Tetrahydrofolate

evidence_span

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experimental_model

Rat DMGDH crystallography and enzyme characterization

exposure

Dimethylglycine turnover and THF-bound structures

limitations

Pathway chemistry interpreted with rat enzyme structures; not proof that dietary folate rescue restores every human choline-dependent function.

nutrient_topic

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

organism

Rat recombinant enzyme

plain_language

Choline-derived methyl metabolism feeds the folate pool.

primary_references

[choline-p24858690] Folate in demethylation: the crystal structure of the rat dimethylglycine dehydrogenase complexed with tetrahydrofolate. (2014). https://pubmed.ncbi.nlm.nih.gov/24858690/ DOI: 10.1016/j.bbrc.2014.05.064

tissue_or_cell_type

Mitochondrial-enzyme preparation

Choline: metabolism, signaling and nutrient connections (2026-09-17) · lines 685–696

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

### choline-dmgdh-one-carbon In the THF-coupled DMGDH pathway, a removed one-carbon unit is captured as 5,10-methylenetetrahydrofolate rather than released as free formaldehyde. Condition category: normal nutrient_topic: Choline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Choline-derived methyl metabolism feeds the folate pool. organism: Rat recombinant enzyme tissue_or_cell_type: Mitochondrial-enzyme preparation experimental_model: Rat DMGDH crystallography and enzyme characterization limitations: Pathway chemistry interpreted with rat enzyme structures; not proof that dietary folate rescue restores every human choline-dependent function. exposure: Dimethylglycine turnover and THF-bound structures evidence_span: {"source_cache": "artifacts/choline-research/24858690.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e00bbb8f1c2c805e9d7261c286bace5758abd277bc95b3e0a830bd9cdb82a34f", "start_char": 0, "end_char": 1506, "text_sha256": "e00bbb8f1c2c805e9d7261c286bace5758abd277bc95b3e0a830bd9cdb82a34f"} [choline-p24858690] Folate in demethylation: the crystal structure of the rat dimethylglycine dehydrogenase complexed with tetrahydrofolate. (2014). https://pubmed.ncbi.nlm.nih.gov/24858690/ DOI: 10.1016/j.bbrc.2014.05.064

evidence_span

{"source_cache": "artifacts/choline-research/24858690.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e00bbb8f1c2c805e9d7261c286bace5758abd277bc95b3e0a830bd9cdb82a34f", "start_char": 0, "end_char": 1506, "text_sha256": "e00bbb8f1c2c805e9d7261c286bace5758abd277bc95b3e0a830bd9cdb82a34f"}

experimental_model

Rat DMGDH crystallography and enzyme characterization

exposure

Dimethylglycine turnover and THF-bound structures

limitations

Species and assay context retained. The proposed intramolecular transfer route is not represented as a directly observed moving intermediate.

nutrient_topic

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

organism

Rat recombinant enzyme

plain_language

Folate and a riboflavin-derived cofactor occupy distinct sites in the same enzyme.

primary_references

[choline-p24858690] Folate in demethylation: the crystal structure of the rat dimethylglycine dehydrogenase complexed with tetrahydrofolate. (2014). https://pubmed.ncbi.nlm.nih.gov/24858690/ DOI: 10.1016/j.bbrc.2014.05.064

tissue_or_cell_type

Mitochondrial-enzyme preparation

Choline: metabolism, signaling and nutrient connections (2026-09-17) · lines 672–683

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

### choline-dmgdh-thf Rat DMGDH structures located THF in a domain separated from the FAD-containing active center and connected by an internal channel. Condition category: normal nutrient_topic: Choline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Folate and a riboflavin-derived cofactor occupy distinct sites in the same enzyme. organism: Rat recombinant enzyme tissue_or_cell_type: Mitochondrial-enzyme preparation experimental_model: Rat DMGDH crystallography and enzyme characterization limitations: Species and assay context retained. The proposed intramolecular transfer route is not represented as a directly observed moving intermediate. exposure: Dimethylglycine turnover and THF-bound structures evidence_span: {"source_cache": "artifacts/choline-research/24858690.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e00bbb8f1c2c805e9d7261c286bace5758abd277bc95b3e0a830bd9cdb82a34f", "start_char": 0, "end_char": 1506, "text_sha256": "e00bbb8f1c2c805e9d7261c286bace5758abd277bc95b3e0a830bd9cdb82a34f"} [choline-p24858690] Folate in demethylation: the crystal structure of the rat dimethylglycine dehydrogenase complexed with tetrahydrofolate. (2014). https://pubmed.ncbi.nlm.nih.gov/24858690/ DOI: 10.1016/j.bbrc.2014.05.064

