L-Methionine

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

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

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

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

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

limitations

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

nutrient_topic

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

plain_language

Nutrient competition reached a specific chromatin and signaling program.

primary_references

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

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

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

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

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

evidence_access

Primary full text

experimental_model

Murine T-cell proteomics and metabolic labeling.

limitations

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

nutrient_topic

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

plain_language

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

primary_references

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

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

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

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

evidence_span

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experimental_model

Rat feeding, isolated hepatocytes and in-vivo hepatic balance

exposure

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

limitations

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

nutrient_topic

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

organism

Rats

plain_language

Methionine helped supply the methyl donor needed to finish creatine.

primary_references

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

tissue_or_cell_type

Kidney, liver, plasma and isolated hepatocytes

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

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

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

evidence_span

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experimental_model

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

exposure

Guanidinoacetate, creatine and methionine exposures

limitations

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

nutrient_topic

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

organism

Rats

plain_language

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

primary_references

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

tissue_or_cell_type

Liver and isolated hepatocytes

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

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

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

evidence_access

Primary abstract

experimental_model

Ex vivo pig tissue; amino-acid uptake inhibition experiment.

limitations

This does not show that normal methionine intake causes human threonine deficiency.

nutrient_topic

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

plain_language

A different essential amino acid can compete at the intestinal transport step.

primary_references

Transport of Neutral Amino Acids in the Jejunum of Pigs with Special Consideration of L-Methionine. · 2024 · https://pubmed.ncbi.nlm.nih.gov/39408384/ · DOI 10.3390/nu16193418

L-Threonine: translation, intestinal barrier, metabolism and cross-nutrient mechanisms (2026-09-19) · lines 50–56

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Ex vivo pig tissue; amino-acid uptake inhibition experiment. · source_derived_draft · unverified_draft

## l-threonine-methionine-competition A different essential amino acid can compete at the intestinal transport step. Mucosal L-methionine inhibited threonine uptake in the pig jejunal transport experiments. Model: Ex vivo pig tissue; amino-acid uptake inhibition experiment. Limitations: This does not show that normal methionine intake causes human threonine deficiency. Evidence access: Primary abstract Transport of Neutral Amino Acids in the Jejunum of Pigs with Special Consideration of L-Methionine. · 2024 · https://pubmed.ncbi.nlm.nih.gov/39408384/ · DOI 10.3390/nu16193418

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Nicotinamide (challenge_substrate); N1-methylnicotinamide (methylated_product)

evidence_span

{"source_cache": "artifacts/niacin-clinical-sources/swendseid1987.abstract.txt", "locator": "Indexed primary abstract", "file_sha256": "9a410f57b23d220c2f97bf589b82b31e6e6f6ca2a7b680c2720e1881a0a71b74", "start_char": 0, "end_char": 1188, "text_sha256": "9a410f57b23d220c2f97bf589b82b31e6e6f6ca2a7b680c2720e1881a0a71b74"}

experimental_model

Sequential controlled diets; five men aged 25–32 years

exposure

10-day ordinary diet; 14 days at 285 mg methionine/day; 7 days at 725 mg/day; end-period nicotinamide challenge 102 micromol/kg

limitations

Methylated metabolite outputs, not all methylation reactions or tissue SAM, were measured. Four participants achieving final-period nitrogen balance contributed the reported comparison. Short exposure, very small study; no inference of unlimited methyl capacity.

nutrient_topic

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

organism

Homo sapiens

plain_language

Using methyl groups to dispose of nicotinamide did not automatically exhaust that capacity during this short low-methionine study.

primary_references

[nia-clin-swendseid1987] Methylated niacin derivatives in plasma and urine after an oral dose of nicotinamide given to subjects fed a low-methionine diet. (1987). https://pubmed.ncbi.nlm.nih.gov/2957911/ DOI: 10.1093/ajcn/46.3.496

tissue_or_cell_type

Urine, plasma and nitrogen balance

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 1177–1189

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Sequential controlled diets; five men aged 25–32 years · source_derived_draft · unverified_draft

