{"id":"d16afe54-4620-5431-8c14-db57c1c196d1","stable_key":"ec174d5a-4903-5745-8646-df0e9d4265e8:folate-methyl-sam-dual-binding","predicate":"occludes_active_site_of","statement":"Dual SAM binding rearranged the human MTHFR linker and inserted a loop that blocked catalytic substrate access.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"negative","is_public":true,"mechanism_event_id":"12673a9c-aecb-5d25-a00d-35b165656d45","mechanism_event_label":"SAM switches MTHFR into a closed shape.","subject":{"id":"825f2da2-01bc-5874-a3c6-64f5ac867db5","slug":"s-adenosylmethionine","display_name":"S-Adenosyl-L-methionine","entity_type_key":"small_molecule"},"object":{"id":"9fc32b1a-0f08-544c-a361-1c728203b6ec","slug":"mthfr","display_name":"Methylenetetrahydrofolate reductase / MTHFR","entity_type_key":"protein"},"evidence_count":1,"mechanism_event":{"id":"12673a9c-aecb-5d25-a00d-35b165656d45","stable_key":"ec174d5a-4903-5745-8646-df0e9d4265e8:folate-methyl-sam-dual-binding-event","event_type":"biochemical_relationship","label":"SAM switches MTHFR into a closed shape.","description":"Dual SAM binding rearranged the human MTHFR linker and inserted a loop that blocked catalytic substrate access.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"e2cd7179-f218-54e8-9ce9-7a836ae35fac","slug":"fad","display_name":"FAD","entity_type_key":"small_molecule"},"role":"cofactor contacted by Tyr404","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":"9fc32b1a-0f08-544c-a361-1c728203b6ec","slug":"mthfr","display_name":"Methylenetetrahydrofolate reductase / MTHFR","entity_type_key":"protein"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""}]},"contexts":[{"dimension":"experimental_model","value_text":"Recombinant human MTHFR; cryo-EM and biochemistry.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"Not a whole-body SAM threshold.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect.","comparator":null,"unit":null,"notes":"","entity":{"slug":"folate","display_name":"Folate (vitamin B9)","entity_type_key":"chemical_species"}},{"dimension":"organism","value_text":"Homo sapiens","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"SAM switches MTHFR into a closed shape.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[mthfr-allostery-2024] Dynamic inter-domain transformations mediate the allosteric regulation of human 5, 10-methylenetetrahydrofolate reductase (2024). https://pubmed.ncbi.nlm.nih.gov/38622112/ DOI: 10.1038/s41467-024-47174-y","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Purified protein","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"82e595a2-171c-5e98-9d43-c34b6d429278","evidence_kind":"source_excerpt","locator":"Lines 460-469","start_line":460,"end_line":469,"excerpt":"### folate-methyl-sam-dual-binding\nDual SAM binding rearranged the human MTHFR linker and inserted a loop that blocked catalytic substrate access.\nCondition category: normal\nnutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect.\nplain_language: SAM switches MTHFR into a closed shape.\norganism: Homo sapiens\ntissue_or_cell_type: Purified protein\nexperimental_model: Recombinant human MTHFR; cryo-EM and biochemistry.\nlimitations: Not a whole-body SAM threshold.\n[mthfr-allostery-2024] Dynamic inter-domain transformations mediate the allosteric regulation of human 5, 10-methylenetetrahydrofolate reductase (2024). https://pubmed.ncbi.nlm.nih.gov/38622112/ DOI: 10.1038/s41467-024-47174-y","model_system":"Recombinant human MTHFR; cryo-EM and biochemistry.","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. Study references: [mthfr-allostery-2024] Dynamic inter-domain transformations mediate the allosteric regulation of human 5, 10-methylenetetrahydrofolate reductase (2024). https://pubmed.ncbi.nlm.nih.gov/38622112/ DOI: 10.1038/s41467-024-47174-y","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"f4ce1a62-9582-5f7a-84f5-a23d0e1bfc68","stable_key":"import-ec174d5a-4903-5745-8646-df0e9d4265e8","title":"Folate and folic acid: 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. Not publisher full text.","file_path":"","sha256":"e564d43989ece1006c95cd0748e9af6fe369074599a2eebba0a99ebff864b0dd","revision_id":"76674a33-b2a1-5e41-b71b-44399038ff7c","review_status":"unverified_draft","notes":""}}],"relations":[],"conflicts":[],"corrections":[],"research":null}