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human cancer cells with FTCD depletion, metabolomics and U-13C-serine tracing.

limitations

Measured under methotrexate; do not generalize to normal folate demand or all tissues. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2

nutrient_topic

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

plain_language

Blocking histidine breakdown spared folate for nucleotide production in this drug-stressed setting.

primary_references

Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 154–160

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human cancer cells with FTCD depletion, metabolomics and U-13C-serine tracing. · source_derived_draft · unverified_draft

## histidine-ftcd-thf-sparing Blocking histidine breakdown spared folate for nucleotide production in this drug-stressed setting. Under methotrexate, FTCD depletion preserved THF and increased serine-derived labeling of IMP and TTP relative to controls. Model: Human cancer cells with FTCD depletion, metabolomics and U-13C-serine tracing. Limitations: Measured under methotrexate; do not generalize to normal folate demand or all tissues. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2 Evidence access: Primary full text Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7

experimental_model

Purified human cytosolic FPGS expressed in bacteria

exposure

Comparative substrate enzyme assays

limitations

Purified substrate preference does not quantify intact-cell flux.

nutrient_topic

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

organism

Homo sapiens protein expressed in Escherichia coli

plain_language

FPGS adds tails that help retain usable folate.

primary_references

[chen1996] Purification and properties of human cytosolic folylpoly-gamma-glutamate synthetase and organization, localization, and differential splicing of its gene (1996). https://pubmed.ncbi.nlm.nih.gov/8662720/ DOI: 10.1074/jbc.271.22.13077

tissue_or_cell_type

Purified enzyme

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 255–265

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

### folate-fpgs-thf-substrate Purified human cytosolic FPGS used tetrahydrofolate as an effective substrate for polyglutamate synthesis. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: FPGS adds tails that help retain usable folate. organism: Homo sapiens protein expressed in Escherichia coli tissue_or_cell_type: Purified enzyme experimental_model: Purified human cytosolic FPGS expressed in bacteria limitations: Purified substrate preference does not quantify intact-cell flux. exposure: Comparative substrate enzyme assays [chen1996] Purification and properties of human cytosolic folylpoly-gamma-glutamate synthetase and organization, localization, and differential splicing of its gene (1996). https://pubmed.ncbi.nlm.nih.gov/8662720/ DOI: 10.1074/jbc.271.22.13077

cross_nutrient

B6-dependent GLDC precedes lipoyl-carrier transfer and folate-dependent AMT chemistry.

experimental_model

Purified human AMT structures and mutational analyses

limitations

AMT is the directly examined human enzyme; this study did not test dietary B6 depletion or the entire pathway flux.

nutrient_topic

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

organism

Homo sapiens

plain_language

Glycine cleavage connects its B6-dependent first step to a separate folate-dependent step.

primary_references

[b6-amt-2005] Crystal structure of human T-protein of glycine cleavage system at 2.0 A resolution and its implication for understanding non-ketotic hyperglycinemia. (2005). https://pubmed.ncbi.nlm.nih.gov/16051266/ DOI: 10.1016/j.jmb.2005.06.056

tissue_or_cell_type

Purified recombinant protein; no intact tissue

Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 682–692

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

### b6-met-amt-onecarbon Human AMT transfers the aminomethyl-lipoyl intermediate's carbon to tetrahydrofolate, yielding 5,10-methylene-THF, ammonia and reduced H-protein. Condition category: normal nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Glycine cleavage connects its B6-dependent first step to a separate folate-dependent step. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Purified human AMT structures and mutational analyses limitations: AMT is the directly examined human enzyme; this study did not test dietary B6 depletion or the entire pathway flux. cross_nutrient: B6-dependent GLDC precedes lipoyl-carrier transfer and folate-dependent AMT chemistry. [b6-amt-2005] Crystal structure of human T-protein of glycine cleavage system at 2.0 A resolution and its implication for understanding non-ketotic hyperglycinemia. (2005). https://pubmed.ncbi.nlm.nih.gov/16051266/ DOI: 10.1016/j.jmb.2005.06.056

cross_nutrient

PLP (B6) and THF (folate) cooperate in one reaction.

experimental_model

Purified human SHMT1 and SHMT2; structures and solution oligomerization

limitations

Reaction is reversible; assembly assays do not establish flux in every cell.

nutrient_topic

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

organism

Homo sapiens

plain_language

The enzyme connects B6-dependent amino-acid chemistry to folate chemistry.