### nia-clin-methionine-output-preserved After the nicotinamide challenge, urinary and plasma methylated-metabolite outputs were similar across ordinary, low-methionine and adequate-methionine periods despite negative nitrogen balance during restriction. Condition category: nutrient_deficiency nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Using methyl groups to dispose of nicotinamide did not automatically exhaust that capacity during this short low-methionine study. organism: Homo sapiens tissue_or_cell_type: Urine, plasma and nitrogen balance experimental_model: Sequential controlled diets; five men aged 25–32 years limitations: Methylated metabolite outputs, not all methylation reactions or tissue SAM, were measured. Four participants achieving final-period nitrogen balance contributed the reported comparison. Short exposure, very small study; no inference of unlimited methyl capacity. exposure: 10-day ordinary diet; 14 days at 285 mg methionine/day; 7 days at 725 mg/day; end-period nicotinamide challenge 102 micromol/kg cross_nutrient: Nicotinamide (challenge_substrate); N1-methylnicotinamide (methylated_product) evidence_span: {"source_cache": "artifacts/niacin-clinical-sources/swendseid1987.abstract.txt", "locator": "Indexed primary abstract", "file_sha256": "9a410f57b23d220c2f97bf589b82b31e6e6f6ca2a7b680c2720e1881a0a71b74", "start_char": 0, "end_char": 1188, "text_sha256": "9a410f57b23d220c2f97bf589b82b31e6e6f6ca2a7b680c2720e1881a0a71b74"} [nia-clin-swendseid1987] Methylated niacin derivatives in plasma and urine after an oral dose of nicotinamide given to subjects fed a low-methionine diet. (1987). https://pubmed.ncbi.nlm.nih.gov/2957911/ DOI: 10.1093/ajcn/46.3.496

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

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

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

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

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

evidence_location

Ghergurovich 2021 Fig. 1C-D: four-hour [U-13C]methionine tracing.

experimental_model

Isotope tracing in tumour cells, mouse tissues and xenografts.

limitations

Restricted here to human cells; not every tissue or nutrient environment.

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

Folate recycling mattered despite small net methionine production.

primary_references

[ghergurovich-2021] Methionine synthase supports tumour tetrahydrofolate pools (2021). https://pubmed.ncbi.nlm.nih.gov/34799699/ DOI: 10.1038/s42255-021-00465-w

tissue_or_cell_type

Human cancer-cell cultures

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 531–541

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Isotope tracing in tumour cells, mouse tissues and xenografts. · source_derived_draft · unverified_draft

### folate-methyl-mtr-minor-methionine Isotope tracing found MTR-derived synthesis contributed only a minor fraction of methionine in the tested human cancer-cell cultures. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Folate recycling mattered despite small net methionine production. organism: Homo sapiens tissue_or_cell_type: Human cancer-cell cultures experimental_model: Isotope tracing in tumour cells, mouse tissues and xenografts. limitations: Restricted here to human cells; not every tissue or nutrient environment. evidence_location: Ghergurovich 2021 Fig. 1C-D: four-hour [U-13C]methionine tracing. [ghergurovich-2021] Methionine synthase supports tumour tetrahydrofolate pools (2021). https://pubmed.ncbi.nlm.nih.gov/34799699/ DOI: 10.1038/s42255-021-00465-w

availability_state

machinery_impairment Imported condition classification; unverified.

experimental_model

Mtrr gene-trap hypomorphic mice and controls.

limitations

Not a direct tissue methylation assay.

nutrient_topic

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

organism

Mus musculus

plain_language

The same defect reduced circulating methionine.

primary_references

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

tissue_or_cell_type

Plasma

trigger_kind

machinery_impairment Imported condition classification; unverified.

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 577–586

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

### folate-methyl-mtrr-mouse-met Mtrr gt/gt mice had lower plasma methionine than controls. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The same defect reduced circulating methionine. organism: Mus musculus tissue_or_cell_type: Plasma experimental_model: Mtrr gene-trap hypomorphic mice and controls. limitations: Not a direct tissue methylation assay. [elmore-2007] Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase (2007). https://pubmed.ncbi.nlm.nih.gov/17369066/ DOI: 10.1016/j.ymgme.2007.02.001

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

B6 intersects methionine/folate metabolism; this experiment does not establish B12 or folate depletion.

experimental_model

Nine healthy adults (five women, four men; ages 20–35), repeated postprandial isotope kinetics.

exposure

28 days dietary B6 restriction; plasma PLP49±4 to 19±2 nmol/L.

limitations

Null group means do not establish identical responses or preserved DNA methylation in every tissue.

nutrient_topic

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

organism

Homo sapiens

plain_language

Lower B6 did not make this measured process uniformly fail.

primary_references

[b6-lamers2011] Moderate vitamin B-6 restriction does not alter postprandial methionine cycle rates of remethylation, transmethylation, and total transsulfuration but increases the fractional synthesis rate of cystathionine in healthy young men and women (2011). https://pubmed.ncbi.nlm.nih.gov/21430249/ DOI: 10.3945/jn.110.134197

tissue_or_cell_type

Human blood and whole-body measurements

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1346–1357

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Nine healthy adults (five women, four men; ages 20–35), repeated postprandial isotope kinetics. · source_derived_draft · unverified_draft

