Component

5,10-Methenyltetrahydrofolate

Chemically distinct folate-pathway or nucleotide intermediate; shared across species.

7 recorded relationships. Experimental role, claim status and evidence remain attached to each record.

Read recorded mechanisms Open recursive mind map

How nutrients influence it

Every nutrient with a recorded effect on this component, credited to the nutrient that acted rather than the chapter that recorded it. Open a nutrient to see the findings and the conditions they were measured under.

How nutrients reach it in more than one step

Chains of two or more recorded steps that end here, grouped by the nutrient they start from. Each step is a separate finding, so a chain is a route a mechanism could take, not proof that it does.

Tracing routes…

What it does

Every recorded relationship this component is part of, grouped by its role. Plain wording comes first; the technical statement follows.

Recorded relationships

What acts on it

  1. The cyclodeaminase domain of FTCD converts 5-formimino-THF to 5,10-methenyl-THF.

    Human formimidoyltransferase cyclodeaminase / FTCD → 5,10-Methenyltetrahydrofolate source_derived_draftungraded
    Experimental context and source evidence
    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
    Two catalytic activities are separately searchable; this does not establish folate depletion in a normally nourished person. 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
    A second activity of the same enzyme hands the group into one-carbon metabolism.
    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 138–144

    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-cyclodeamination A second activity of the same enzyme hands the group into one-carbon metabolism. The cyclodeaminase domain of FTCD converts 5-formimino-THF to 5,10-methenyl-THF. 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: Two catalytic activities are separately searchable; this does not establish folate depletion in a normally nourished person. 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
    Complete structured claim and evidence

Where it participates (unsigned role)

  1. Purified human MTHFD2 oxidizes 5,10-methylene-THF using NAD+ to form methenyl-THF and NADH.

    Human MTHFD2 → 5,10-Methylenetetrahydrofolate source_derived_draftungraded
    Experimental context and source evidence
    cross_nutrient
    Nicotinamide cofactors connect folate chemistry to redox metabolism.
    experimental_model
    Purified recombinant enzyme
    exposure
    Assay conditions described in the linked primary study.
    limitations
    Cellular cofactor partition is not quantified.
    nutrient_topic
    Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
    organism
    Homo sapiens
    plain_language
    This mitochondrial enzyme extracts electrons from folate-bound carbon.
    primary_references
    [shin-2017] Human mitochondrial MTHFD2 is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase (2017). https://pubmed.ncbi.nlm.nih.gov/29225823/ DOI: 10.1186/s40170-017-0173-0
    tissue_or_cell_type
    Cell-free

    Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 812–823

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

    ### mthfd2-nad-oxidation Purified human MTHFD2 oxidizes 5,10-methylene-THF using NAD+ to form methenyl-THF and NADH. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: This mitochondrial enzyme extracts electrons from folate-bound carbon. organism: Homo sapiens tissue_or_cell_type: Cell-free experimental_model: Purified recombinant enzyme limitations: Cellular cofactor partition is not quantified. exposure: Assay conditions described in the linked primary study. cross_nutrient: Nicotinamide cofactors connect folate chemistry to redox metabolism. [shin-2017] Human mitochondrial MTHFD2 is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase (2017). https://pubmed.ncbi.nlm.nih.gov/29225823/ DOI: 10.1186/s40170-017-0173-0
    Complete structured claim and evidence

  2. Purified human liver MTHFS converts 5-formyl-THF into 5,10-methenyl-THF.

    Human methenyltetrahydrofolate synthetase / MTHFS → 5-Formyltetrahydrofolate source_derived_draftungraded
    Experimental context and source evidence
    experimental_model
    Purified liver enzyme
    exposure
    Purified human liver enzyme and folate substrates; initial-velocity measurements.
    limitations
    An enzyme assay does not establish clinical benefit from folinic acid.
    nutrient_topic
    Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
    organism
    Homo sapiens
    plain_language
    This enzyme moves folinic acid into the methenyl-folate pool.
    primary_references
    [bertrand-1987] Human liver methenyltetrahydrofolate synthetase: improved purification and increased affinity for folate polyglutamate substrates (1987). https://pubmed.ncbi.nlm.nih.gov/3801490/ DOI: 10.1016/0167-4838(87)90004-5
    tissue_or_cell_type
    Liver-derived, cell-free

    Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1243–1253

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

    ### mthfs-folinic-acid-conversion Purified human liver MTHFS converts 5-formyl-THF into 5,10-methenyl-THF. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: This enzyme moves folinic acid into the methenyl-folate pool. organism: Homo sapiens tissue_or_cell_type: Liver-derived, cell-free experimental_model: Purified liver enzyme limitations: An enzyme assay does not establish clinical benefit from folinic acid. exposure: Purified human liver enzyme and folate substrates; initial-velocity measurements. [bertrand-1987] Human liver methenyltetrahydrofolate synthetase: improved purification and increased affinity for folate polyglutamate substrates (1987). https://pubmed.ncbi.nlm.nih.gov/3801490/ DOI: 10.1016/0167-4838(87)90004-5
    Complete structured claim and evidence

  3. Patient 1 fibroblast lysate had no detectable MTHFS activity in the reported product-formation assay.

    Human MTHFS gene → Human methenyltetrahydrofolate synthetase / MTHFS source_derived_draftungraded
    Experimental context and source evidence
    availability_state
    machinery_impairment Imported condition classification; unverified.
    evidence_location
    Results 3.3 and Figure 4.
    experimental_model
    Fibroblast lysate enzyme assay
    exposure
    Lysate enzyme assay versus control; Figure 4.
    limitations
    Assay-specific nondetection does not prove zero activity in every tissue or separate the two alleles.
    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
    These patient cells could not measurably perform the tested folate conversion.
    primary_references
    [rodan-2018] 5,10-methenyltetrahydrofolate synthetase deficiency causes a neurometabolic disorder associated with microcephaly, epilepsy, and cerebral hypomyelination (2018). https://pubmed.ncbi.nlm.nih.gov/30031689/ DOI: 10.1016/j.ymgme.2018.06.006
    tissue_or_cell_type
    Patient 1 skin fibroblasts
    trigger_kind
    machinery_impairment Imported condition classification; unverified.

    Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1268–1279

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

    ### mthfs-patient1-enzyme-activity Patient 1 fibroblast lysate had no detectable MTHFS activity in the reported product-formation assay. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: These patient cells could not measurably perform the tested folate conversion. organism: Homo sapiens tissue_or_cell_type: Patient 1 skin fibroblasts experimental_model: Fibroblast lysate enzyme assay limitations: Assay-specific nondetection does not prove zero activity in every tissue or separate the two alleles. exposure: Lysate enzyme assay versus control; Figure 4. evidence_location: Results 3.3 and Figure 4. [rodan-2018] 5,10-methenyltetrahydrofolate synthetase deficiency causes a neurometabolic disorder associated with microcephaly, epilepsy, and cerebral hypomyelination (2018). https://pubmed.ncbi.nlm.nih.gov/30031689/ DOI: 10.1016/j.ymgme.2018.06.006
    Complete structured claim and evidence

  4. Rat FTCD cyclodeaminase converts 5-formimino-THF to 5,10-methenyl-THF with ammonia release.

    Rat formiminotransferase cyclodeaminase / FTCD → 5-Formiminotetrahydrofolate source_derived_draftungraded
    Experimental context and source evidence
    evidence_location
    Cyclodeaminase active-site results and enzyme assay methods.
    experimental_model
    Recombinant protein catalytic assay and mutagenesis
    exposure
    Recombinant rat FTCD and CD-site mutants.
    limitations
    Rat enzyme; human catalytic rates are not measured.
    nutrient_topic
    Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
    organism
    Rattus norvegicus
    plain_language
    A second enzyme domain converts the transferred group into methenyl-folate.
    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 1308–1319