primary_references

[b6-shmt-2015] How pyridoxal 5'-phosphate differentially regulates human cytosolic and mitochondrial serine hydroxymethyltransferase oligomeric state (2015). https://febs.onlinelibrary.wiley.com/doi/10.1111/febs.13211 DOI: 10.1111/febs.13211

tissue_or_cell_type

Purified recombinant protein; no intact tissue

Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 602–612

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human SHMT1 and SHMT2; structures and solution oligomerization · source_derived_draft · unverified_draft

### b6-met-shmt1-onecarbon Human SHMT1 uses PLP to couple serine-to-glycine conversion with transfer of a one-carbon unit to tetrahydrofolate. Condition category: normal nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The enzyme connects B6-dependent amino-acid chemistry to folate chemistry. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Purified human SHMT1 and SHMT2; structures and solution oligomerization limitations: Reaction is reversible; assembly assays do not establish flux in every cell. cross_nutrient: PLP (B6) and THF (folate) cooperate in one reaction. [b6-shmt-2015] How pyridoxal 5'-phosphate differentially regulates human cytosolic and mitochondrial serine hydroxymethyltransferase oligomeric state (2015). https://febs.onlinelibrary.wiley.com/doi/10.1111/febs.13211 DOI: 10.1111/febs.13211

cross_nutrient

PLP (B6) and THF (folate) cooperate in one reaction.

experimental_model

Purified human SHMT1 and SHMT2; structures and solution oligomerization

limitations

Reaction is reversible; assembly assays do not establish flux in every cell.

nutrient_topic

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

organism

Homo sapiens

plain_language

The enzyme connects B6-dependent amino-acid chemistry to folate chemistry.

primary_references

[b6-shmt-2015] How pyridoxal 5'-phosphate differentially regulates human cytosolic and mitochondrial serine hydroxymethyltransferase oligomeric state (2015). https://febs.onlinelibrary.wiley.com/doi/10.1111/febs.13211 DOI: 10.1111/febs.13211

tissue_or_cell_type

Purified recombinant protein; no intact tissue

Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 614–624

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human SHMT1 and SHMT2; structures and solution oligomerization · source_derived_draft · unverified_draft

### b6-met-shmt2-onecarbon Human SHMT2 uses PLP to couple serine-to-glycine conversion with transfer of a one-carbon unit to tetrahydrofolate. Condition category: normal nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The enzyme connects B6-dependent amino-acid chemistry to folate chemistry. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Purified human SHMT1 and SHMT2; structures and solution oligomerization limitations: Reaction is reversible; assembly assays do not establish flux in every cell. cross_nutrient: PLP (B6) and THF (folate) cooperate in one reaction. [b6-shmt-2015] How pyridoxal 5'-phosphate differentially regulates human cytosolic and mitochondrial serine hydroxymethyltransferase oligomeric state (2015). https://febs.onlinelibrary.wiley.com/doi/10.1111/febs.13211 DOI: 10.1111/febs.13211

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Mouse gene-trap model; enzyme activity and tissue metabolites.

limitations

Inherited processing failure is distinct from insufficient dietary glycine.

nutrient_topic

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

plain_language

Excess glycine can coexist with a shortage of products made from it.

primary_references

Glycine decarboxylase deficiency causes neural tube defects and features of non-ketotic hyperglycinemia in mice. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25736695/ · DOI 10.1038/ncomms7388

trigger_kind

machinery_impairment Imported condition classification; unverified.

Glycine: supply, one-carbon allocation, receptors and cross-nutrient mechanisms (2026-09-19) · lines 130–136

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse gene-trap model; enzyme activity and tissue metabolites. · source_derived_draft · unverified_draft

## glycine-gldc-one-carbon-loss Excess glycine can coexist with a shortage of products made from it. Reducing Gldc expression in mice suppressed glycine cleavage and depleted one-carbon-bearing folates while glycine accumulated. Model: Mouse gene-trap model; enzyme activity and tissue metabolites. Limitations: Inherited processing failure is distinct from insufficient dietary glycine. Evidence access: Primary full text Glycine decarboxylase deficiency causes neural tube defects and features of non-ketotic hyperglycinemia in mice. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25736695/ · DOI 10.1038/ncomms7388

evidence_access

Primary abstract

experimental_model

Cancer cultures deprived of serine, glycine exposure and metabolic analysis.

limitations

No exposure threshold for humans is derived; one-carbon depletion is the pathway interpretation supported by the rescue experiment.

nutrient_topic

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

plain_language

Using glycine to rebuild missing serine can draw from the folate carbon pool.

primary_references

Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24813884/ · DOI 10.1016/j.celrep.2014.04.045

Glycine: supply, one-carbon allocation, receptors and cross-nutrient mechanisms (2026-09-19) · lines 178–184