### b6-fed-remethylation-preserved Mean postprandial homocysteine remethylation did not significantly change after restriction, with substantial individual variation. Condition category: nutrient_deficiency nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Lower B6 did not make this measured process uniformly fail. organism: Homo sapiens tissue_or_cell_type: Human blood and whole-body measurements experimental_model: Nine healthy adults (five women, four men; ages 20–35), repeated postprandial isotope kinetics. limitations: Null group means do not establish identical responses or preserved DNA methylation in every tissue. exposure: 28 days dietary B6 restriction; plasma PLP49±4 to 19±2 nmol/L. cross_nutrient: B6 intersects methionine/folate metabolism; this experiment does not establish B12 or folate depletion. [b6-lamers2011] Moderate vitamin B-6 restriction does not alter postprandial methionine cycle rates of remethylation, transmethylation, and total transsulfuration but increases the fractional synthesis rate of cystathionine in healthy young men and women (2011). https://pubmed.ncbi.nlm.nih.gov/21430249/ DOI: 10.3945/jn.110.134197

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

B6 intersects methionine/folate metabolism; this experiment does not establish B12 or folate depletion.

experimental_model

Nine healthy adults (five women, four men; ages 20–35), repeated postprandial isotope kinetics.

exposure

28 days dietary B6 restriction; plasma PLP49±4 to 19±2 nmol/L.

limitations

Null group means do not establish identical responses or preserved DNA methylation in every tissue.

nutrient_topic

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

organism

Homo sapiens

plain_language

Lower B6 did not make this measured process uniformly fail.

primary_references

[b6-lamers2011] Moderate vitamin B-6 restriction does not alter postprandial methionine cycle rates of remethylation, transmethylation, and total transsulfuration but increases the fractional synthesis rate of cystathionine in healthy young men and women (2011). https://pubmed.ncbi.nlm.nih.gov/21430249/ DOI: 10.3945/jn.110.134197

tissue_or_cell_type

Human blood and whole-body measurements

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1359–1370

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Nine healthy adults (five women, four men; ages 20–35), repeated postprandial isotope kinetics. · source_derived_draft · unverified_draft

### b6-fed-transmethylation-preserved Mean postprandial transmethylation did not significantly change after restriction, with substantial individual variation. Condition category: nutrient_deficiency nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Lower B6 did not make this measured process uniformly fail. organism: Homo sapiens tissue_or_cell_type: Human blood and whole-body measurements experimental_model: Nine healthy adults (five women, four men; ages 20–35), repeated postprandial isotope kinetics. limitations: Null group means do not establish identical responses or preserved DNA methylation in every tissue. exposure: 28 days dietary B6 restriction; plasma PLP49±4 to 19±2 nmol/L. cross_nutrient: B6 intersects methionine/folate metabolism; this experiment does not establish B12 or folate depletion. [b6-lamers2011] Moderate vitamin B-6 restriction does not alter postprandial methionine cycle rates of remethylation, transmethylation, and total transsulfuration but increases the fractional synthesis rate of cystathionine in healthy young men and women (2011). https://pubmed.ncbi.nlm.nih.gov/21430249/ DOI: 10.3945/jn.110.134197

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

B6 intersects methionine/folate metabolism; this experiment does not establish B12 or folate depletion.

experimental_model

Nine healthy adults (five women, four men; ages 20–35), repeated postprandial isotope kinetics.

exposure

28 days dietary B6 restriction; plasma PLP49±4 to 19±2 nmol/L.

limitations

Null group means do not establish identical responses or preserved DNA methylation in every tissue.

nutrient_topic

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

organism

Homo sapiens

plain_language

Lower B6 did not make this measured process uniformly fail.

primary_references

[b6-lamers2011] Moderate vitamin B-6 restriction does not alter postprandial methionine cycle rates of remethylation, transmethylation, and total transsulfuration but increases the fractional synthesis rate of cystathionine in healthy young men and women (2011). https://pubmed.ncbi.nlm.nih.gov/21430249/ DOI: 10.3945/jn.110.134197

tissue_or_cell_type

Human blood and whole-body measurements

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1372–1383

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Nine healthy adults (five women, four men; ages 20–35), repeated postprandial isotope kinetics. · source_derived_draft · unverified_draft

