Component

Cobalamin-dependent methionine synthase / MTR

Transfers a folate-derived methyl group to homocysteine through enzyme-bound cobalamin.

8 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 it acts on

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

    Cobalamin-dependent methionine synthase / MTR → L-Methionine source_derived_draftungraded
    Experimental context and source evidence
    cross_nutrient
    Folate methyl transfer requires B12.
    experimental_model
    Human MTR/MTRR expressed in insect cells; purified enzymes and extracts.
    limitations
    Chemistry, not dietary response.
    nutrient_topic
    Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
    organism
    Homo sapiens
    plain_language
    B12-dependent MTR recycles both homocysteine and folate.
    primary_references
    [yamada-2006] Human methionine synthase reductase is a molecular chaperone for human methionine synthase (2006). https://pubmed.ncbi.nlm.nih.gov/16769880/ DOI: 10.1073/pnas.0603694103
    tissue_or_cell_type
    Purified protein

    Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 482–492

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human MTR/MTRR expressed in insect cells; purified enzymes and extracts. · source_derived_draft · unverified_draft

    ### folate-methyl-mtr-methyl-transfer Reconstituted human MTR transfers methylfolate-derived methyl groups through cobalamin to homocysteine, producing methionine and THF. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: B12-dependent MTR recycles both homocysteine and folate. organism: Homo sapiens tissue_or_cell_type: Purified protein experimental_model: Human MTR/MTRR expressed in insect cells; purified enzymes and extracts. limitations: Chemistry, not dietary response. cross_nutrient: Folate methyl transfer requires B12. [yamada-2006] Human methionine synthase reductase is a molecular chaperone for human methionine synthase (2006). https://pubmed.ncbi.nlm.nih.gov/16769880/ DOI: 10.1073/pnas.0603694103
    Complete structured claim and evidence

  2. Isotope tracing found MTR-derived synthesis contributed only a minor fraction of methionine in the tested human cancer-cell cultures.

    Cobalamin-dependent methionine synthase / MTR → L-Methionine source_derived_draftungraded
    Experimental context and source evidence
    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
    Complete structured claim and evidence

What acts on it

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

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

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

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

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

  2. Human MTRR stabilized apo-MTR and enhanced holoenzyme formation from methylcobalamin in the presence of NADPH.

    Methionine synthase reductase / MTRR → Cobalamin-dependent methionine synthase / MTR source_derived_draftungraded
    Experimental context and source evidence
    cross_nutrient
    Flavin-dependent MTRR supports B12-enzyme assembly.
    experimental_model
    Human MTR/MTRR expressed in insect cells; purified enzymes and extracts.
    limitations
    In-vitro assembly.
    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
    MTRR also helps MTR acquire its cofactor.
    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
    Human proteins expressed in insect cells

    Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 494–504

    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-mtrr-apoenzyme Human MTRR stabilized apo-MTR and enhanced holoenzyme formation from methylcobalamin in the presence of NADPH. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: MTRR also helps MTR acquire its cofactor. organism: Homo sapiens tissue_or_cell_type: Human proteins expressed in insect cells experimental_model: Human MTR/MTRR expressed in insect cells; purified enzymes and extracts. limitations: In-vitro assembly. cross_nutrient: Flavin-dependent MTRR supports B12-enzyme assembly. [yamada-2006] Human methionine synthase reductase is a molecular chaperone for human methionine synthase (2006). https://pubmed.ncbi.nlm.nih.gov/16769880/ DOI: 10.1073/pnas.0603694103
    Complete structured claim and evidence

  3. Human MTRR sustained human MTR, whereas bacterial flavodoxin/flavodoxin reductase did not significantly support the human enzyme.

    Methionine synthase reductase / MTRR → Cobalamin-dependent methionine synthase / MTR source_derived_draftungraded
    Experimental context and source evidence
    experimental_model
    Human MTR/MTRR expressed in insect cells; purified enzymes and extracts.
    limitations
    Bacterial proteins are assay comparators.
    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 electron-donor partners were species selective.
    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 proteins

    Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 506–515

    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-mtrr-species-recognition Human MTRR sustained human MTR, whereas bacterial flavodoxin/flavodoxin reductase did not significantly support the human enzyme. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The electron-donor partners were species selective. organism: Homo sapiens tissue_or_cell_type: Purified proteins experimental_model: Human MTR/MTRR expressed in insect cells; purified enzymes and extracts. limitations: Bacterial proteins are assay comparators. [yamada-2006] Human methionine synthase reductase is a molecular chaperone for human methionine synthase (2006). https://pubmed.ncbi.nlm.nih.gov/16769880/ DOI: 10.1073/pnas.0603694103
    Complete structured claim and evidence

Where it participates (unsigned role)

  1. The fraction of measured intracellular folate present as 5-methyl-THF was 2.5-fold higher in cblG WG4215 fibroblasts than in control MCH058 fibroblasts.

    MTR gene (Homo sapiens) → 5-Methyltetrahydrofolate source_derived_draftungraded
    Experimental context and source evidence
    availability_state
    machinery_impairment Imported condition classification; unverified.
    experimental_model
    N2O-treated HeLa cells and cblG patient fibroblasts.
    limitations
    Fig. 2A reports folate-species percentages, not absolute amounts; one disease/control cell-line comparison.
    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
    Genetic MTR loss shifted the measured folate mixture 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
    Patient fibroblasts
    trigger_kind
    machinery_impairment Imported condition classification; unverified.

    Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 555–564

    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-cblg-methyl-trap The fraction of measured intracellular folate present as 5-methyl-THF was 2.5-fold higher in cblG WG4215 fibroblasts than in control MCH058 fibroblasts. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Genetic MTR loss shifted the measured folate mixture toward methylfolate. organism: Homo sapiens tissue_or_cell_type: Patient fibroblasts experimental_model: N2O-treated HeLa cells and cblG patient fibroblasts. limitations: Fig. 2A reports folate-species percentages, not absolute amounts; one disease/control cell-line comparison. [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
    Complete structured claim and evidence

  2. MTR knockout in tumour cells using physiological extracellular folates caused trapping and limited assimilation into other folate forms.

    MTR gene (Homo sapiens) → 5-Methyltetrahydrofolate source_derived_draftungraded
    Experimental context and source evidence
    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
    Complete structured claim and evidence

  3. 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.

    Nitrous oxide → 5-Methyltetrahydrofolate source_derived_draftungraded
    Experimental context and source evidence
    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
    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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