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Cancer cultures deprived of serine, glycine exposure and metabolic analysis. · source_derived_draft · unverified_draft

## glycine-glycine-reverse-flux Using glycine to rebuild missing serine can draw from the folate carbon pool. With serine absent, higher glycine concentrations inhibited growth and glycine was converted to serine, a reaction consuming one-carbon units. Model: Cancer cultures deprived of serine, glycine exposure and metabolic analysis. Limitations: No exposure threshold for humans is derived; one-carbon depletion is the pathway interpretation supported by the rescue experiment. Evidence access: Primary abstract Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24813884/ · DOI 10.1016/j.celrep.2014.04.045

evidence_access

Primary abstract

experimental_model

Primary cancer-cell nutrient-restriction and metabolic tracing study.

limitations

Abstract-level extraction; model-specific result does not negate glycine-dependent growth in other culture conditions.

nutrient_topic

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

plain_language

The ability to interconvert two amino acids does not make their supplies interchangeable.

primary_references

Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24813884/ · DOI 10.1016/j.celrep.2014.04.045

Glycine: supply, one-carbon allocation, receptors and cross-nutrient mechanisms (2026-09-19) · lines 170–176

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

## glycine-serine-required-context The ability to interconvert two amino acids does not make their supplies interchangeable. In the tested cancer cultures, exogenous glycine did not replace serine for nucleotide synthesis and proliferation; glycine restriction or glycine-cleavage depletion did not impede growth. Model: Primary cancer-cell nutrient-restriction and metabolic tracing study. Limitations: Abstract-level extraction; model-specific result does not negate glycine-dependent growth in other culture conditions. Evidence access: Primary abstract Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24813884/ · DOI 10.1016/j.celrep.2014.04.045

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Retrospective two-center newborn-screen cohort.

limitations

Ascertainment differs from early severe case series; follow-up is limited and this does not exclude later or rare severe effects. Correction record: The 2019 publisher erratum corrects patient 4 genotypes to c.1366dupG (p.E456Gfs*56) and c.236A>C (p.Q79P). The imported cohort-outcome claim does not use the erroneous genotype labels. https://onlinelibrary.wiley.com/doi/10.1002/jimd.12145

nutrient_topic

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

plain_language

A biochemical processing defect did not uniformly produce severe disease.

primary_references

Characteristics and outcomes of patients with formiminoglutamic aciduria detected through newborn screening. · 2019 · https://pubmed.ncbi.nlm.nih.gov/30740726/ · DOI 10.1002/jimd.12035

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 194–200

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Retrospective two-center newborn-screen cohort. · source_derived_draft · unverified_draft

## histidine-ftcd-screening-spectrum A biochemical processing defect did not uniformly produce severe disease. Among 18 newborn-screen-detected FTCD-deficient patients, most were asymptomatic at mean 56-month follow-up; 3/18 had educationally significant developmental delay and 4/16 mild self-limited anemia. Model: Retrospective two-center newborn-screen cohort. Limitations: Ascertainment differs from early severe case series; follow-up is limited and this does not exclude later or rare severe effects. Correction record: The 2019 publisher erratum corrects patient 4 genotypes to c.1366dupG (p.E456Gfs*56) and c.236A>C (p.Q79P). The imported cohort-outcome claim does not use the erroneous genotype labels. https://onlinelibrary.wiley.com/doi/10.1002/jimd.12145 Evidence access: Primary abstract Characteristics and outcomes of patients with formiminoglutamic aciduria detected through newborn screening. · 2019 · https://pubmed.ncbi.nlm.nih.gov/30740726/ · DOI 10.1002/jimd.12035

evidence_access

Primary full text

experimental_model

Established reaction in the pathway map of a primary human cancer-cell study; genetic perturbation and metabolomics investigate pathway flux rather than purified kinetics of every individual enzyme.

limitations

The existing rat FTCD biochemical claim remains a separate species-specific record. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2

nutrient_topic

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

plain_language

Folate accepts a group from a histidine-derived intermediate.

primary_references

Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7

L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 130–136

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Established reaction in the pathway map of a primary human cancer-cell study; genetic perturbation and metabolomics investigate pathway flux rather than purified kinetics of every individual enzyme. · source_derived_draft · unverified_draft

## histidine-ftcd-transfer Folate accepts a group from a histidine-derived intermediate. The formiminotransferase domain of FTCD transfers the formimino group from FIGLU to THF, producing 5-formimino-THF and glutamate. Model: Established reaction in the pathway map of a primary human cancer-cell study; genetic perturbation and metabolomics investigate pathway flux rather than purified kinetics of every individual enzyme. Limitations: The existing rat FTCD biochemical claim remains a separate species-specific record. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2 Evidence access: Primary full text Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7

evidence_access

Primary full text

experimental_model

NOD-SCID mice with human leukemia xenografts; daily injections for five days, histidine 400 microliters at 46 mg/mL and methotrexate 50 mg/kg.