### b6-fed-transsulfuration-preserved Mean postprandial total transsulfuration did not significantly change after restriction, with substantial individual variation. Condition category: nutrient_deficiency nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Lower B6 did not make this measured process uniformly fail. organism: Homo sapiens tissue_or_cell_type: Human blood and whole-body measurements experimental_model: Nine healthy adults (five women, four men; ages 20–35), repeated postprandial isotope kinetics. limitations: Null group means do not establish identical responses or preserved DNA methylation in every tissue. exposure: 28 days dietary B6 restriction; plasma PLP49±4 to 19±2 nmol/L. cross_nutrient: B6 intersects methionine/folate metabolism; this experiment does not establish B12 or folate depletion. [b6-lamers2011] Moderate vitamin B-6 restriction does not alter postprandial methionine cycle rates of remethylation, transmethylation, and total transsulfuration but increases the fractional synthesis rate of cystathionine in healthy young men and women (2011). https://pubmed.ncbi.nlm.nih.gov/21430249/ DOI: 10.3945/jn.110.134197

availability_state

biomarker_context Imported condition classification; unverified.

cross_nutrient

Methionine handling depends on more than circulating B6.

experimental_model

Double-blind randomized placebo-controlled RA trial: 36 recruited, 33 baseline completers, 28 low-PLP patients eligible for supplementation.

exposure

Pyridoxine hydrochloride 50 mg/day or placebo for 30 days; historical trial exposure, not a regimen recommendation.

limitations

Subgroup findings are exploratory; methotrexate, inflammation and enzyme differences can affect the challenge.

nutrient_topic

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

organism

Homo sapiens

plain_language

The homocysteine test did not improve as consistently as the other B6 tests.

primary_references

[b6-chiang2005-trial] Pyridoxine supplementation corrects vitamin B6 deficiency but does not improve inflammation in patients with rheumatoid arthritis (2005). https://pubmed.ncbi.nlm.nih.gov/16277693/ DOI: 10.1186/ar1839

tissue_or_cell_type

Human blood and whole-body measurements

trigger_kind

biomarker_context Imported condition classification; unverified.

Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1497–1508

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind randomized placebo-controlled RA trial: 36 recruited, 33 baseline completers, 28 low-PLP patients eligible for supplementation. · source_derived_draft · unverified_draft

### b6-ra-homocysteine-response-boundary The overall post-methionine homocysteine treatment effect was a nonsignificant trend (P=0.086); an elevated-baseline subgroup showed a stronger signal. Condition category: biomarker_context nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The homocysteine test did not improve as consistently as the other B6 tests. organism: Homo sapiens tissue_or_cell_type: Human blood and whole-body measurements experimental_model: Double-blind randomized placebo-controlled RA trial: 36 recruited, 33 baseline completers, 28 low-PLP patients eligible for supplementation. limitations: Subgroup findings are exploratory; methotrexate, inflammation and enzyme differences can affect the challenge. exposure: Pyridoxine hydrochloride 50 mg/day or placebo for 30 days; historical trial exposure, not a regimen recommendation. cross_nutrient: Methionine handling depends on more than circulating B6. [b6-chiang2005-trial] Pyridoxine supplementation corrects vitamin B6 deficiency but does not improve inflammation in patients with rheumatoid arthritis (2005). https://pubmed.ncbi.nlm.nih.gov/16277693/ DOI: 10.1186/ar1839

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

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

limitations

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

nutrient_topic

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

plain_language

Removing one reaction product helps keep the recycling pathway moving.

primary_references

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

trigger_kind

machinery_impairment Imported condition classification; unverified.

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

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

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

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

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

limitations

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

nutrient_topic

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

plain_language

Abundant methyl-donor substrate can coexist with blocked recycling.

primary_references

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

trigger_kind

machinery_impairment Imported condition classification; unverified.

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

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

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

availability_state

biomarker_context Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

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

limitations

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

nutrient_topic

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

plain_language

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

primary_references

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

trigger_kind

biomarker_context Imported condition classification; unverified.

