults. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9799203/ · DOI 10.1161/01.cir.98.18.1848
Complete structured claim and evidence
Slc43a2 knockdown in B16F10/ID8 mouse tumor cells reduced methionine consumption and improved T-cell supply/function in coculture experiments.
Mouse methionine transporter LAT4 / Slc43a2 → Methionine competition between mouse tumor and T cells source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
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.
L-Methionine → H3K79me2 and STAT5 expression in human T cells source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Methionine-derived SAM supported m6A modification and YTHDF1-associated translation of PD-L1 and VISTA transcripts in the tumor study.
S-Adenosyl-L-methionine → m6A-dependent immune-checkpoint translation in tumor models source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Methionine restriction or YTHDF1 depletion increased CD8 infiltration and improved tumor control with PD-1 blockade in the tested mouse models.
Experimentally methionine-restricted diet → Antitumor response in the YTHDF1/m6A mouse study source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Murine tumor models; diet and YTHDF1 perturbations.
limitations
Other immune-competent models report harm; diet, tumor stage and microbiome differ. No universal direction or human efficacy is established.
nutrient_topic
L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine
plain_language
One experimental setting favored restricting the tumor methylation pathway.
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 452–458
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Murine tumor models; diet and YTHDF1 perturbations. · source_derived_draft · unverified_draft
## methionine-restriction-checkpoint-benefit One experimental setting favored restricting the tumor methylation pathway. Methionine restriction or YTHDF1 depletion increased CD8 infiltration and improved tumor control with PD-1 blockade in the tested mouse models. Model: Murine tumor models; diet and YTHDF1 perturbations. Limitations: Other immune-competent models report harm; diet, tumor stage and microbiome differ. No universal direction or human efficacy is established. 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
Complete structured claim and evidence
Methionine restriction reduced microbial hydrogen-sulfide production and impaired immune-cell survival/activation in the study models.
Experimentally methionine-restricted diet → Gut microbial hydrogen-sulfide production in the MR tumor study source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Immunocompetent male/female mouse tumor models with microbiome and sulfur interventions.
limitations
Microbial sulfur production is not identical to host CBS/CTH flux.
nutrient_topic
L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine
plain_language
Dietary sulfur supply also changes support coming from gut microbes.
primary_references
Methionine restriction-induced sulfur deficiency impairs antitumour immunity partially through gut microbiota. · 2023 · https://pubmed.ncbi.nlm.nih.gov/37537369/ · DOI 10.1038/s42255-023-00854-3
L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 460–466
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Immunocompetent male/female mouse tumor models with microbiome and sulfur interventions. · source_derived_draft · unverified_draft
## methionine-restriction-microbial-sulfur Dietary sulfur supply also changes support coming from gut microbes. Methionine restriction reduced microbial hydrogen-sulfide production and impaired immune-cell survival/activation in the study models. Model: Immunocompetent male/female mouse tumor models with microbiome and sulfur interventions. Limitations: Microbial sulfur production is not identical to host CBS/CTH flux. Evidence access: Primary abstract Methionine restriction-induced sulfur deficiency impairs antitumour immunity partially through gut microbiota. · 2023 · https://pubmed.ncbi.nlm.nih.gov/37537369/ · DOI 10.1038/s42255-023-00854-3
Complete structured claim and evidence
Restriction reduced T-cell abundance and worsened tumor growth and immunotherapy response in immunocompetent mice, while inhibiting growth in immunocompromised mice.
Experimentally methionine-restricted diet → Antitumor immunity in the sulfur/microbiome MR study source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Multiple mouse tumor settings with differing immune competence.
limitations
Comparison does not prove the exact cause of every difference from the YTHDF1 study; matched-model replication remains needed.
nutrient_topic
L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine
plain_language
Tumor and immune-cell effects can point in opposite directions.
primary_references
Methionine restriction-induced sulfur deficiency impairs antitumour immunity partially through gut microbiota. · 2023 · https://pubmed.ncbi.nlm.nih.gov/37537369/ · DOI 10.1038/s42255-023-00854-3
L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 468–474
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Multiple mouse tumor settings with differing immune competence. · source_derived_draft · unverified_draft
## methionine-restriction-immune-harm Tumor and immune-cell effects can point in opposite directions. Restriction reduced T-cell abundance and worsened tumor growth and immunotherapy response in immunocompetent mice, while inhibiting growth in immunocompromised mice. Model: Multiple mouse tumor settings with differing immune competence. Limitations: Comparison does not prove the exact cause of every difference from the YTHDF1 study; matched-model replication remains needed. Evidence access: Primary abstract Methionine restriction-induced sulfur deficiency impairs antitumour immunity partially through gut microbiota. · 2023 · https://pubmed.ncbi.nlm.nih.gov/37537369/ · DOI 10.1038/s42255-023-00854-3
Complete structured claim and evidence
Supplementation with an H2S donor, a precursor or methionine restored antitumor immune responses in the tested restriction setting.
Hydrogen sulfide / H2S → Antitumor immunity in the sulfur/microbiome MR study source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Dietary/add-back mouse experiments reported in the primary study.
limitations
Donor identity and exposure matter; this is not a human H2S or methionine treatment recommendation.
nutrient_topic
L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine
plain_language
Restoring sulfur support changed the net tumor response.
primary_references
Methionine restriction-induced sulfur deficiency impairs antitumour immunity partially through gut microbiota. · 2023 · https://pubmed.ncbi.nlm.nih.gov/37537369/ · DOI 10.1038/s42255-023-00854-3
L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 476–482
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Dietary/add-back mouse experiments reported in the primary study. · source_derived_draft · unverified_draft
## methionine-sulfur-rescue Restoring sulfur support changed the net tumor response. Supplementation with an H2S donor, a precursor or methionine restored antitumor immune responses in the tested restriction setting. Model: Dietary/add-back mouse experiments reported in the primary study. Limitations: Donor identity and exposure matter; this is not a human H2S or methionine treatment recommendation. Evidence access: Primary abstract Methionine restriction-induced sulfur deficiency impairs antitumour immunity partially through gut microbiota. · 2023 · https://pubmed.ncbi.nlm.nih.gov/37537369/ · DOI 10.1038/s42255-023-00854-3
Complete structured claim and evidence
Restriction altered one-carbon, nucleotide and redox metabolism and improved treatment responses in colorectal xenograft and autochthonous sarcoma models.
Experimentally methionine-restricted diet → Cancer treatment response in the methionine-restriction mouse study source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Patient-derived colorectal xenografts and Kras/Trp53-driven mouse sarcoma; antimetabolite/radiation settings.
limitations
Different models and immune contexts from other tumor studies; not a human cancer efficacy trial.
nutrient_topic
L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine
plain_language
Diet composition modified pathways also targeted by cancer treatment.
primary_references
Dietary methionine influences therapy in mouse cancer models and alters human metabolism. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31367041/ · DOI 10.1038/s41586-019-1437-3
L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 484–490
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Patient-derived colorectal xenografts and Kras/Trp53-driven mouse sarcoma; antimetabolite/radiation settings. · source_derived_draft · unverified_draft
## methionine-restriction-therapy-metabolism Diet composition modified pathways also targeted by cancer treatment. Restriction altered one-carbon, nucleotide and redox metabolism and improved treatment responses in colorectal xenograft and autochthonous sarcoma models. Model: Patient-derived colorectal xenografts and Kras/Trp53-driven mouse sarcoma; antimetabolite/radiation settings. Limitations: Different models and immune contexts from other tumor studies; not a human cancer efficacy trial. Evidence access: Primary abstract Dietary methionine influences therapy in mouse cancer models and alters human metabolism. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31367041/ · DOI 10.1038/s41586-019-1437-3
Complete structured claim and evidence