limitations

Main methods specify injections despite dietary terminology in the abstract. No oral human combination trial or treatment recommendation; longer mouse experiments do not establish human safety. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2

nutrient_topic

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

plain_language

Changing substrate supply strengthened a drug effect in this animal model.

primary_references

Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7

L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 178–184

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · NOD-SCID mice with human leukemia xenografts; daily injections for five days, histidine 400 microliters at 46 mg/mL and methotrexate 50 mg/kg. · source_derived_draft · unverified_draft

## histidine-histidine-mtx-xenograft Changing substrate supply strengthened a drug effect in this animal model. Combined histidine and methotrexate reduced HEL/SEM xenograft size more than either single treatment in the reported main mouse experiment. Model: NOD-SCID mice with human leukemia xenografts; daily injections for five days, histidine 400 microliters at 46 mg/mL and methotrexate 50 mg/kg. Limitations: Main methods specify injections despite dietary terminology in the abstract. No oral human combination trial or treatment recommendation; longer mouse experiments do not establish human safety. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2 Evidence access: Primary full text Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7

cross_nutrient

CoA maturation enables the folate-to-NADPH reaction.

experimental_model

Recombinant enzyme activation assay

exposure

Assay conditions described in the linked primary study.

limitations

Figure 5 used stable dideazafolate analogue rather than physiological folate.

nutrient_topic

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

organism

Homo sapiens

plain_language

The installed arm enables oxidation of folate-bound carbon.

primary_references

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

tissue_or_cell_type

Cell-free

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

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

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

experimental_model

Recombinant enzyme kinetics

exposure

Assay conditions described in the linked primary study.

limitations

Reported folate kinetics used a 6R/6S mixture.

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

A second folate donation helps finish the purine ring.

primary_references

[rayl-1996] The human purH gene product, 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase. Cloning, sequencing, expression, purification, kinetic analysis, and domain mapping (1996). https://pubmed.ncbi.nlm.nih.gov/8567683/ DOI: 10.1074/jbc.271.4.2225

tissue_or_cell_type

Cell-free

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1010–1020

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

### atic-aicar-formylation Purified human ATIC uses 10-formyl-THF for its AICAR formyltransferase reaction, yielding FAICAR. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: A second folate donation helps finish the purine ring. organism: Homo sapiens tissue_or_cell_type: Cell-free experimental_model: Recombinant enzyme kinetics limitations: Reported folate kinetics used a 6R/6S mixture. exposure: Assay conditions described in the linked primary study. [rayl-1996] The human purH gene product, 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase. Cloning, sequencing, expression, purification, kinetic analysis, and domain mapping (1996). https://pubmed.ncbi.nlm.nih.gov/8567683/ DOI: 10.1074/jbc.271.4.2225

cross_nutrient

Handoff to existing PLP-dependent glycine decarboxylase and lipoyl-GCSH/AMT folate transfer evidence; not new deficiency evidence.

experimental_model

Radiolabeled mitochondrial flux assay

exposure

Assay conditions described in the linked primary study.

limitations

No B6 or lipoate dietary perturbation tested.

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

Glycine cleavage can feed folate-bound carbon into mitochondrial formate production.

primary_references

[pike-2010] Mitochondrial C1-tetrahydrofolate synthase (MTHFD1L) supports the flow of mitochondrial one-carbon units into the methyl cycle in embryos (2010). https://pubmed.ncbi.nlm.nih.gov/19948730/ DOI: 10.1074/jbc.m109.079855

tissue_or_cell_type

Embryonic mitochondria

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1096–1107

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

### embryonic-glycine-formate Isolated mouse embryonic mitochondria converted labeled glycine carbon into formate. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Glycine cleavage can feed folate-bound carbon into mitochondrial formate production. organism: Mus musculus tissue_or_cell_type: Embryonic mitochondria experimental_model: Radiolabeled mitochondrial flux assay limitations: No B6 or lipoate dietary perturbation tested. exposure: Assay conditions described in the linked primary study. cross_nutrient: Handoff to existing PLP-dependent glycine decarboxylase and lipoyl-GCSH/AMT folate transfer evidence; not new deficiency evidence. [pike-2010] Mitochondrial C1-tetrahydrofolate synthase (MTHFD1L) supports the flow of mitochondrial one-carbon units into the methyl cycle in embryos (2010). https://pubmed.ncbi.nlm.nih.gov/19948730/ DOI: 10.1074/jbc.m109.079855

experimental_model

Fresh human liver extracts from six donors and rat comparison

exposure

DHF substrate; THF quantified by HPLC

limitations

Assay chemistry, not an outcome study.