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

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

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

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

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

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

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

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

evidence_access

Primary abstract

experimental_model

Human CBS structural study with SAM-bound activated conformation.

limitations

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

nutrient_topic

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

plain_language

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

primary_references

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

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

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

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

evidence_access

Primary abstract

experimental_model

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

limitations

Does not mean all methionine methylation suppresses immunity.

nutrient_topic

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

plain_language

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

primary_references

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

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

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

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

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

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

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

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

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

evidence_access

Primary full text

experimental_model

Human MRS/MARS1 biochemical and HeLa-cell experiments.

limitations

Baseline charging and stress-related mistranslation are separate observations.

nutrient_topic

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

plain_language

A dedicated enzyme attaches methionine to the translation machinery.

primary_references

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

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

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

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

evidence_access

Primary 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

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

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

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

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

evidence_access

Primary abstract

experimental_model

Human MAT2A structure with nonhydrolyzable imidotriphosphate and methylthioadenosine.

limitations

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

nutrient_topic

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

plain_language

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

primary_references

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

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

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

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

evidence_access

Primary abstract

experimental_model

Purified human MAT2A crystallography and kinetic study.

limitations

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

nutrient_topic

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

plain_language

Potassium participates directly in the enzyme chemistry.

primary_references

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

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

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

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

evidence_access

Primary abstract

experimental_model

Human MAT1A disease cohort; established isoenzyme chemistry.

limitations

MAT1A and MAT2A retain separate identities.

nutrient_topic

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

plain_language

The liver has distinct enzyme assemblies for activating methionine.

primary_references

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

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

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

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

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

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

limitations

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

nutrient_topic

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

plain_language

High substrate can signal failure to process it.

primary_references

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

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 156–162

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Aggregated clinical data from 64 homozygous/compound-heterozygous patients. · source_derived_draft · unverified_draft

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

availability_state

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

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human cancer-cell genetic depletion experiments.

limitations

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

nutrient_topic

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

plain_language

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

primary_references

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

trigger_kind

machinery_impairment Imported condition classification; unverified.

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

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

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

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human doxycycline-regulated MAT2A cells; starvation and repletion.

limitations

Cellular SAM addition is not evidence for equivalent oral delivery.

nutrient_topic

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

plain_language

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

primary_references

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

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 252–258

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human doxycycline-regulated MAT2A cells; starvation and repletion. · source_derived_draft · unverified_draft

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

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human MAT2A reporter/cell and RNA-biochemistry experiments.

limitations

Increased transcript processing does not replace the missing methionine substrate.

nutrient_topic

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

plain_language

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

primary_references

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

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 260–266

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human MAT2A reporter/cell and RNA-biochemistry experiments. · source_derived_draft · unverified_draft

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

evidence_access

Primary abstract

experimental_model

Human RNA methylation/biochemical study.

limitations

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

nutrient_topic

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

plain_language

The same enzyme also modifies RNA used in splicing.

primary_references

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

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

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

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

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human mitochondrial disease study and functional models.

limitations

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

nutrient_topic

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

plain_language

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

primary_references

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

trigger_kind

machinery_impairment Imported condition classification; unverified.

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

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

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

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

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

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

evidence_access

Primary abstract

experimental_model

Human cancer-cell and purified-enzyme study.

limitations

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

nutrient_topic

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

plain_language

A recycling product can inhibit another methylation enzyme.

primary_references

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

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

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

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

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

evidence_access

Primary abstract

experimental_model

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

limitations

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

nutrient_topic

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

plain_language

A neighboring cell can change supply without a dietary deficiency.

primary_references

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

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

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

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

evidence_span

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experimental_model

Two-week feeding and isolated hepatocyte experiments

exposure

Guanidinoacetate or creatine feeding; guanidinoacetate plus methionine in hepatocytes

limitations

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

nutrient_topic

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

organism

Rats

plain_language

The precursor and finished creatine were metabolically different in liver cells.

primary_references

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

tissue_or_cell_type

Plasma and liver cells

Creatine: synthesis, transport, phosphocreatine energetics and nutrient interactions (2026-09-17) · lines 711–722

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

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

cross_nutrient

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

evidence_location

Abstract

experimental_model

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

exposure

Purified-enzyme assay

limitations

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

nutrient_topic

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

organism

Homo sapiens

plain_language

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

primary_references

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

tissue_or_cell_type

Purified recombinant enzyme; no intact tissue

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

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

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

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_span

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experimental_model

Nine factorial dietary experiments in rats

exposure

Six to ten weeks; boron supplement 0 or 3 µg/g; magnesium 100/200 versus 400 µg/g; methionine and arginine contexts varied

limitations

Dependence on severe magnesium restriction and amino-acid background is central. Rat growth/bone findings do not establish an essential human role, a methylation mechanism or a human rescue regimen.

nutrient_topic

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

organism

Sprague-Dawley rats and one spontaneously hypertensive rat experiment

plain_language

The effect of low boron depended strongly on the rest of the diet.