A controlled human feeding component changed systemic metabolism in directions overlapping the mouse experiments.
Experimentally methionine-restricted diet → Human systemic metabolome during controlled methionine restriction source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Small controlled human feeding study alongside animal cancer experiments.
limitations
No cancer response or survival benefit was demonstrated in the human feeding component.
nutrient_topic
L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine
plain_language
Human metabolic feasibility was tested separately from tumor treatment.
primary_references
Dietary methionine influences therapy in mouse cancer models and alters human metabolism. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31367041/ · DOI 10.1038/s41586-019-1437-3
L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 492–498
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Small controlled human feeding study alongside animal cancer experiments. · source_derived_draft · unverified_draft
## methionine-restriction-human-metabolome Human metabolic feasibility was tested separately from tumor treatment. A controlled human feeding component changed systemic metabolism in directions overlapping the mouse experiments. Model: Small controlled human feeding study alongside animal cancer experiments. Limitations: No cancer response or survival benefit was demonstrated in the human feeding component. Evidence access: Primary abstract Dietary methionine influences therapy in mouse cancer models and alters human metabolism. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31367041/ · DOI 10.1038/s41586-019-1437-3
Complete structured claim and evidence
Human MAT2A formed S-adenosylmethionine before rapid triphosphate hydrolysis and product release in the kinetic study.
Human methionine adenosyltransferase 2A / MAT2A → S-Adenosyl-L-methionine source_derived_draftungraded
Experimental context and source evidence
evidence_span
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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
Complete structured claim and evidence
Reconstituted human MTR transfers methylfolate-derived methyl groups through cobalamin to homocysteine, producing methionine and THF.
Cobalamin-dependent methionine synthase / MTR → L-Methionine source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Folate methyl transfer requires B12.
experimental_model
Human MTR/MTRR expressed in insect cells; purified enzymes and extracts.
limitations
Chemistry, not dietary response.
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
B12-dependent MTR recycles both homocysteine and folate.
primary_references
[yamada-2006] Human methionine synthase reductase is a molecular chaperone for human methionine synthase (2006). https://pubmed.ncbi.nlm.nih.gov/16769880/ DOI: 10.1073/pnas.0603694103
tissue_or_cell_type
Purified protein
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 482–492
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human MTR/MTRR expressed in insect cells; purified enzymes and extracts. · source_derived_draft · unverified_draft
### folate-methyl-mtr-methyl-transfer Reconstituted human MTR transfers methylfolate-derived methyl groups through cobalamin to homocysteine, producing methionine and THF. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: B12-dependent MTR recycles both homocysteine and folate. organism: Homo sapiens tissue_or_cell_type: Purified protein experimental_model: Human MTR/MTRR expressed in insect cells; purified enzymes and extracts. limitations: Chemistry, not dietary response. cross_nutrient: Folate methyl transfer requires B12. [yamada-2006] Human methionine synthase reductase is a molecular chaperone for human methionine synthase (2006). https://pubmed.ncbi.nlm.nih.gov/16769880/ DOI: 10.1073/pnas.0603694103
Complete structured claim and evidence
Reconstituted assays showed human MTRR sufficient to support NADPH-dependent activity of cobalamin-dependent methionine synthase.
Methionine synthase reductase / MTRR → Cobalamin-dependent methionine synthase / MTR source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
B2 flavins support reactivation of B12-dependent folate/homocysteine metabolism.
evidence_location
Abstract
experimental_model
Recombinant human MTRR purification, flavin analysis, NADPH spectroscopy and methionine-synthase reconstitution.
exposure
Purified-enzyme assay
limitations
Reconstituted biochemistry; the accessible abstract identifies human MTRR but not the target MTR species. No dietary B2/B12 synergy was tested.
nutrient_topic
Riboflavin research collection; topical membership is not evidence of a direct dietary effect. · Riboflavin (vitamin B2)
organism
Homo sapiens
plain_language
The flavin reductase helps restore an enzyme that uses B12 and methylfolate.
primary_references
[olteanu2001] Human methionine synthase reductase, a soluble P-450 reductase-like dual flavoprotein, is sufficient for NADPH-dependent methionine synthase activation. (2001). https://pubmed.ncbi.nlm.nih.gov/11466310/ DOI: 10.1074/jbc.m103707200
tissue_or_cell_type
Purified recombinant enzyme; no intact tissue
Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1122–1134
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human MTRR purification, flavin analysis, NADPH spectroscopy and methionine-synthase reconstitution. · source_derived_draft · unverified_draft
### b2-mtrr-mtr-reactivation Reconstituted assays showed human MTRR sufficient to support NADPH-dependent activity of cobalamin-dependent methionine synthase. Condition category: normal nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The flavin reductase helps restore an enzyme that uses B12 and methylfolate. organism: Homo sapiens tissue_or_cell_type: Purified recombinant enzyme; no intact tissue experimental_model: Recombinant human MTRR purification, flavin analysis, NADPH spectroscopy and methionine-synthase reconstitution. limitations: Reconstituted biochemistry; the accessible abstract identifies human MTRR but not the target MTR species. No dietary B2/B12 synergy was tested. exposure: Purified-enzyme assay cross_nutrient: B2 flavins support reactivation of B12-dependent folate/homocysteine metabolism. evidence_location: Abstract [olteanu2001] Human methionine synthase reductase, a soluble P-450 reductase-like dual flavoprotein, is sufficient for NADPH-dependent methionine synthase activation. (2001). https://pubmed.ncbi.nlm.nih.gov/11466310/ DOI: 10.1074/jbc.m103707200
Complete structured claim and evidence
Purified human BHMT uses betaine and homocysteine in the alternative methionine-forming reaction.
Betaine-homocysteine S-methyltransferase / BHMT → L-Methionine source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Betaine/choline and folate routes meet at homocysteine.
experimental_model
Recombinant human BHMT and human liver-derived BHMT.
limitations
Does not establish complete folate substitution in vivo.
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
Betaine supplies another recycling route.
primary_references
[millian-1998] Human betaine-homocysteine methyltransferase is a zinc metalloenzyme (1998). https://pubmed.ncbi.nlm.nih.gov/9681996/ DOI: 10.1006/abbi.1998.0757
tissue_or_cell_type
Recombinant and liver-derived enzyme
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 610–620
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human BHMT and human liver-derived BHMT. · source_derived_draft · unverified_draft
### folate-methyl-bhmt-reaction Purified human BHMT uses betaine and homocysteine in the alternative methionine-forming reaction. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Betaine supplies another recycling route. organism: Homo sapiens tissue_or_cell_type: Recombinant and liver-derived enzyme experimental_model: Recombinant human BHMT and human liver-derived BHMT. limitations: Does not establish complete folate substitution in vivo. cross_nutrient: Betaine/choline and folate routes meet at homocysteine. [millian-1998] Human betaine-homocysteine methyltransferase is a zinc metalloenzyme (1998). https://pubmed.ncbi.nlm.nih.gov/9681996/ DOI: 10.1006/abbi.1998.0757
Complete structured claim and evidence
HPLC assays measured human MTHFR reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate using NADPH.
Methylenetetrahydrofolate reductase / MTHFR → 5-Methyltetrahydrofolate source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
B2-FAD, folate and nicotinamide-containing NADPH participate in one reaction.
evidence_location
Results: kinetics, FAD occupancy and SAM inhibition; Table 1; Figs 2-4, 6
experimental_model
Recombinant human MTHFR expressed in Sf9 cells; mass spectrometry, 2.5-A structure, HPLC activity assays.
exposure
Purified-enzyme assay
limitations
Biochemical evidence does not establish a dietary threshold or supplementation benefit.
nutrient_topic
Riboflavin research collection; topical membership is not evidence of a direct dietary effect. · Riboflavin (vitamin B2)
organism
Homo sapiens
plain_language
