{"id":"bb267997-1721-53ee-ac5f-be917847832f","stable_key":"548ab9d6-3a9b-5bed-879c-17d03813b636:b2-mthfr-ala222val-fad-loss","predicate":"destabilizes-retention-of","statement":"Ala222Val MTHFR released FAD about three times faster than wild type after dilution; concentration dependence supported dimer dissociation before cofactor loss.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"negative","is_public":true,"mechanism_event_id":"4723b513-9f13-52fd-9c55-5b943fab44da","mechanism_event_label":"This variant loses its cofactor more readily in the dilution experiment.","subject":{"id":"7dfc117d-3ae8-592f-b13f-d7b38798e043","slug":"mthfr-ala222val","display_name":"MTHFR Ala222Val protein","entity_type_key":"protein_state"},"object":{"id":"e2cd7179-f218-54e8-9ce9-7a836ae35fac","slug":"fad","display_name":"FAD","entity_type_key":"small_molecule"},"evidence_count":1,"mechanism_event":{"id":"4723b513-9f13-52fd-9c55-5b943fab44da","stable_key":"548ab9d6-3a9b-5bed-879c-17d03813b636:b2-mthfr-ala222val-fad-loss-event","event_type":"biochemical_relationship","label":"This variant loses its cofactor more readily in the dilution experiment.","description":"Ala222Val MTHFR released FAD about three times faster than wild type after dilution; concentration dependence supported dimer dissociation before cofactor loss.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"9fc32b1a-0f08-544c-a361-1c728203b6ec","slug":"mthfr","display_name":"Methylenetetrahydrofolate reductase / MTHFR","entity_type_key":"protein"},"role":"wild-type comparator","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"e2cd7179-f218-54e8-9ce9-7a836ae35fac","slug":"fad","display_name":"FAD","entity_type_key":"small_molecule"},"role":"released cofactor","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"7dfc117d-3ae8-592f-b13f-d7b38798e043","slug":"mthfr-ala222val","display_name":"MTHFR Ala222Val protein","entity_type_key":"protein_state"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""}]},"contexts":[{"dimension":"availability_state","value_text":"machinery_impairment","comparator":null,"unit":null,"notes":"Imported condition classification; unverified.","entity":null},{"dimension":"cross_nutrient","value_text":"Genetic variation modifies retention of the B2-derived cofactor at a folate enzyme.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"evidence_location","value_text":"Results: FAD loss; Figs 1-3","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Baculovirus-produced purified human wild-type, Ala222Val, Glu429Ala and double-mutant MTHFR; dilution/cofactor-release assays.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Purified-enzyme assay","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"The diluted purified-protein experiment does not measure intracellular cofactor occupancy in every 677TT carrier.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"Riboflavin research collection; topical membership is not evidence of a direct dietary effect.","comparator":null,"unit":null,"notes":"","entity":{"slug":"riboflavin","display_name":"Riboflavin (vitamin B2)","entity_type_key":"small_molecule"}},{"dimension":"organism","value_text":"Homo sapiens","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"This variant loses its cofactor more readily in the dilution experiment.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[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","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Purified recombinant enzyme; no intact tissue","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"trigger_kind","value_text":"machinery_impairment","comparator":null,"unit":null,"notes":"Imported condition classification; unverified.","entity":null}],"evidence":[{"id":"bf643494-32bd-5c97-9e75-3f1d9fd155a5","evidence_kind":"source_excerpt","locator":"Lines 1038-1050","start_line":1038,"end_line":1050,"excerpt":"### b2-mthfr-ala222val-fad-loss\nAla222Val MTHFR released FAD about three times faster than wild type after dilution; concentration dependence supported dimer dissociation before cofactor loss.\nCondition category: machinery_impairment\nnutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect.\nplain_language: This variant loses its cofactor more readily in the dilution experiment.\norganism: Homo sapiens\ntissue_or_cell_type: Purified recombinant enzyme; no intact tissue\nexperimental_model: Baculovirus-produced purified human wild-type, Ala222Val, Glu429Ala and double-mutant MTHFR; dilution/cofactor-release assays.\nlimitations: The diluted purified-protein experiment does not measure intracellular cofactor occupancy in every 677TT carrier.\nexposure: Purified-enzyme assay\ncross_nutrient: Genetic variation modifies retention of the B2-derived cofactor at a folate enzyme.\nevidence_location: Results: FAD loss; Figs 1-3\n[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","model_system":"Baculovirus-produced purified human wild-type, Ala222Val, Glu429Ala and double-mutant MTHFR; dilution/cofactor-release assays.","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. Study 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","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"4f7c9578-82bf-5e2d-b5c4-72a79fb4f6af","stable_key":"import-548ab9d6-3a9b-5bed-879c-17d03813b636","title":"Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17)","document_type":"imported_text","citation_label":"AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. 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