primary_references

[boron-p2484371] Magnesium and methionine deprivation affect the response of rats to boron deprivation. (1988). https://pubmed.ncbi.nlm.nih.gov/2484371/ DOI: 10.1007/bf02795449

tissue_or_cell_type

Whole-animal growth and bone mineral endpoints

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Boron: chemistry, nutrient interactions, low-intake studies and mechanistic uncertainties (2026-09-17) · lines 794–805

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Nine factorial dietary experiments in rats · source_derived_draft · unverified_draft

### boron-rat-mg-amino-acid-context Boron-deprived rats with marginal methionine had lower bone magnesium; interactions with magnesium deprivation were strongest under severe restriction and abundant arginine. Condition category: nutrient_deficiency nutrient_topic: Boron research collection; topical membership is not evidence of a direct dietary effect. plain_language: The effect of low boron depended strongly on the rest of the diet. organism: Sprague-Dawley rats and one spontaneously hypertensive rat experiment tissue_or_cell_type: Whole-animal growth and bone mineral endpoints experimental_model: Nine factorial dietary experiments in rats limitations: Dependence on severe magnesium restriction and amino-acid background is central. Rat growth/bone findings do not establish an essential human role, a methylation mechanism or a human rescue regimen. exposure: Six to ten weeks; boron supplement 0 or 3 µg/g; magnesium 100/200 versus 400 µg/g; methionine and arginine contexts varied evidence_span: {"source_cache": "artifacts/boron-research/2484371.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "324fa75871a385d9890c32c6d4ddd62af6fff561174e439afb94f3bd4662ed13", "start_char": 0, "end_char": 2179, "text_sha256": "324fa75871a385d9890c32c6d4ddd62af6fff561174e439afb94f3bd4662ed13"} [boron-p2484371] Magnesium and methionine deprivation affect the response of rats to boron deprivation. (1988). https://pubmed.ncbi.nlm.nih.gov/2484371/ DOI: 10.1007/bf02795449

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Fgf21-null versus control mice on no-methionine/no-cysteine diets; separate from the Cse-null cysteine-only experiment.

limitations

Do not silently replace the combined restriction with cysteine-only restriction. Correction record: Author correction published 12 December 2025 (2026 issue), PMID 41388205, DOI 10.1038/s41586-025-09780-8: two incorrect day-3 muscle histology panels in Extended Data Fig. 2f,g duplicated day-7 panels and were replaced. The authors state that figure and paper conclusions were unaffected. This is a figure correction, not independent validation. https://www.nature.com/articles/s41586-025-09780-8

nutrient_topic

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

plain_language

A stress hormone contributed under combined sulfur-amino-acid withdrawal.

primary_references

Unravelling cysteine-deficiency-associated rapid weight loss. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40399674/ · DOI 10.1038/s41586-025-08996-y

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Cysteine: sulfur allocation, redox supply 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 · Fgf21-null versus control mice on no-methionine/no-cysteine diets; separate from the Cse-null cysteine-only experiment. · source_derived_draft · unverified_draft

## l-cysteine-fgf21-combined-restriction A stress hormone contributed under combined sulfur-amino-acid withdrawal. Fgf21 knockout attenuated weight loss in mice fed a diet lacking both methionine and cysteine. Model: Fgf21-null versus control mice on no-methionine/no-cysteine diets; separate from the Cse-null cysteine-only experiment. Limitations: Do not silently replace the combined restriction with cysteine-only restriction. Correction record: Author correction published 12 December 2025 (2026 issue), PMID 41388205, DOI 10.1038/s41586-025-09780-8: two incorrect day-3 muscle histology panels in Extended Data Fig. 2f,g duplicated day-7 panels and were replaced. The authors state that figure and paper conclusions were unaffected. This is a figure correction, not independent validation. https://www.nature.com/articles/s41586-025-09780-8 Evidence access: Primary full text Unravelling cysteine-deficiency-associated rapid weight loss. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40399674/ · DOI 10.1038/s41586-025-08996-y

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

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human HEK293 metabolic tracing and enzyme perturbation.

limitations

Compensation requires intact transsulfuration and does not prove that B6 supplementation rescues every transport defect.

nutrient_topic

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

plain_language

An internal synthesis route compensated when imported cystine was harder to use.

primary_references

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

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Cysteine: sulfur allocation, redox supply and cross-nutrient mechanisms (2026-09-19) · lines 76–82

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human HEK293 metabolic tracing and enzyme perturbation. · source_derived_draft · unverified_draft