The enzyme makes the methylfolate used in homocysteine recycling.
primary_references
[froese2018] Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition. (2018). https://pubmed.ncbi.nlm.nih.gov/29891918/ DOI: 10.1038/s41467-018-04735-2
tissue_or_cell_type
Purified recombinant enzyme; no intact tissue
Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1010–1022
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human MTHFR expressed in Sf9 cells; mass spectrometry, 2.5-A structure, HPLC activity assays. · source_derived_draft · unverified_draft
### b2-mthfr-methylfolate-production HPLC assays measured human MTHFR reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate using NADPH. Condition category: normal nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The enzyme makes the methylfolate used in homocysteine recycling. organism: Homo sapiens tissue_or_cell_type: Purified recombinant enzyme; no intact tissue experimental_model: Recombinant human MTHFR expressed in Sf9 cells; mass spectrometry, 2.5-A structure, HPLC activity assays. limitations: Biochemical evidence does not establish a dietary threshold or supplementation benefit. exposure: Purified-enzyme assay cross_nutrient: B2-FAD, folate and nicotinamide-containing NADPH participate in one reaction. evidence_location: Results: kinetics, FAD occupancy and SAM inhibition; Table 1; Figs 2-4, 6 [froese2018] Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition. (2018). https://pubmed.ncbi.nlm.nih.gov/29891918/ DOI: 10.1038/s41467-018-04735-2
Complete structured claim and evidence
Native mass spectrometry and crystallography identified FAD bound to recombinant human MTHFR catalytic domains.
FAD → Methylenetetrahydrofolate reductase / MTHFR source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
B2-FAD supports a folate-processing enzyme.
evidence_location
Results: kinetics, FAD occupancy and SAM inhibition; Table 1; Figs 2-4, 6
experimental_model
Recombinant human MTHFR expressed in Sf9 cells; mass spectrometry, 2.5-A structure, HPLC activity assays.
exposure
Purified-enzyme assay
limitations
Biochemical evidence does not establish a dietary threshold or supplementation benefit.
nutrient_topic
Riboflavin research collection; topical membership is not evidence of a direct dietary effect. · Riboflavin (vitamin B2)
organism
Homo sapiens
plain_language
MTHFR carries a B2-derived FAD cofactor.
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 996–1008
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-fad-occupancy Native mass spectrometry and crystallography identified FAD bound to recombinant human MTHFR catalytic domains. Condition category: normal nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: MTHFR carries a B2-derived FAD cofactor. organism: Homo sapiens tissue_or_cell_type: Purified recombinant enzyme; no intact tissue experimental_model: Recombinant human MTHFR expressed in Sf9 cells; mass spectrometry, 2.5-A structure, HPLC activity assays. limitations: Biochemical evidence does not establish a dietary threshold or supplementation benefit. exposure: Purified-enzyme assay cross_nutrient: B2-FAD supports a folate-processing enzyme. 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
Complete structured claim and evidence
SAM inhibited recombinant human MTHFR; phosphorylated protein was more sensitive to this inhibition than phosphatase-treated protein.
S-Adenosyl-L-methionine → Methylenetetrahydrofolate reductase / MTHFR source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Dual SAM binding rearranged the human MTHFR linker and inserted a loop that blocked catalytic substrate access.
S-Adenosyl-L-methionine → Methylenetetrahydrofolate reductase / MTHFR source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Single SAH occupancy accompanied a flexible catalytic domain with an exposed active site in human MTHFR structures.
S-Adenosyl-L-homocysteine → Methylenetetrahydrofolate reductase / MTHFR source_derived_draftungraded
Experimental context and source evidence
experimental_model
Recombinant human MTHFR; cryo-EM and biochemistry.
limitations
Does not imply SAH promotes all methyltransferases.
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 SAH-bound structure leaves the catalytic site accessible.
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 471–480
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-sah-active-state Single SAH occupancy accompanied a flexible catalytic domain with an exposed active site in human MTHFR structures. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The SAH-bound structure leaves the catalytic site accessible. organism: Homo sapiens tissue_or_cell_type: Purified protein experimental_model: Recombinant human MTHFR; cryo-EM and biochemistry. limitations: Does not imply SAH promotes all methyltransferases. [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
Complete structured claim and evidence
PLP-dependent human CBS condenses serine with homocysteine to produce cystathionine.
Human cystathionine beta-synthase / CBS → Cystathionine source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Methionine-derived sulfur enters cysteine synthesis.
experimental_model
Recombinant truncated human CBS crystallography
limitations
Enzyme chemistry alone does not predict whole-body homocysteine during mild deficiency.
nutrient_topic
Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6
organism
Homo sapiens
plain_language
This B6-dependent step channels homocysteine into transsulfuration.
primary_references
[b6-cbs-2001] Structure of human cystathionine beta-synthase: a unique pyridoxal 5'-phosphate-dependent heme protein. (2001). https://pmc.ncbi.nlm.nih.gov/articles/PMC149156/ DOI: 10.1093/emboj/20.15.3910
tissue_or_cell_type
Purified recombinant protein; no intact tissue
Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 517–527
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant truncated human CBS crystallography · source_derived_draft · unverified_draft
### b6-met-cbs-condensation PLP-dependent human CBS condenses serine with homocysteine to produce cystathionine. Condition category: normal nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: This B6-dependent step channels homocysteine into transsulfuration. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Recombinant truncated human CBS crystallography limitations: Enzyme chemistry alone does not predict whole-body homocysteine during mild deficiency. cross_nutrient: Methionine-derived sulfur enters cysteine synthesis. [b6-cbs-2001] Structure of human cystathionine beta-synthase: a unique pyridoxal 5'-phosphate-dependent heme protein. (2001). https://pmc.ncbi.nlm.nih.gov/articles/PMC149156/ DOI: 10.1093/emboj/20.15.3910
Complete structured claim and evidence
Human CTH cleaves cystathionine to cysteine, 2-oxobutanoate and ammonia in a PLP-dependent reaction.
Human cystathionine gamma-lyase / CTH → Cystathionine source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
B6-dependent sulfur transfer supplies cysteine; glutathione synthesis requires additional enzymes.
experimental_model
Purified human CTH apo/holo crystal structures and assays
limitations
Purified-enzyme evidence does not define dietary requirements or cellular PLP thresholds.
nutrient_topic
Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6
organism
Homo sapiens
plain_language
This step releases cysteine for downstream metabolism.
primary_references
[b6-cth-structure-2009] Structural Basis for the Inhibition Mechanism of Human Cystathionine gamma-Lyase, an Enzyme Responsible for the Production of H2S (2009). https://doi.org/10.1074/jbc.M805459200 DOI: 10.1074/jbc.M805459200
tissue_or_cell_type
Purified recombinant protein; no intact tissue
Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 554–564
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human CTH apo/holo crystal structures and assays · source_derived_draft · unverified_draft
### b6-met-cth-cleavage Human CTH cleaves cystathionine to cysteine, 2-oxobutanoate and ammonia in a PLP-dependent reaction. Condition category: normal nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: This step releases cysteine for downstream metabolism. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Purified human CTH apo/holo crystal structures and assays limitations: Purified-enzyme evidence does not define dietary requirements or cellular PLP thresholds. cross_nutrient: B6-dependent sulfur transfer supplies cysteine; glutathione synthesis requires additional enzymes. [b6-cth-structure-2009] Structural Basis for the Inhibition Mechanism of Human Cystathionine gamma-Lyase, an Enzyme Responsible for the Production of H2S (2009). https://doi.org/10.1074/jbc.M805459200 DOI: 10.1074/jbc.M805459200
Complete structured claim and evidence
Tracing in a cultured human hepatoma cell line estimated that transsulfuration supplied homocysteine-derived sulfur to approximately half of the intracellular glutathione pool.
Homocysteine → GSH source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
B6-dependent transsulfuration connects methionine/homocysteine to the cysteine supply for glutathione.
experimental_model
Cultured human hepatoma cell line; metabolic sulfur tracing
limitations
Fraction is culture-specific and traces sulfur, not all glutathione atoms; this experiment did not measure dietary B6 depletion.