nutrient_topic

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

organism

Homo sapiens

plain_language

DHFR regenerates reduced folate from DHF.

primary_references

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

tissue_or_cell_type

Liver extracts

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

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

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

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

Methylfolate does not remove the B12-dependent MTR requirement.

evidence_location

Ghergurovich 2021 Fig. 3A; physiological folate experiments Fig. 2 and Extended Data Fig. 2.

experimental_model

Isotope tracing in tumour cells, mouse tissues and xenografts.

exposure

CRISPR MTR deletion; folic acid or 5-methyl-THF medium; physiological folate-mixture experiments

limitations

Nutrient environment matters.

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

Methylfolate still needs MTR for reuse.

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

HCT116 human colorectal cancer cells (folate profiling)

trigger_kind

machinery_impairment Imported condition classification; unverified.

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 517–529

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-ko-trap MTR knockout in tumour cells using physiological extracellular folates caused trapping and limited assimilation into other folate forms. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Methylfolate still needs MTR for reuse. organism: Homo sapiens tissue_or_cell_type: HCT116 human colorectal cancer cells (folate profiling) experimental_model: Isotope tracing in tumour cells, mouse tissues and xenografts. limitations: Nutrient environment matters. cross_nutrient: Methylfolate does not remove the B12-dependent MTR requirement. exposure: CRISPR MTR deletion; folic acid or 5-methyl-THF medium; physiological folate-mixture experiments evidence_location: Ghergurovich 2021 Fig. 3A; physiological folate experiments Fig. 2 and Extended Data Fig. 2. [ghergurovich-2021] Methionine synthase supports tumour tetrahydrofolate pools (2021). https://pubmed.ncbi.nlm.nih.gov/34799699/ DOI: 10.1038/s42255-021-00465-w

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

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

B12 function controls usable folate.

experimental_model

N2O-treated HeLa cells and cblG patient fibroblasts.

limitations

Fig. 2 reports percentages of measured folate species, not absolute concentrations; chemical/culture impairment is not a dietary threshold.

nutrient_topic

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

organism

Homo sapiens

plain_language

The nuclear folate mixture shifted toward methylfolate.

primary_references

[palmer-2017] Folate rescues vitamin B12 depletion-induced inhibition of nuclear thymidylate biosynthesis and genome instability (2017). https://pubmed.ncbi.nlm.nih.gov/28461497/ DOI: 10.1073/pnas.1619582114

tissue_or_cell_type

HeLa nuclear fractions

trigger_kind

machinery_impairment Imported condition classification; unverified.

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 543–553

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · N2O-treated HeLa cells and cblG patient fibroblasts. · source_derived_draft · unverified_draft

### folate-methyl-nuclear-methyl-trap In B12-impaired HeLa nuclei, the fraction of measured nuclear folate present as 5-methyl-THF increased over fourfold, while the THF fraction fell approximately 50%, versus replete 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 nuclear folate mixture shifted toward methylfolate. organism: Homo sapiens tissue_or_cell_type: HeLa nuclear fractions experimental_model: N2O-treated HeLa cells and cblG patient fibroblasts. limitations: Fig. 2 reports percentages of measured folate species, not absolute concentrations; chemical/culture impairment is not a dietary threshold. cross_nutrient: B12 function controls usable folate. [palmer-2017] Folate rescues vitamin B12 depletion-induced inhibition of nuclear thymidylate biosynthesis and genome instability (2017). https://pubmed.ncbi.nlm.nih.gov/28461497/ DOI: 10.1073/pnas.1619582114

experimental_model

X-ray crystallography

exposure

Assay conditions described in the linked primary study.

limitations

Structures used 10-formyl-dideazafolate and hydroxyacetamide ribonucleotide analogues.

