{"id":"947595d9-c135-54b0-a7e5-9ba6f49a778b","stable_key":"0f17db03-207f-5910-ac8e-13dfc2f378ce:mg-pdh-variant-disrupts-coordination","predicate":"disrupts-binding-of","statement":"The alphaV138M E1 structure displaced ThDP and disrupted the canonical Mg coordination site.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"negative","is_public":true,"mechanism_event_id":"1fb2b59f-fdc8-5962-90ad-256bfd536b2b","mechanism_event_label":"An altered protein can impair cofactor use despite cofactors being supplied.","subject":{"id":"ede16316-1426-5212-b266-ac23a7f3a0a0","slug":"pyruvate-dehydrogenase-e1-alpha-v138m","display_name":"Human pyruvate dehydrogenase E1 alphaV138M variant","entity_type_key":"protein_state"},"object":{"id":"bff427ab-35f9-59c2-bb24-fd5953bbaec2","slug":"magnesium-ion","display_name":"Mg2+","entity_type_key":"ion"},"evidence_count":1,"mechanism_event":{"id":"1fb2b59f-fdc8-5962-90ad-256bfd536b2b","stable_key":"0f17db03-207f-5910-ac8e-13dfc2f378ce:mg-pdh-variant-disrupts-coordination-event","event_type":"biochemical_relationship","label":"An altered protein can impair cofactor use despite cofactors being supplied.","description":"The alphaV138M E1 structure displaced ThDP and disrupted the canonical Mg coordination site.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"187db168-8028-5ce6-9f8b-4bc61ebad1a0","slug":"thiamine-diphosphate","display_name":"Thiamine diphosphate","entity_type_key":"small_molecule"},"role":"displaced cofactor","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"d2a2b619-f60a-5ace-9bcb-cdf2a6e194e6","slug":"pyruvate-dehydrogenase-e1","display_name":"Human pyruvate dehydrogenase E1","entity_type_key":"protein_complex"},"role":"wild-type comparator","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"ede16316-1426-5212-b266-ac23a7f3a0a0","slug":"pyruvate-dehydrogenase-e1-alpha-v138m","display_name":"Human pyruvate dehydrogenase E1 alphaV138M variant","entity_type_key":"protein_state"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"bff427ab-35f9-59c2-bb24-fd5953bbaec2","slug":"magnesium-ion","display_name":"Mg2+","entity_type_key":"ion"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":3,"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":"Magnesium and thiamine-derived ThDP intersect at mitochondrial carbon metabolism; purified-enzyme responses do not measure whole-body energy supply.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Recombinant human wild-type and alphaV138M E1 structures and reconstituted PDH complex activity.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"The variant also alters loop structure; Mg loss alone was not isolated as the cause.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"Magnesium research collection; topical membership is not evidence of a direct dietary effect.","comparator":null,"unit":null,"notes":"","entity":{"slug":"magnesium","display_name":"Magnesium","entity_type_key":"nutrient_element"}},{"dimension":"organism","value_text":"Homo sapiens","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"An altered protein can impair cofactor use despite cofactors being supplied.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[whitley-2018-pdh] Pyruvate dehydrogenase complex deficiency is linked to regulatory loop disorder in the αV138M variant of human pyruvate dehydrogenase (2018). https://pmc.ncbi.nlm.nih.gov/articles/PMC6109939/ DOI: 10.1074/jbc.RA118.003996","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Recombinant mitochondrial enzyme","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":"35654f62-54c5-5641-8e3c-211a3db5a813","evidence_kind":"source_excerpt","locator":"Lines 625-635","start_line":625,"end_line":635,"excerpt":"### mg-pdh-variant-disrupts-coordination\nThe alphaV138M E1 structure displaced ThDP and disrupted the canonical Mg coordination site.\nCondition category: machinery_impairment\nnutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect.\nplain_language: An altered protein can impair cofactor use despite cofactors being supplied.\norganism: Homo sapiens\ntissue_or_cell_type: Recombinant mitochondrial enzyme\nexperimental_model: Recombinant human wild-type and alphaV138M E1 structures and reconstituted PDH complex activity.\nlimitations: The variant also alters loop structure; Mg loss alone was not isolated as the cause.\ncross_nutrient: Magnesium and thiamine-derived ThDP intersect at mitochondrial carbon metabolism; purified-enzyme responses do not measure whole-body energy supply.\n[whitley-2018-pdh] Pyruvate dehydrogenase complex deficiency is linked to regulatory loop disorder in the αV138M variant of human pyruvate dehydrogenase (2018). https://pmc.ncbi.nlm.nih.gov/articles/PMC6109939/ DOI: 10.1074/jbc.RA118.003996","model_system":"Recombinant human wild-type and alphaV138M E1 structures and reconstituted PDH complex activity.","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. Study references: [whitley-2018-pdh] Pyruvate dehydrogenase complex deficiency is linked to regulatory loop disorder in the αV138M variant of human pyruvate dehydrogenase (2018). https://pmc.ncbi.nlm.nih.gov/articles/PMC6109939/ DOI: 10.1074/jbc.RA118.003996","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"dd101e28-1a2e-5a48-9d1e-809c77514866","stable_key":"import-0f17db03-207f-5910-ac8e-13dfc2f378ce","title":"Magnesium: cross-nutrient mechanisms and deficiency (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":"e111c412f57143a17e8e65e74e8f7888b5bb9a61099873f4767f527fac19bb07","revision_id":"6b7f04f2-66ed-5859-955f-c2b50d4bf041","review_status":"unverified_draft","notes":""}}],"relations":[],"conflicts":[],"corrections":[],"research":null}