nutrient_topic
Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6
organism
Homo sapiens
plain_language
In this cell system, sulfur routed through B6-dependent enzymes helped supply glutathione.
primary_references
[b6-glutathione-2000] The quantitatively important relationship between homocysteine metabolism and glutathione synthesis by the transsulfuration pathway and its regulation by redox changes (2000). https://pubmed.ncbi.nlm.nih.gov/11041866/ DOI: 10.1021/bi001088w
tissue_or_cell_type
Cultured human hepatoma cell line
Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 590–600
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cultured human hepatoma cell line; metabolic sulfur tracing · source_derived_draft · unverified_draft
### b6-met-transsulfuration-glutathione Tracing in a cultured human hepatoma cell line estimated that transsulfuration supplied homocysteine-derived sulfur to approximately half of the intracellular glutathione pool. Condition category: normal nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: In this cell system, sulfur routed through B6-dependent enzymes helped supply glutathione. organism: Homo sapiens tissue_or_cell_type: Cultured human hepatoma cell line experimental_model: Cultured human hepatoma cell line; metabolic sulfur tracing limitations: Fraction is culture-specific and traces sulfur, not all glutathione atoms; this experiment did not measure dietary B6 depletion. cross_nutrient: B6-dependent transsulfuration connects methionine/homocysteine to the cysteine supply for glutathione. [b6-glutathione-2000] The quantitatively important relationship between homocysteine metabolism and glutathione synthesis by the transsulfuration pathway and its regulation by redox changes (2000). https://pubmed.ncbi.nlm.nih.gov/11041866/ DOI: 10.1021/bi001088w
Complete structured claim and evidence
Rat GNMT activity assays measured SAM-dependent glycine methylation to sarcosine.
Glycine N-methyltransferase (Rattus norvegicus) → Sarcosine source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Folate pentaglutamate produced 50% inhibition of native rat GNMT at 1.3 micromolar.
5-Methyltetrahydrofolate pentaglutamate → Glycine N-methyltransferase (Rattus norvegicus) source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Non-acetylated recombinant GNMT required 590 micromolar folate pentaglutamate for 50% inhibition, versus 1.3 micromolar for native acetylated GNMT.
5-Methyltetrahydrofolate pentaglutamate → Glycine N-methyltransferase (Rattus norvegicus) source_derived_draftungraded
Experimental context and source evidence
experimental_model
Native rat liver and bacterially expressed rat GNMT.
limitations
Recombinant potency cannot be directly transferred to liver.
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
Protein modification changed inhibitory sensitivity.
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 versus recombinant rat enzyme
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 778–787
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Native rat liver and bacterially expressed rat GNMT. · source_derived_draft · unverified_draft
### folate-methyl-gnmt-acetylation Non-acetylated recombinant GNMT required 590 micromolar folate pentaglutamate for 50% inhibition, versus 1.3 micromolar for native acetylated GNMT. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Protein modification changed inhibitory sensitivity. organism: Rattus norvegicus tissue_or_cell_type: Native versus recombinant rat enzyme experimental_model: Native rat liver and bacterially expressed rat GNMT. limitations: Recombinant potency cannot be directly transferred to liver. [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
Complete structured claim and evidence
GAMT transfers a methyl group from S-adenosylmethionine to guanidinoacetate, producing creatine and S-adenosylhomocysteine.
Rat guanidinoacetate methyltransferase / Gamt → Guanidinoacetate source_derived_draftungraded
Experimental context and source evidence
evidence_span
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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
Complete structured claim and evidence
PEMT converts PE to PC through three sequential SAM-dependent methylation reactions.
Human phosphatidylethanolamine N-methyltransferase / PEMT → Phosphatidylethanolamine source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Human ASMT catalyzes the terminal methylation step converting N-acetylserotonin to melatonin using SAM.
Human acetylserotonin O-methyltransferase / ASMT → Melatonin source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
AMD1 decarboxylation generates the aminopropyl donor used in polyamine synthesis.
S-Adenosyl-L-methionine → Decarboxylated S-adenosylmethionine source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Human SRM uses putrescine as the amine acceptor for aminopropyl transfer from decarboxylated SAM.
Putrescine → Spermidine source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human enzyme structural, biochemical and mutagenesis experiments.
limitations
This consumes an aminopropyl donor, not a direct methyl transfer from ordinary SAM.
nutrient_topic
L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine
plain_language
Polyamine synthesis combines an ornithine-derived branch with a SAM-derived branch.
primary_references
Structure and mechanism of spermidine synthases. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17585781/ · DOI 10.1021/bi602498k
L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 134–140
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human enzyme structural, biochemical and mutagenesis experiments. · source_derived_draft · unverified_draft
## arg-srm Polyamine synthesis combines an ornithine-derived branch with a SAM-derived branch. Human SRM uses putrescine as the amine acceptor for aminopropyl transfer from decarboxylated SAM. Model: Human enzyme structural, biochemical and mutagenesis experiments. Limitations: This consumes an aminopropyl donor, not a direct methyl transfer from ordinary SAM. Evidence access: Primary abstract Structure and mechanism of spermidine synthases. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17585781/ · DOI 10.1021/bi602498k
Complete structured claim and evidence
Putrescine stimulated human AMD1 autoprocessing and decarboxylation through a binding pocket separate from the active site.
Putrescine → Human S-adenosylmethionine decarboxylase / AMD1 source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
NNMT transfers a methyl group from SAM to nicotinamide, yielding N1-methylnicotinamide and S-adenosylhomocysteine.
Human NNMT → N1-Methylnicotinamide source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
In 769P cells cultured with 10 micromolar methionine, NNMT overexpression significantly lowered SAM relative to control cells.
Human NNMT → Cellular S-adenosylmethionine concentration source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
At 10–20 micromolar medium methionine, NNMT-overexpressing 769P cells had reduced methylation of several histone lysine marks compared with controls.
Human NNMT → Histone methylation source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Riboflavin lowered plasma homocysteine in the MTHFR 677TT group by 22% overall; the lower-baseline-B2 subgroup showed a 40% decrease.
Riboflavin (vitamin B2) → Homocysteine source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
B2 cofactor supply interacts with folate-cycle enzyme genotype.
experimental_model
Genotype-stratified randomized trial; 35 TT, 26 CT and 28 CC adults selected, ages 18-65.
exposure
1.6 mg/day riboflavin versus placebo for 12 weeks; experimental regimen.
genotype
MTHFR 677TT; common variant rather than complete loss of enzyme
limitations
Small genotype strata; subgroup magnitude is not an expected response for every TT carrier. The trial did not test cardiovascular events.
nutrient_topic
Riboflavin research collection; topical membership is not evidence of a direct dietary effect. · Riboflavin (vitamin B2)
organism
Homo sapiens
plain_language
In this trial, improving B2 supply lowered a folate-pathway blood marker in people with two copies of the studied MTHFR variant.
primary_references
[b2-mcnulty2006] Riboflavin lowers homocysteine in individuals homozygous for the MTHFR 677C->T polymorphism (2006). https://pubmed.ncbi.nlm.nih.gov/16380544/ DOI: 10.1161/circulationaha.105.580332
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 1486–1498
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Genotype-stratified randomized trial; 35 TT, 26 CT and 28 CC adults selected, ages 18-65. · source_derived_draft · unverified_draft
### b2-tt-homocysteine-response Riboflavin lowered plasma homocysteine in the MTHFR 677TT group by 22% overall; the lower-baseline-B2 subgroup showed a 40% decrease. Condition category: machinery_impairment nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: In this trial, improving B2 supply lowered a folate-pathway blood marker in people with two copies of the studied MTHFR variant. organism: Homo sapiens tissue_or_cell_type: Human clinical setting experimental_model: Genotype-stratified randomized trial; 35 TT, 26 CT and 28 CC adults selected, ages 18-65. limitations: Small genotype strata; subgroup magnitude is not an expected response for every TT carrier. The trial did not test cardiovascular events. exposure: 1.6 mg/day riboflavin versus placebo for 12 weeks; experimental regimen. cross_nutrient: B2 cofactor supply interacts with folate-cycle enzyme genotype. genotype: MTHFR 677TT; common variant rather than complete loss of enzyme [b2-mcnulty2006] Riboflavin lowers homocysteine in individuals homozygous for the MTHFR 677C->T polymorphism (2006). https://pubmed.ncbi.nlm.nih.gov/16380544/ DOI: 10.1161/circulationaha.105.580332
Complete structured claim and evidence
