Component

MTHFR Ala222Val protein

Protein substitution encoded by the common historical C677T variant; distinct from a human genotype or dietary deficiency.

5 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. Ala222Val MTHFR released FAD about three times faster than wild type after dilution; concentration dependence supported dimer dissociation before cofactor loss.

    MTHFR Ala222Val protein → FAD source_derived_draftungraded
    Experimental context and source evidence
    availability_state
    machinery_impairment Imported condition classification; unverified.
    cross_nutrient
    Genetic variation modifies retention of the B2-derived cofactor at a folate enzyme.
    evidence_location
    Results: FAD loss; Figs 1-3
    experimental_model
    Baculovirus-produced purified human wild-type, Ala222Val, Glu429Ala and double-mutant MTHFR; dilution/cofactor-release assays.
    exposure
    Purified-enzyme assay
    limitations
    The diluted purified-protein experiment does not measure intracellular cofactor occupancy in every 677TT carrier.
    nutrient_topic
    Riboflavin research collection; topical membership is not evidence of a direct dietary effect. · Riboflavin (vitamin B2)
    organism
    Homo sapiens
    plain_language
    This variant loses its cofactor more readily in the dilution experiment.
    primary_references
    [yamada2001] Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductase. (2001). https://pubmed.ncbi.nlm.nih.gov/11742092/ DOI: 10.1073/pnas.261469998
    tissue_or_cell_type
    Purified recombinant enzyme; no intact tissue
    trigger_kind
    machinery_impairment Imported condition classification; unverified.

    Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1038–1050

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Baculovirus-produced purified human wild-type, Ala222Val, Glu429Ala and double-mutant MTHFR; dilution/cofactor-release assays. · source_derived_draft · unverified_draft

    ### b2-mthfr-ala222val-fad-loss Ala222Val MTHFR released FAD about three times faster than wild type after dilution; concentration dependence supported dimer dissociation before cofactor loss. Condition category: machinery_impairment nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: This variant loses its cofactor more readily in the dilution experiment. organism: Homo sapiens tissue_or_cell_type: Purified recombinant enzyme; no intact tissue experimental_model: Baculovirus-produced purified human wild-type, Ala222Val, Glu429Ala and double-mutant MTHFR; dilution/cofactor-release assays. limitations: The diluted purified-protein experiment does not measure intracellular cofactor occupancy in every 677TT carrier. exposure: Purified-enzyme assay cross_nutrient: Genetic variation modifies retention of the B2-derived cofactor at a folate enzyme. evidence_location: Results: FAD loss; Figs 1-3 [yamada2001] Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductase. (2001). https://pubmed.ncbi.nlm.nih.gov/11742092/ DOI: 10.1073/pnas.261469998
    Complete structured claim and evidence

  2. Nonpregnant MTHFR rs1801133 carriers had lower labeled betaine:phosphatidylcholine enrichment ratios than noncarriers (0.8 versus 0.9).

    MTHFR Ala222Val protein → Choline partitioning between betaine and phosphatidylcholine source_derived_draftungraded
    Experimental context and source evidence
    availability_state
    machinery_impairment Imported condition classification; unverified.
    cross_nutrient
    Folate-pathway genotype relates to choline allocation.
    experimental_model
    Choline feeding and isotope tracing in women across reproductive states.
    limitations
    Genotypes not randomized; ratio is a pathway proxy.
    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
    Relative choline allocation shifted toward phosphatidylcholine.
    primary_references
    [ganz-2016] Genetic impairments in folate enzymes increase dependence on dietary choline for phosphatidylcholine production at the expense of betaine synthesis (2016). https://pubmed.ncbi.nlm.nih.gov/27342765/ DOI: 10.1096/fj.201500138rr
    tissue_or_cell_type
    Plasma tracer metabolites
    trigger_kind
    machinery_impairment Imported condition classification; unverified.

    Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 731–741

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Choline feeding and isotope tracing in women across reproductive states. · source_derived_draft · unverified_draft

    ### folate-methyl-variant-choline-allocation Nonpregnant MTHFR rs1801133 carriers had lower labeled betaine:phosphatidylcholine enrichment ratios than noncarriers (0.8 versus 0.9). Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Relative choline allocation shifted toward phosphatidylcholine. organism: Homo sapiens tissue_or_cell_type: Plasma tracer metabolites experimental_model: Choline feeding and isotope tracing in women across reproductive states. limitations: Genotypes not randomized; ratio is a pathway proxy. cross_nutrient: Folate-pathway genotype relates to choline allocation. [ganz-2016] Genetic impairments in folate enzymes increase dependence on dietary choline for phosphatidylcholine production at the expense of betaine synthesis (2016). https://pubmed.ncbi.nlm.nih.gov/27342765/ DOI: 10.1096/fj.201500138rr
    Complete structured claim and evidence

What acts on it

  1. Methyltetrahydrofolate slowed FAD loss from diluted Ala222Val MTHFR in the tested concentration series.

    5-Methyltetrahydrofolate → MTHFR Ala222Val protein source_derived_draftungraded
    Experimental context and source evidence
    availability_state
    machinery_impairment Imported condition classification; unverified.
    cross_nutrient
    Folate binding can stabilize a B2-derived cofactor interaction.
    evidence_location
    Results: FAD loss; Figs 1-3
    experimental_model
    Baculovirus-produced purified human wild-type, Ala222Val, Glu429Ala and double-mutant MTHFR; dilution/cofactor-release assays.
    exposure
    Purified-enzyme assay
    limitations
    Protein-stability assay; clinical folate or riboflavin treatment effects were not tested here.
    nutrient_topic
    Riboflavin research collection; topical membership is not evidence of a direct dietary effect. · Riboflavin (vitamin B2)
    organism
    Homo sapiens
    plain_language
    Folate product helped the variant retain FAD in vitro.
    primary_references
    [yamada2001] Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductase. (2001). https://pubmed.ncbi.nlm.nih.gov/11742092/ DOI: 10.1073/pnas.261469998
    tissue_or_cell_type
    Purified recombinant enzyme; no intact tissue
    trigger_kind
    machinery_impairment Imported condition classification; unverified.

    Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1052–1064

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Baculovirus-produced purified human wild-type, Ala222Val, Glu429Ala and double-mutant MTHFR; dilution/cofactor-release assays. · source_derived_draft · unverified_draft

    ### b2-methylfolate-mthfr-retention Methyltetrahydrofolate slowed FAD loss from diluted Ala222Val MTHFR in the tested concentration series. Condition category: machinery_impairment nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Folate product helped the variant retain FAD in vitro. organism: Homo sapiens tissue_or_cell_type: Purified recombinant enzyme; no intact tissue experimental_model: Baculovirus-produced purified human wild-type, Ala222Val, Glu429Ala and double-mutant MTHFR; dilution/cofactor-release assays. limitations: Protein-stability assay; clinical folate or riboflavin treatment effects were not tested here. exposure: Purified-enzyme assay cross_nutrient: Folate binding can stabilize a B2-derived cofactor interaction. evidence_location: Results: FAD loss; Figs 1-3 [yamada2001] Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductase. (2001). https://pubmed.ncbi.nlm.nih.gov/11742092/ DOI: 10.1073/pnas.261469998
    Complete structured claim and evidence

  2. SAM slowed FAD dissociation after MTHFR dilution, including Ala222Val, despite its separate reversible inhibition of catalytic activity.