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 donates one carbon early in purine-base construction.

primary_references

[dahms-2005] The apo and ternary complex structures of a chemotherapeutic target: human glycinamide ribonucleotide transformylase (2005). https://pubmed.ncbi.nlm.nih.gov/16026156/ DOI: 10.1021/bi050307g

tissue_or_cell_type

Purified domain

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 998–1008

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

### gart-formyl-transfer The human GART transformylase domain binds a folate formyl donor and GAR-site acceptor in a ternary complex supporting GAR formylation to FGAR. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Folate donates one carbon early in purine-base construction. organism: Homo sapiens tissue_or_cell_type: Purified domain experimental_model: X-ray crystallography limitations: Structures used 10-formyl-dideazafolate and hydroxyacetamide ribonucleotide analogues. exposure: Assay conditions described in the linked primary study. [dahms-2005] The apo and ternary complex structures of a chemotherapeutic target: human glycinamide ribonucleotide transformylase (2005). https://pubmed.ncbi.nlm.nih.gov/16026156/ DOI: 10.1021/bi050307g

availability_state

nutrient_deficiency Imported condition classification; unverified.

experimental_model

Dietary depletion and liver fractionation

exposure

Assay conditions described in the linked primary study.

limitations

Nuclear protection is conditional; it does not prove indefinite resistance to deficiency.

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 enzyme redistributed toward the nucleus as folate supply fell.

primary_references

[field-2014] Nuclear enrichment of folate cofactors and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) protect de novo thymidylate biosynthesis during folate deficiency (2014). https://pubmed.ncbi.nlm.nih.gov/25213861/ DOI: 10.1074/jbc.m114.599589

tissue_or_cell_type

Liver

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 961–971

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

### mouse-folate-depletion-mthfd1-enrichment Dietary folate depletion increased nuclear Mthfd1 more than twofold in mouse liver at the expense of cytosolic levels. Condition category: nutrient_deficiency nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The enzyme redistributed toward the nucleus as folate supply fell. organism: Mus musculus tissue_or_cell_type: Liver experimental_model: Dietary depletion and liver fractionation limitations: Nuclear protection is conditional; it does not prove indefinite resistance to deficiency. exposure: Assay conditions described in the linked primary study. [field-2014] Nuclear enrichment of folate cofactors and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) protect de novo thymidylate biosynthesis during folate deficiency (2014). https://pubmed.ncbi.nlm.nih.gov/25213861/ DOI: 10.1074/jbc.m114.599589

availability_state

nutrient_deficiency Imported condition classification; unverified.

experimental_model

Dietary depletion and liver fractionation

exposure

Assay conditions described in the linked primary study.

limitations

Nuclear protection is conditional; it does not prove indefinite resistance to deficiency.

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 nucleus retained folate even when whole-cell stores fell.

primary_references

[field-2014] Nuclear enrichment of folate cofactors and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) protect de novo thymidylate biosynthesis during folate deficiency (2014). https://pubmed.ncbi.nlm.nih.gov/25213861/ DOI: 10.1074/jbc.m114.599589

tissue_or_cell_type

Liver

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1347–1357

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

### mouse-folate-depletion-nuclear-retention Nuclear folate levels resisted depletion despite more than 50% lower total cellular folate in folate-depleted mouse liver. Condition category: nutrient_deficiency nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The nucleus retained folate even when whole-cell stores fell. organism: Mus musculus tissue_or_cell_type: Liver experimental_model: Dietary depletion and liver fractionation limitations: Nuclear protection is conditional; it does not prove indefinite resistance to deficiency. exposure: Assay conditions described in the linked primary study. [field-2014] Nuclear enrichment of folate cofactors and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) protect de novo thymidylate biosynthesis during folate deficiency (2014). https://pubmed.ncbi.nlm.nih.gov/25213861/ DOI: 10.1074/jbc.m114.599589

experimental_model

Genetic and tRNA-formylation experiments

exposure

Assay conditions described in the linked primary study.

limitations

Does not imply that plasma folate directly reports mitochondrial folate.

nutrient_topic

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

organism

Homo sapiens

plain_language

Folate supplies the small chemical tag used to start mitochondrial proteins.

primary_references

[minton-2018] Serine Catabolism by SHMT2 Is Required for Proper Mitochondrial Translation Initiation and Maintenance of Formylmethionyl-tRNAs (2018). https://pubmed.ncbi.nlm.nih.gov/29452640/ DOI: 10.1016/j.molcel.2018.01.024

tissue_or_cell_type

Jurkat cells

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1133–1143

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

### mtfmt-folate-formylation MTFMT uses mitochondrial 10-formyl-THF to generate formylmethionyl-tRNA needed for translation initiation. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Folate supplies the small chemical tag used to start mitochondrial proteins. organism: Homo sapiens tissue_or_cell_type: Jurkat cells experimental_model: Genetic and tRNA-formylation experiments limitations: Does not imply that plasma folate directly reports mitochondrial folate. exposure: Assay conditions described in the linked primary study. [minton-2018] Serine Catabolism by SHMT2 Is Required for Proper Mitochondrial Translation Initiation and Maintenance of Formylmethionyl-tRNAs (2018). https://pubmed.ncbi.nlm.nih.gov/29452640/ DOI: 10.1016/j.molcel.2018.01.024

cross_nutrient

ATP and NADPH support folate-mediated carbon use.

