{"id":"72589bc1-6ad9-5de0-836a-f2b9aacd300b","stable_key":"548ab9d6-3a9b-5bed-879c-17d03813b636:b2-sam-mthfr-retention","predicate":"stabilizes","statement":"SAM slowed FAD dissociation after MTHFR dilution, including Ala222Val, despite its separate reversible inhibition of catalytic activity.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"positive","is_public":true,"mechanism_event_id":"d2671dd2-9af5-54b0-9825-281cd90f8ee4","mechanism_event_label":"Cofactor retention and catalytic speed respond differently to SAM.","subject":{"id":"825f2da2-01bc-5874-a3c6-64f5ac867db5","slug":"s-adenosylmethionine","display_name":"S-Adenosyl-L-methionine","entity_type_key":"small_molecule"},"object":{"id":"7dfc117d-3ae8-592f-b13f-d7b38798e043","slug":"mthfr-ala222val","display_name":"MTHFR Ala222Val protein","entity_type_key":"protein_state"},"evidence_count":1,"mechanism_event":{"id":"d2671dd2-9af5-54b0-9825-281cd90f8ee4","stable_key":"548ab9d6-3a9b-5bed-879c-17d03813b636:b2-sam-mthfr-retention-event","event_type":"biochemical_relationship","label":"Cofactor retention and catalytic speed respond differently to SAM.","description":"SAM slowed FAD dissociation after MTHFR dilution, including Ala222Val, despite its separate reversible inhibition of catalytic activity.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"e2cd7179-f218-54e8-9ce9-7a836ae35fac","slug":"fad","display_name":"FAD","entity_type_key":"small_molecule"},"role":"retained cofactor","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"825f2da2-01bc-5874-a3c6-64f5ac867db5","slug":"s-adenosylmethionine","display_name":"S-Adenosyl-L-methionine","entity_type_key":"small_molecule"},"role":"subject","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":"target","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":"Methionine-cycle feedback affects both folate-enzyme activity and B2-cofactor retention.","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":"In-vitro effects; stabilization is not equivalent to increased reaction flux.","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":"Cofactor retention and catalytic speed respond differently to SAM.","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":"241405fa-ca00-5f81-8156-571cb81b95a8","evidence_kind":"source_excerpt","locator":"Lines 1066-1078","start_line":1066,"end_line":1078,"excerpt":"### b2-sam-mthfr-retention\nSAM slowed FAD dissociation after MTHFR dilution, including Ala222Val, despite its separate reversible inhibition of catalytic activity.\nCondition category: machinery_impairment\nnutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect.\nplain_language: Cofactor retention and catalytic speed respond differently to SAM.\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: In-vitro effects; stabilization is not equivalent to increased reaction flux.\nexposure: Purified-enzyme assay\ncross_nutrient: Methionine-cycle feedback affects both folate-enzyme activity and B2-cofactor retention.\nevidence_location: Results: FAD loss; Figs 1-3\n[yamada2001] Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductase. 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