No homocysteine response was observed in the CC or CT groups despite improved riboflavin-status measures in all genotype groups.
Riboflavin (vitamin B2) → Homocysteine source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Folate-cycle biomarker response was genotype dependent.
experimental_model
Genotype-stratified randomized trial; 35 TT, 26 CT and 28 CC adults selected, ages 18-65.
exposure
1.6 mg/day riboflavin versus placebo for 12 weeks; experimental regimen.
genotype
MTHFR 677CC or 677CT
limitations
Null findings in modest samples do not prove an effect is impossible; context differs from the TT arm.
nutrient_topic
Riboflavin research collection; topical membership is not evidence of a direct dietary effect. · Riboflavin (vitamin B2)
organism
Homo sapiens
plain_language
A better B2 test result did not automatically lower homocysteine in everyone.
primary_references
[b2-mcnulty2006] Riboflavin lowers homocysteine in individuals homozygous for the MTHFR 677C->T polymorphism (2006). https://pubmed.ncbi.nlm.nih.gov/16380544/ DOI: 10.1161/circulationaha.105.580332
tissue_or_cell_type
Human clinical setting
Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1500–1512
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Genotype-stratified randomized trial; 35 TT, 26 CT and 28 CC adults selected, ages 18-65. · source_derived_draft · unverified_draft
### b2-cc-ct-homocysteine-nonresponse No homocysteine response was observed in the CC or CT groups despite improved riboflavin-status measures in all genotype groups. Condition category: normal nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: A better B2 test result did not automatically lower homocysteine in everyone. organism: Homo sapiens tissue_or_cell_type: Human clinical setting experimental_model: Genotype-stratified randomized trial; 35 TT, 26 CT and 28 CC adults selected, ages 18-65. limitations: Null findings in modest samples do not prove an effect is impossible; context differs from the TT arm. exposure: 1.6 mg/day riboflavin versus placebo for 12 weeks; experimental regimen. cross_nutrient: Folate-cycle biomarker response was genotype dependent. genotype: MTHFR 677CC or 677CT [b2-mcnulty2006] Riboflavin lowers homocysteine in individuals homozygous for the MTHFR 677C->T polymorphism (2006). https://pubmed.ncbi.nlm.nih.gov/16380544/ DOI: 10.1161/circulationaha.105.580332
Complete structured claim and evidence
After two weeks, the post-methionine-load homocysteine rise was 29% lower than with placebo.
Study-specific phosphatidylcholine supplements → Human post-methionine-load plasma total homocysteine response source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/choline-research/16002808.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ad206000c96c52d280ac135c03d531122121a82c436dce40c7d13e55d0976ae1", "start_char": 0, "end_char": 1797, "text_sha256": "ad206000c96c52d280ac135c03d531122121a82c436dce40c7d13e55d0976ae1"}
experimental_model
Randomized crossover feeding trial
exposure
About 2.6 g choline/day as PC versus matched placebo oil for two weeks; methionine-load testing
limitations
High experimental intake and biomarker endpoint; no cardiovascular-event benefit was tested.
nutrient_topic
Choline research collection; topical membership is not evidence of a direct dietary effect. · Choline
organism
Human
plain_language
The response to a methionine challenge also changed.
primary_references
[choline-p16002808] Choline supplemented as phosphatidylcholine decreases fasting and postmethionine-loading plasma homocysteine concentrations in healthy men. (2005). https://pubmed.ncbi.nlm.nih.gov/16002808/ DOI: 10.1093/ajcn.82.1.111
tissue_or_cell_type
26 men with mildly elevated plasma homocysteine
Choline: metabolism, signaling and nutrient connections (2026-09-17) · lines 1088–1099
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized crossover feeding trial · source_derived_draft · unverified_draft
### choline-pc-hcy-load After two weeks, the post-methionine-load homocysteine rise was 29% lower than with placebo. Condition category: normal nutrient_topic: Choline research collection; topical membership is not evidence of a direct dietary effect. plain_language: The response to a methionine challenge also changed. organism: Human tissue_or_cell_type: 26 men with mildly elevated plasma homocysteine experimental_model: Randomized crossover feeding trial limitations: High experimental intake and biomarker endpoint; no cardiovascular-event benefit was tested. exposure: About 2.6 g choline/day as PC versus matched placebo oil for two weeks; methionine-load testing evidence_span: {"source_cache": "artifacts/choline-research/16002808.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ad206000c96c52d280ac135c03d531122121a82c436dce40c7d13e55d0976ae1", "start_char": 0, "end_char": 1797, "text_sha256": "ad206000c96c52d280ac135c03d531122121a82c436dce40c7d13e55d0976ae1"} [choline-p16002808] Choline supplemented as phosphatidylcholine decreases fasting and postmethionine-loading plasma homocysteine concentrations in healthy men. (2005). https://pubmed.ncbi.nlm.nih.gov/16002808/ DOI: 10.1093/ajcn.82.1.111
Complete structured claim and evidence
MSRB1 repairs one specific form of oxidized methionine in proteins.
MSRB1 reduces protein methionine-R-sulfoxide back toward the methionine state; stereochemistry and protein context matter.
MSRB1 → Protein-bound methionine-R-sulfoxide source_derived_draftliterature_reviewed:direct_experimental
Experimental context and source evidence
experimental_model
Human and mouse MsrB protein characterization and localization.
limitations
This experiment-specific relationship does not establish a human dietary-deficiency threshold or supplementation benefit.
organism
Human and mouse proteins
Selenium: literature corrections and mechanism additions · lines 1042–1051
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Human and mouse MsrB protein characterization and localization. · secondary_verified · secondary_verified
## msrb1-repairs-methionine MSRB1 repairs one specific form of oxidized methionine in proteins. MSRB1 reduces protein methionine-R-sulfoxide back toward the methionine state; stereochemistry and protein context matter. Experimental model: Human and mouse MsrB protein characterization and localization. Organism: Human and mouse proteins Limitations: This experiment-specific relationship does not establish a human dietary-deficiency threshold or supplementation benefit. Primary reference: [Methionine sulfoxide reduction in mammals: characterization of methionine-R-sulfoxide reductases](https://pubmed.ncbi.nlm.nih.gov/14699060/)
Complete structured claim and evidence
In eight healthy adults, adding 6.5 mg/kg/day cystine to a diet containing 5 mg/kg/day methionine did not significantly change methionine oxidation compared with the same low-methionine diet without cystine.
Cystine → Fed methionine oxidation in the 1997 cystine-intake study source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Six-day dietary periods followed by oral tracers and fasting/fed measurements on day seven.
limitations
This endpoint and regimen do not disprove every methionine-sparing effect or define current intake recommendations.
nutrient_topic
L-Cysteine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Cysteine
plain_language
A plausible nutrient-saving relationship was not detectable with this particular short-term measurement.
primary_references
Effect of cystine intake on methionine kinetics and oxidation determined with oral tracers of methionine and cysteine in healthy adults. · 1997 · https://pubmed.ncbi.nlm.nih.gov/9250106/ · DOI 10.1093/ajcn/66.2.283
L-Cysteine: sulfur allocation, redox supply 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 · Six-day dietary periods followed by oral tracers and fasting/fed measurements on day seven. · source_derived_draft · unverified_draft
## l-cysteine-methionine-sparing-limit A plausible nutrient-saving relationship was not detectable with this particular short-term measurement. In eight healthy adults, adding 6.5 mg/kg/day cystine to a diet containing 5 mg/kg/day methionine did not significantly change methionine oxidation compared with the same low-methionine diet without cystine. Model: Six-day dietary periods followed by oral tracers and fasting/fed measurements on day seven. Limitations: This endpoint and regimen do not disprove every methionine-sparing effect or define current intake recommendations. Evidence access: Primary abstract Effect of cystine intake on methionine kinetics and oxidation determined with oral tracers of methionine and cysteine in healthy adults. · 1997 · https://pubmed.ncbi.nlm.nih.gov/9250106/ · DOI 10.1093/ajcn/66.2.283
Complete structured claim and evidence