## l-cysteine-trp14-compensation An internal synthesis route compensated when imported cystine was harder to use. TXNDC17 knockout shifted human-cell cysteine supply toward transsulfuration, as assessed using labeled methionine and downstream sulfur metabolites. Model: Human HEK293 metabolic tracing and enzyme perturbation. Limitations: Compensation requires intact transsulfuration and does not prove that B6 supplementation rescues every transport defect. Evidence access: Primary full text TRP14 is the rate-limiting enzyme for intracellular cystine reduction and regulates proteome cysteinylation. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38811853/ · DOI 10.1038/s44318-024-00117-1

cross_nutrient

true

evidence_span

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experimental_model

Immunoblotting of histone methylation in engineered cells

exposure

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

limitations

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

nutrient_topic

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

organism

Human

plain_language

NNMT changed several histone methylation marks in this culture model.

primary_references

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

tissue_or_cell_type

Human 769P renal carcinoma cells

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

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

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

cross_nutrient

true

evidence_span

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experimental_model

Targeted LC-MS metabolomics

exposure

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

limitations

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

nutrient_topic

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

organism

Human

plain_language

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

primary_references

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

tissue_or_cell_type

Human 769P renal carcinoma cells

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

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

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

cross_nutrient

true

evidence_span

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experimental_model

Targeted LC-MS metabolomics

exposure

100 micromolar methionine culture medium; NNMT overexpression

limitations

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

nutrient_topic

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

organism

Human

plain_language

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

primary_references

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

tissue_or_cell_type

Human cancer-cell overexpression models

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

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

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

acting_entity

s-allylcysteine

availability_state

nutrient_deficiency Imported condition classification; unverified.

dose

SAC 1 g/L drinking water

duration

Seven weeks

evidence_access

Primary abstract

experimental_comparison

SAC or S-ethylcysteine separately with deficient diet versus diet controls

experimental_model

Methionine/choline-deficient diet; liver and serum measurements

interpretation_status

Source-derived research curation; not independent primary verification

limitations

Does not establish replacement of methionine or choline, or direct donation of cysteine to GSH.

nutrient_topic

S-allylcysteine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · S-allyl-L-cysteine / SAC

organism

Mus musculus

plain_language

A nutrient-deficiency model connects SAC to glutathione status.

primary_references

[18786595] Alleviative effects of s-allyl cysteine and s-ethyl cysteine on MCD diet-induced hepatotoxicity in mice. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18786595/ · DOI 10.1016/j.fct.2008.08.010

route

Oral drinking water

tissue_or_cell_type

Methionine/choline-deficient diet; liver and serum measurements

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

S-allylcysteine: sulfur signaling, redox responses and cross-nutrient mechanisms (2026-09-20) · lines 365–372

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Methionine/choline-deficient diet; liver and serum measurements · source_derived_draft · unverified_draft

## s-allylcysteine-mcd-glutathione A nutrient-deficiency model connects SAC to glutathione status. SAC in drinking water increased serum and hepatic GSH during methionine/choline-deficient feeding. Model: Methionine/choline-deficient diet; liver and serum measurements Limitations: Does not establish replacement of methionine or choline, or direct donation of cysteine to GSH. Evidence access: Primary abstract [18786595] Alleviative effects of s-allyl cysteine and s-ethyl cysteine on MCD diet-induced hepatotoxicity in mice. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18786595/ · DOI 10.1016/j.fct.2008.08.010 Structured context: {"organism": "Mus musculus", "tissue_or_cell_type": "Methionine/choline-deficient diet; liver and serum measurements", "dose": "SAC 1 g/L drinking water", "duration": "Seven weeks", "route": "Oral drinking water", "experimental_comparison": "SAC or S-ethylcysteine separately with deficient diet versus diet controls", "acting_entity": "s-allylcysteine", "interpretation_status": "Source-derived research curation; not independent primary verification"}

acting_entity

s-allylcysteine

availability_state

nutrient_deficiency Imported condition classification; unverified.

dose

SAC 1 g/L drinking water

duration

Seven weeks

evidence_access

Primary abstract

experimental_comparison

SAC or S-ethylcysteine separately with deficient diet versus diet controls

experimental_model

Methionine/choline-deficient diet; liver and serum measurements

interpretation_status

Source-derived research curation; not independent primary verification

limitations

Model-specific enzyme activities; not evidence of direct G6PDH binding or a universal NADPH effect.

nutrient_topic

S-allylcysteine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · S-allyl-L-cysteine / SAC

organism

Mus musculus

plain_language

The response involved lipid metabolism as well as redox markers.