    S-Adenosyl-L-methionine → MTHFR Ala222Val protein source_derived_draftungraded
    Experimental context and source evidence
    availability_state
    machinery_impairment Imported condition classification; unverified.
    cross_nutrient
    Methionine-cycle feedback affects both folate-enzyme activity and B2-cofactor retention.
    evidence_location
    Results: FAD loss; Figs 1-3
    experimental_model
    Baculovirus-produced purified human wild-type, Ala222Val, Glu429Ala and double-mutant MTHFR; dilution/cofactor-release assays.
    exposure
    Purified-enzyme assay
    limitations
    In-vitro effects; stabilization is not equivalent to increased reaction flux.
    nutrient_topic
    Riboflavin research collection; topical membership is not evidence of a direct dietary effect. · Riboflavin (vitamin B2)
    organism
    Homo sapiens
    plain_language
    Cofactor retention and catalytic speed respond differently to SAM.
    primary_references
    [yamada2001] Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductase. (2001). https://pubmed.ncbi.nlm.nih.gov/11742092/ DOI: 10.1073/pnas.261469998
    tissue_or_cell_type
    Purified recombinant enzyme; no intact tissue
    trigger_kind
    machinery_impairment Imported condition classification; unverified.

    Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1066–1078

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Baculovirus-produced purified human wild-type, Ala222Val, Glu429Ala and double-mutant MTHFR; dilution/cofactor-release assays. · source_derived_draft · unverified_draft

    ### b2-sam-mthfr-retention SAM slowed FAD dissociation after MTHFR dilution, including Ala222Val, despite its separate reversible inhibition of catalytic activity. Condition category: machinery_impairment nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Cofactor retention and catalytic speed respond differently to SAM. organism: Homo sapiens tissue_or_cell_type: Purified recombinant enzyme; no intact tissue experimental_model: Baculovirus-produced purified human wild-type, Ala222Val, Glu429Ala and double-mutant MTHFR; dilution/cofactor-release assays. limitations: In-vitro effects; stabilization is not equivalent to increased reaction flux. exposure: Purified-enzyme assay cross_nutrient: Methionine-cycle feedback affects both folate-enzyme activity and B2-cofactor retention. evidence_location: Results: FAD loss; Figs 1-3 [yamada2001] Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductase. (2001). https://pubmed.ncbi.nlm.nih.gov/11742092/ DOI: 10.1073/pnas.261469998
    Complete structured claim and evidence

Where it participates (unsigned role)

  1. During 400 micrograms DFE/day repletion, DNA methylcytosine:total-cytosine increased significantly only in MTHFR 677TT women.

    Folate (vitamin B9) → Genomic DNA methylation source_derived_draftungraded
    Experimental context and source evidence
    availability_state
    nutrient_deficiency Imported condition classification; unverified.
    experimental_model
    Young MTHFR 677CC/TT women; controlled folate feeding.
    exposure
    Seven weeks after depletion
    limitations
    Within-group significance alone does not establish a genotype interaction.
    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 directly measured DNA-base response differed across genotype groups.
    primary_references
    [shelnutt-2004] Methylenetetrahydrofolate reductase 677C-->T polymorphism affects DNA methylation in response to controlled folate intake in young women (2004). https://pubmed.ncbi.nlm.nih.gov/15350988/ DOI: 10.1016/j.jnutbio.2004.04.003
    tissue_or_cell_type
    Blood-derived genomic DNA
    trigger_kind
    nutrient_deficiency Imported condition classification; unverified.

    Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 800–810

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Young MTHFR 677CC/TT women; controlled folate feeding. · source_derived_draft · unverified_draft

    ### folate-methyl-young-tt-repletion During 400 micrograms DFE/day repletion, DNA methylcytosine:total-cytosine increased significantly only in MTHFR 677TT women. 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 directly measured DNA-base response differed across genotype groups. organism: Homo sapiens tissue_or_cell_type: Blood-derived genomic DNA experimental_model: Young MTHFR 677CC/TT women; controlled folate feeding. limitations: Within-group significance alone does not establish a genotype interaction. exposure: Seven weeks after depletion [shelnutt-2004] Methylenetetrahydrofolate reductase 677C-->T polymorphism affects DNA methylation in response to controlled folate intake in young women (2004). https://pubmed.ncbi.nlm.nih.gov/15350988/ DOI: 10.1016/j.jnutbio.2004.04.003
    Complete structured claim and evidence

In the sources

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

    This is a research prototype built from draft material. It is not medical advice, and its statements still await verification against the original studies.

    Evidence, AI assistance and curation standards