Availability and dependencies

Each situation shows the normal role first, then what the sources report under a specific condition. A shortfall in the diet, a fault in the machinery, and a low blood reading are kept separate because they are not the same thing.

Transport can limit an activated immune cell

Condition: machinery_impairment · Genetic loss of Slc7a5 in activated mouse T cells.

Normal role: Methionine supports translation, SAM production and sulfur pathways when supply and machinery function.

Recorded consequence: Reduced methionine uptake despite extracellular substrate.

Scope: Species, tissue, exposure and manipulation are specified in each linked record.

Mitochondrial translation can fail at the charging step

Condition: machinery_impairment · Human MARS2 variants.

Normal role: Methionine supports translation, SAM production and sulfur pathways when supply and machinery function.

Recorded consequence: Respiratory protein/enzyme defects; gene rescue is distinct from nutrient rescue.

Scope: Species, tissue, exposure and manipulation are specified in each linked record.

SAM must reach the mitochondrial compartment

Condition: machinery_impairment · Recessive human SLC25A26 variants.

Normal role: Methionine supports translation, SAM production and sulfur pathways when supply and machinery function.

Recorded consequence: Methylation, translation and cofactor-biosynthesis defects.

Scope: Species, tissue, exposure and manipulation are specified in each linked record.

High methionine can reflect failed activation

Condition: machinery_impairment · MAT1A deficiency.

Normal role: Methionine supports translation, SAM production and sulfur pathways when supply and machinery function.

Recorded consequence: Persistent substrate accumulation with variable downstream consequences.

Scope: Species, tissue, exposure and manipulation are specified in each linked record.

A blood concentration is a context-specific risk marker

Condition: biomarker_context · Marked methionine elevation in the MAT1A cohort.

Normal role: Methionine supports translation, SAM production and sulfur pathways when supply and machinery function.

Recorded consequence: Association with CNS abnormalities; not a universal threshold.

Scope: Species, tissue, exposure and manipulation are specified in each linked record.

The spent methyl donor can accumulate

Condition: machinery_impairment · AHCY deficiency.

Normal role: Methionine supports translation, SAM production and sulfur pathways when supply and machinery function.

Recorded consequence: Elevated SAH, SAM and methionine with severe clinical findings.

Scope: Species, tissue, exposure and manipulation are specified in each linked record.

Methylation does not change uniformly across readouts

Condition: biomarker_context · AHCY index-case biochemical and leukocyte measurements.

Normal role: Methionine supports translation, SAM production and sulfur pathways when supply and machinery function.

Recorded consequence: DNA hypermethylation coexisted with disrupted metabolite pools.

Scope: Species, tissue, exposure and manipulation are specified in each linked record.

Adenosine disposal affects the methionine cycle

Condition: machinery_impairment · Human ADK loss-of-function variants.

Normal role: Methionine supports translation, SAM production and sulfur pathways when supply and machinery function.

Recorded consequence: Product-removal failure accompanied SAM/SAH/methionine accumulation.

Scope: Species, tissue, exposure and manipulation are specified in each linked record.

Low methionine did not abolish nicotinamide methylation in this short feeding study

Condition: nutrient_deficiency · Two weeks of low methionine caused negative nitrogen balance.

Normal role: Available precursors and functioning enzymes sustain the measured pathway or nutrient-derived pool.

Recorded consequence: Measured methylated nicotinamide output was preserved despite negative nitrogen balance.

Scope: The specified study population or experimental model.

Removing feedback can waste ATP

Condition: machinery_impairment · Engineered feedback-insensitive yeast MTHFR.

Normal role: Methionine supports translation, SAM production and sulfur pathways when supply and machinery function.

Recorded consequence: Futile SAM cycling and nucleotide depletion; not assigned to human common variants.

Scope: Species, tissue, exposure and manipulation are specified in each linked record.

Low methionine can suppress a growth signal

Condition: nutrient_deficiency · Acute methionine removal from human cell culture.

Normal role: Methionine supports translation, SAM production and sulfur pathways when supply and machinery function.