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

    ### rat-ftcd-cyclodeamination Rat FTCD cyclodeaminase converts 5-formimino-THF to 5,10-methenyl-THF with ammonia release. 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 enzyme domain converts the transferred group into methenyl-folate. organism: Rattus norvegicus tissue_or_cell_type: Cell-free experimental_model: Recombinant protein catalytic assay and mutagenesis limitations: Rat enzyme; human catalytic rates are not measured. exposure: Recombinant rat FTCD and CD-site mutants. evidence_location: Cyclodeaminase active-site results and enzyme assay methods. [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
    Complete structured claim and evidence

  5. Rat MTHFD2L also has methenyl-THF cyclohydrolase activity, linking methenyl-THF to 10-formyl-THF.

    Rat mitochondrial MTHFD2L → 10-Formyltetrahydrofolate source_derived_draftungraded
    Experimental context and source evidence
    experimental_model
    Purified recombinant rat protein
    exposure
    Assay conditions described in the linked primary study.
    limitations
    Reaction direction depends on chemical conditions.
    nutrient_topic
    Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
    organism
    Rattus norvegicus
    plain_language
    The same protein performs the next folate conversion.
    primary_references
    [shin-2014] Mitochondrial MTHFD2L is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase expressed in both adult and embryonic tissues (2014). https://pubmed.ncbi.nlm.nih.gov/24733394/ DOI: 10.1074/jbc.m114.555573
    tissue_or_cell_type
    Cell-free

    Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 850–860

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

    ### rat-mthfd2l-cyclohydrolase Rat MTHFD2L also has methenyl-THF cyclohydrolase activity, linking methenyl-THF to 10-formyl-THF. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The same protein performs the next folate conversion. organism: Rattus norvegicus tissue_or_cell_type: Cell-free experimental_model: Purified recombinant rat protein limitations: Reaction direction depends on chemical conditions. exposure: Assay conditions described in the linked primary study. [shin-2014] Mitochondrial MTHFD2L is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase expressed in both adult and embryonic tissues (2014). https://pubmed.ncbi.nlm.nih.gov/24733394/ DOI: 10.1074/jbc.m114.555573
    Complete structured claim and evidence

  6. Rat MTHFD2L catalyzes methylene-THF oxidation with either NAD+ or NADP+.

    Rat mitochondrial MTHFD2L → 5,10-Methylenetetrahydrofolate source_derived_draftungraded
    Experimental context and source evidence
    experimental_model
    Purified recombinant rat protein
    exposure
    Assay conditions described in the linked primary study.
    limitations
    Human ortholog flux was not measured.
    nutrient_topic
    Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
    organism
    Rattus norvegicus
    plain_language
    A second mitochondrial enzyme can use either electron carrier.
    primary_references
    [shin-2014] Mitochondrial MTHFD2L is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase expressed in both adult and embryonic tissues (2014). https://pubmed.ncbi.nlm.nih.gov/24733394/ DOI: 10.1074/jbc.m114.555573
    tissue_or_cell_type
    Cell-free

    Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 838–848

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

    ### rat-mthfd2l-oxidation Rat MTHFD2L catalyzes methylene-THF oxidation with either NAD+ or NADP+. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: A second mitochondrial enzyme can use either electron carrier. organism: Rattus norvegicus tissue_or_cell_type: Cell-free experimental_model: Purified recombinant rat protein limitations: Human ortholog flux was not measured. exposure: Assay conditions described in the linked primary study. [shin-2014] Mitochondrial MTHFD2L is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase expressed in both adult and embryonic tissues (2014). https://pubmed.ncbi.nlm.nih.gov/24733394/ DOI: 10.1074/jbc.m114.555573
    Complete structured claim and evidence

In the sources

Preserved passages that mention this component, quoted exactly. Open one to read it in context.

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