primary_references

[18786595] Alleviative effects of s-allyl cysteine and s-ethyl cysteine on MCD diet-induced hepatotoxicity in mice. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18786595/ · DOI 10.1016/j.fct.2008.08.010

route

Oral drinking water

tissue_or_cell_type

Methionine/choline-deficient diet; liver and serum measurements

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

S-allylcysteine: sulfur signaling, redox responses and cross-nutrient mechanisms (2026-09-20) · lines 374–381

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Methionine/choline-deficient diet; liver and serum measurements · source_derived_draft · unverified_draft

## s-allylcysteine-mcd-lipogenesis The response involved lipid metabolism as well as redox markers. SAC reduced hepatic G6PDH and FAS activities and triglyceride accumulation during the deficient diet. Model: Methionine/choline-deficient diet; liver and serum measurements Limitations: Model-specific enzyme activities; not evidence of direct G6PDH binding or a universal NADPH effect. Evidence access: Primary abstract [18786595] Alleviative effects of s-allyl cysteine and s-ethyl cysteine on MCD diet-induced hepatotoxicity in mice. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18786595/ · DOI 10.1016/j.fct.2008.08.010 Structured context: {"organism": "Mus musculus", "tissue_or_cell_type": "Methionine/choline-deficient diet; liver and serum measurements", "dose": "SAC 1 g/L drinking water", "duration": "Seven weeks", "route": "Oral drinking water", "experimental_comparison": "SAC or S-ethylcysteine separately with deficient diet versus diet controls", "acting_entity": "s-allylcysteine", "interpretation_status": "Source-derived research curation; not independent primary verification"}

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/molybdenum-research/6795919.publisher-abstract.txt", "locator": "Exact primary publisher abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d2838a46a598539818059c1a1f8295e283334afced15326a6b5ba1a6104cbfd7", "start_char": 0, "end_char": 1820, "text_sha256": "d2838a46a598539818059c1a1f8295e283334afced15326a6b5ba1a6104cbfd7"}

experimental_model

Single case during prolonged total parenteral nutrition

exposure

Prolonged parenteral nutrition followed by ammonium molybdate

limitations

Rare single case. The paper reports 300 micrograms/day ammonium molybdate, not 300 micrograms elemental molybdenum. Historical observation, not a general regimen.

nutrient_topic

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

organism

Homo sapiens

plain_language

The sulfur-handling pathway stalled when molybdenum supply was inadequate.

primary_references

[mo-p6795919] Amino acid intolerance during prolonged total parenteral nutrition reversed by molybdate therapy. (1981). https://pubmed.ncbi.nlm.nih.gov/6795919/ DOI: 10.1093/ajcn/34.11.2551

tissue_or_cell_type

Systemic symptoms; plasma and urine

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Molybdenum: cofactor assembly, sulfur metabolism and nutrient interactions (2026-09-17) · lines 1119–1130

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Single case during prolonged total parenteral nutrition · source_derived_draft · unverified_draft

### mo-tpn-sulfur The prolonged-TPN case developed amino-acid intolerance with high plasma methionine, high urinary sulfite/thiosulfate and low urinary sulfate. Condition category: nutrient_deficiency nutrient_topic: Molybdenum research collection; topical membership is not evidence of a direct dietary effect. plain_language: The sulfur-handling pathway stalled when molybdenum supply was inadequate. organism: Homo sapiens tissue_or_cell_type: Systemic symptoms; plasma and urine experimental_model: Single case during prolonged total parenteral nutrition limitations: Rare single case. The paper reports 300 micrograms/day ammonium molybdate, not 300 micrograms elemental molybdenum. Historical observation, not a general regimen. exposure: Prolonged parenteral nutrition followed by ammonium molybdate evidence_span: {"source_cache": "artifacts/molybdenum-research/6795919.publisher-abstract.txt", "locator": "Exact primary publisher abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d2838a46a598539818059c1a1f8295e283334afced15326a6b5ba1a6104cbfd7", "start_char": 0, "end_char": 1820, "text_sha256": "d2838a46a598539818059c1a1f8295e283334afced15326a6b5ba1a6104cbfd7"} [mo-p6795919] Amino acid intolerance during prolonged total parenteral nutrition reversed by molybdate therapy. (1981). https://pubmed.ncbi.nlm.nih.gov/6795919/ DOI: 10.1093/ajcn/34.11.2551

evidence_span

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

experimental_model

Human MAT2A kinetics, isotope exchange and inhibitor-bound crystallography

exposure

ATP/methionine reactions and PNPNP ligand complexes

limitations

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

nutrient_topic

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

organism

Human recombinant enzyme

plain_language

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

primary_references

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

tissue_or_cell_type

Purified MAT2A active site

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

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

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