Recorded consequence: Reduced SAM and SAMTOR-dependent mTORC1 inhibition.

Scope: Species, tissue, exposure and manipulation are specified in each linked record.

Sensing and conversion are separate requirements

Condition: machinery_impairment · SAMTOR loss or acute MAT2A depletion in human cells.

Normal role: Methionine supports translation, SAM production and sulfur pathways when supply and machinery function.

Recorded consequence: Altered methionine-to-mTORC1 signaling with other nutrient routes retained.

Scope: Species, tissue, exposure and manipulation are specified in each linked record.

Cells alter donor synthesis and chromatin during shortage

Condition: nutrient_deficiency · Defined methionine starvation/restriction in human cultures.

Normal role: Methionine supports translation, SAM production and sulfur pathways when supply and machinery function.

Recorded consequence: MAT2A splicing feedback and specific histone-mark changes.

Scope: Species, tissue, exposure and manipulation are specified in each linked record.

Salvage loss changes methyltransferase sensitivity

Condition: machinery_impairment · MTAP deletion in human cancer cells.

Normal role: Methionine supports translation, SAM production and sulfur pathways when supply and machinery function.

Recorded consequence: MTA accumulation and greater vulnerability to reduced MAT2A/PRMT5 activity.

Scope: Species, tissue, exposure and manipulation are specified in each linked record.

APIP function depends on its intact catalytic structure

Condition: machinery_impairment · APIP depletion or site mutation.

Normal role: Methionine supports translation, SAM production and sulfur pathways when supply and machinery function.

Recorded consequence: Reduced salvage-supported growth and altered inflammatory cell death.

Scope: Species, tissue, exposure and manipulation are specified in each linked record.

An oxidized protein needs a repair pathway

Condition: machinery_impairment · Msra deletion in mouse cardiac models.

Normal role: Methionine supports translation, SAM production and sulfur pathways when supply and machinery function.

Recorded consequence: Greater oxidation-dependent CaMKII activity and injury.

Scope: Species, tissue, exposure and manipulation are specified in each linked record.

Restriction can bypass a familiar stress sensor

Condition: machinery_impairment · Gcn2 deletion during controlled mouse methionine restriction.

Normal role: Methionine supports translation, SAM production and sulfur pathways when supply and machinery function.

Recorded consequence: Selected physiological responses persist despite absent GCN2.

Scope: Species, tissue, exposure and manipulation are specified in each linked record.

A large load challenges homocysteine handling

Condition: biomarker_context · 0.1 g/kg oral methionine challenge in healthy adults.

Normal role: Methionine supports translation, SAM production and sulfur pathways when supply and machinery function.

Recorded consequence: Acute homocysteine increase and reduced flow-mediated dilation.

Scope: Species, tissue, exposure and manipulation are specified in each linked record.

Local competition can lower T-cell methyl donors

Condition: nutrient_deficiency · Tumor-conditioned nutrient competition in human-cell experiments.

Normal role: Methionine supports translation, SAM production and sulfur pathways when supply and machinery function.

Recorded consequence: Reduced H3K79me2/STAT5 readouts; correction notice retained with source.

Scope: Species, tissue, exposure and manipulation are specified in each linked record.

Methionine repletion cannot bypass absent downstream machinery

Condition: machinery_impairment · T-cell Dot1l deletion in mouse models.

Normal role: Methionine supports translation, SAM production and sulfur pathways when supply and machinery function.

Recorded consequence: Methionine add-back failed to restore the measured survival and cytokine responses.

Scope: Species, tissue, exposure and manipulation are specified in each linked record.

The sources

Every document behind this chapter is preserved word for word. Open one to read it in full with its recorded conflicts marked in place.

Choline: metabolism, signaling and nutrient connections (2026-09-17)AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · unverified_draftRead preserved source
Creatine: synthesis, transport, phosphocreatine energetics and nutrient interactions (2026-09-17)AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · unverified_draftRead preserved source
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17)AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · unverified_draftRead preserved source
L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18)AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · unverified_draftRead preserved source
L-Cysteine: sulfur allocation, redox supply and cross-nutrient mechanisms (2026-09-19)AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · unverified_draftRead preserved source
L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19)AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · unverified_draftRead preserved source
Melatonin: synthesis, receptors, circadian timing and nutrient interactions (2026-09-17)AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · unverified_draftRead preserved source
Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17)AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · unverified_draftRead preserved source
Phosphorus: metabolism, signaling and nutrient connections (2026-09-17)AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · unverified_draftRead preserved source
Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17)AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · unverified_draftRead preserved source
Selenium: literature corrections and mechanism additionsMetabolic Ledger literature curation, 17 September 2026; primary papers linked individually · secondary_verifiedRead preserved source
Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17)AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · unverified_draftRead preserved source

Recorded disagreements

Where two sources say different things, both are kept and the difference is explained. You can discuss a disagreement or propose a mechanism that might account for it.

Open questions in this collection

Questions the curators could not answer from the sources in front of them, kept here with the reason each one is still open. These are gaps in this collection, not findings or proof that no one has studied them.

Chapters are assembled from supplied drafts and curated literature summaries. Statements remain unverified against the primary studies, and the ledger is not medical advice.

Evidence, AI assistance and curation standards

L-Methionine

The mechanisms

Human LAT1 with its SLC3A2 partner transported radiolabeled methionine with an apparent Km of 99 +/- 9 micromolar.

Human LAT2/SLC3A2 transported methionine; leucine and phenylalanine stimulated methionine efflux even against an inward methionine gradient.

Methylmercury-L-cysteine used human LAT1/LAT2 in oocyte assays, with substrate exchange characteristics resembling methionine.

Antigen-receptor activation increased methionine transport; Slc7a5 loss impaired uptake in activated mouse CD4 T cells.

Methionine availability and induced transport supported protein synthesis, methionine-cycle flux and RNA/histone methylation in activated murine T cells.

Human MARS1 catalyzes methionylation of cognate tRNA; the study compared this activity with stress-induced charging of non-cognate tRNAs.

Oxidative-stress experiments identified ERK-dependent MARS1 phosphorylation at Ser209 and Ser825.

Phosphorylation-mimicking MARS1 favored non-cognate tRNAs and increased methionine incorporation at normally non-methionine positions.

Expression of the MARS1 S209D/S825D phosphorylation mimic reduced ROS and cell death in the tested stress conditions.

MARS2 is the mitochondrial methionyl-tRNA synthetase, connecting methionine to organelle translation.

Biallelic MARS2 variants lowered protein abundance; patient cells had complex I/IV defects, and wild-type MARS2 expression increased NDUFB8 and COXII proteins.

Human SLC25A26 imports cytosol-derived SAM into mitochondria for intramitochondrial methylation.

Recessive SLC25A26 variants impaired mitochondrial methylation with defects in RNA stability, protein modification and translation.

SLC25A26 mutations were associated with impaired CoQ10 and lipoic-acid biosynthesis in the functional study.

The human MAT2A inhibitor-bound structure contained two magnesium ions coordinating phosphate groups at the catalytic site.

An essential potassium ion contacted the beta-phosphoryl oxygen in the human MAT2A catalytic-site ligand structure.

MAT1A supplies subunits of tetrameric MAT I and dimeric MAT III, which convert methionine and ATP to SAM.

Reduced MAT I/III function caused persistent hypermethioninemia in patients with biallelic MAT1A variants.