experimental_model

Localization and folate-pathway experiments

exposure

Assay conditions described in the linked primary study.

limitations

Compartmental flux varies with cell cycle.

nutrient_topic

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

organism

Homo sapiens

plain_language

Formate can feed DNA-base production inside the nucleus.

primary_references

[field-2014] Nuclear enrichment of folate cofactors and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) protect de novo thymidylate biosynthesis during folate deficiency (2014). https://pubmed.ncbi.nlm.nih.gov/25213861/ DOI: 10.1074/jbc.m114.599589

tissue_or_cell_type

HeLa and MCF7 cells

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 936–947

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

### mthfd1-formate-nuclear-carbon Nuclear MTHFD1 supplies formate-derived one-carbon units for thymidylate synthesis through its folate-interconversion activities. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Formate can feed DNA-base production inside the nucleus. organism: Homo sapiens tissue_or_cell_type: HeLa and MCF7 cells experimental_model: Localization and folate-pathway experiments limitations: Compartmental flux varies with cell cycle. exposure: Assay conditions described in the linked primary study. cross_nutrient: ATP and NADPH support folate-mediated carbon use. [field-2014] Nuclear enrichment of folate cofactors and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) protect de novo thymidylate biosynthesis during folate deficiency (2014). https://pubmed.ncbi.nlm.nih.gov/25213861/ DOI: 10.1074/jbc.m114.599589

cross_nutrient

Shared QDPR machinery connects biopterin and folate redox maintenance.

experimental_model

Biochemical enzyme experiments

exposure

Assay conditions described in the linked primary study.

limitations

Repair capacity is finite; no human dietary requirement was determined.

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

An enzyme also used in biopterin metabolism helps preserve reduced folate.

primary_references

[zheng-2018] Mitochondrial One-Carbon Pathway Supports Cytosolic Folate Integrity in Cancer Cells (2018). https://pubmed.ncbi.nlm.nih.gov/30500537/ DOI: 10.1016/j.cell.2018.09.041

tissue_or_cell_type

Cell-free and cancer-cell experiments

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1230–1241

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

### qdpr-folate-repair Biochemical experiments identified QDPR activity that repairs oxidatively damaged tetrahydrofolate. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: An enzyme also used in biopterin metabolism helps preserve reduced folate. organism: Homo sapiens tissue_or_cell_type: Cell-free and cancer-cell experiments experimental_model: Biochemical enzyme experiments limitations: Repair capacity is finite; no human dietary requirement was determined. exposure: Assay conditions described in the linked primary study. cross_nutrient: Shared QDPR machinery connects biopterin and folate redox maintenance. [zheng-2018] Mitochondrial One-Carbon Pathway Supports Cytosolic Folate Integrity in Cancer Cells (2018). https://pubmed.ncbi.nlm.nih.gov/30500537/ DOI: 10.1016/j.cell.2018.09.041

cross_nutrient

Histidine degradation supplies a folate-bound carbon group.

evidence_location

Introduction reaction definition; Figure 1 and FT-domain structural analysis.

experimental_model

Recombinant protein structure and functional analysis

exposure

Recombinant rat FTCD; FT-domain structural analysis.

limitations

Rat enzyme; no human histidine-loading response is inferred.

nutrient_topic

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

organism

Rattus norvegicus

plain_language

This step brings histidine-derived carbon into folate chemistry.

primary_references

[mao-2004] Structure of the bifunctional and Golgi-associated formiminotransferase cyclodeaminase octamer (2004). https://pubmed.ncbi.nlm.nih.gov/15272307/ DOI: 10.1038/sj.emboj.7600327

tissue_or_cell_type

Cell-free

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1294–1306

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

### rat-ftcd-formimino-transfer The FT activity of rat FTCD transfers the FIGLU formimino group to THF, yielding 5-formimino-THF and glutamate. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: This step brings histidine-derived carbon into folate chemistry. organism: Rattus norvegicus tissue_or_cell_type: Cell-free experimental_model: Recombinant protein structure and functional analysis limitations: Rat enzyme; no human histidine-loading response is inferred. exposure: Recombinant rat FTCD; FT-domain structural analysis. cross_nutrient: Histidine degradation supplies a folate-bound carbon group. evidence_location: Introduction reaction definition; Figure 1 and FT-domain structural analysis. [mao-2004] Structure of the bifunctional and Golgi-associated formiminotransferase cyclodeaminase octamer (2004). https://pubmed.ncbi.nlm.nih.gov/15272307/ DOI: 10.1038/sj.emboj.7600327