The cohort contained 32 patients with and 32 without CNS findings; higher mean methionine, often at least 800 micromolar, was associated with abnormalities.

AHCY catalyzes reversible conversion between SAH and adenosine plus homocysteine; product clearance favors net SAH removal.

The index AHCY-deficient patient had very low enzyme activity and markedly elevated plasma SAH, SAM and methionine.

Despite SAH accumulation, the index case showed leukocyte DNA hypermethylation, along with low plasma choline/phosphatidylcholine and high guanidinoacetate.

ADK variants impaired recombinant enzyme activity and were linked to increased adenosine excretion and SAM/SAH/methionine accumulation.

SAM binding rearranged the human CBS regulatory domain and relieved autoinhibition, improving access to its catalytic pocket.

Rat GNMT structures located two folate-binding sites between subunits; occupancy restricts the N-terminal movements needed for substrate access.

Feedback-insensitive yeast MTHFR mutants underwent excessive methionine/SAM cycling with ATP and nucleotide depletion and poor growth in methionine-containing medium.

SAM bound human SAMTOR with an approximate dissociation constant of 7 micromolar and disrupted SAMTOR interaction with GATOR1.

Two-hour methionine starvation lowered cellular SAM, promoted SAMTOR-GATOR1 association and inhibited mTORC1 signaling.

SAMTOR loss made mTORC1 resistant to methionine starvation while leaving leucine- and arginine-starvation sensitivity intact.

Acute MAT2A depletion reduced mTORC1 responsiveness to methionine while largely preserving responsiveness to supplied SAM.

Methionine-starvation-induced SAM depletion increased MAT2A expression through METTL16-dependent splicing involving a conserved 3-prime-UTR hairpin.

METTL16 was identified as a SAM-dependent U6 snRNA m6A methyltransferase.

Methionine restriction changed SAM/SAH pools and rapidly reduced H3K4me3; restoring methionine restored the metabolic and methylation response.

MTAP loss caused methylthioadenosine accumulation in the study cancer-cell systems, identifying salvage failure as a change in the intracellular metabolite environment.

Biochemical methyltransferase profiling identified MTA as a potent selective PRMT5 inhibitor; MTAP-deleted cells had reduced PRMT5 methylation activity.

MAT2A depletion preferentially reduced growth and PRMT5 methylation activity in MTAP-deleted cells.

APIP depletion impaired HeLa growth when methionine was replaced by MTA, supporting its role in the salvage pathway.

Mutation of the predicted zinc-binding site abolished APIP salvage function, whereas three tested potential phosphorylation-site mutations did not.

Reduced APIP expression or added MTA increased Salmonella-induced cell death in the human-cell study.

Oxidation of paired CaMKII regulatory methionines sustained kinase activity after calcium/calmodulin was removed.

Msra-null mice had greater CaMKII oxidation, myocardial apoptosis and post-infarction dysfunction; methionine-sulfoxide reduction reversed oxidation-dependent activation in supporting assays.

T-cell Dot1l deletion removed H3K79me2 and prevented methionine supplementation from rescuing tumor-medium-induced apoptosis and impaired cytokine production.

Reducing dietary methionine from 0.86% to 0.17% extended male F344 rat lifespan by about 30% while abolishing growth in the original experiment.

Adding 0.5% cysteine for twelve weeks largely reversed the low-adiposity and related metabolic phenotype of methionine restriction without restoring serum methionine.

Methionine restriction reduced hepatic Scd1 expression and serum fatty-acid desaturation indices; cysteine supplementation reversed these changes.

Gcn2-null mice retained the methionine-restriction changes in adiposity, energy expenditure, insulin sensitivity and FGF21 induction.

Methionine restriction activated hepatic PERK and an antioxidant/ISR program in wild-type and Gcn2-null mice, without the measured ER-stress pattern.

In twenty adults, four-week methionine-only restriction changed fewer metabolic markers than combined methionine/cysteine restriction; both increased FGF21 in the reported comparisons.

An eight-week randomized study of 59 adults found 1.14 kg greater weight loss with lower versus higher sulfur-amino-acid intake; resting metabolic rate did not differ.

A 0.1 g/kg oral methionine load increased mean plasma homocysteine from 7.9 to 23.1 micromolar at four hours in 24 healthy volunteers.

The methionine-loading visit showed reduced flow-mediated dilation alongside higher homocysteine; the time courses were similar in a smaller follow-up group.

Slc43a2 knockdown in B16F10/ID8 mouse tumor cells reduced methionine consumption and improved T-cell supply/function in coculture experiments.

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.

Methionine-derived SAM supported m6A modification and YTHDF1-associated translation of PD-L1 and VISTA transcripts in the tumor study.

Methionine restriction or YTHDF1 depletion increased CD8 infiltration and improved tumor control with PD-1 blockade in the tested mouse models.

Methionine restriction reduced microbial hydrogen-sulfide production and impaired immune-cell survival/activation in the study models.

Restriction reduced T-cell abundance and worsened tumor growth and immunotherapy response in immunocompetent mice, while inhibiting growth in immunocompromised mice.

Supplementation with an H2S donor, a precursor or methionine restored antitumor immune responses in the tested restriction setting.

Restriction altered one-carbon, nucleotide and redox metabolism and improved treatment responses in colorectal xenograft and autochthonous sarcoma models.

A controlled human feeding component changed systemic metabolism in directions overlapping the mouse experiments.

Human MAT2A formed S-adenosylmethionine before rapid triphosphate hydrolysis and product release in the kinetic study.

Reconstituted human MTR transfers methylfolate-derived methyl groups through cobalamin to homocysteine, producing methionine and THF.

Reconstituted assays showed human MTRR sufficient to support NADPH-dependent activity of cobalamin-dependent methionine synthase.

Purified human BHMT uses betaine and homocysteine in the alternative methionine-forming reaction.

HPLC assays measured human MTHFR reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate using NADPH.

Native mass spectrometry and crystallography identified FAD bound to recombinant human MTHFR catalytic domains.

SAM inhibited recombinant human MTHFR; phosphorylated protein was more sensitive to this inhibition than phosphatase-treated protein.

Dual SAM binding rearranged the human MTHFR linker and inserted a loop that blocked catalytic substrate access.

Single SAH occupancy accompanied a flexible catalytic domain with an exposed active site in human MTHFR structures.

PLP-dependent human CBS condenses serine with homocysteine to produce cystathionine.

Human CTH cleaves cystathionine to cysteine, 2-oxobutanoate and ammonia in a PLP-dependent reaction.

Tracing in a cultured human hepatoma cell line estimated that transsulfuration supplied homocysteine-derived sulfur to approximately half of the intracellular glutathione pool.

Rat GNMT activity assays measured SAM-dependent glycine methylation to sarcosine.

Folate pentaglutamate produced 50% inhibition of native rat GNMT at 1.3 micromolar.

Non-acetylated recombinant GNMT required 590 micromolar folate pentaglutamate for 50% inhibition, versus 1.3 micromolar for native acetylated GNMT.

GAMT transfers a methyl group from S-adenosylmethionine to guanidinoacetate, producing creatine and S-adenosylhomocysteine.

PEMT converts PE to PC through three sequential SAM-dependent methylation reactions.

Human ASMT catalyzes the terminal methylation step converting N-acetylserotonin to melatonin using SAM.