{"id":"e67ad100-e731-5792-af25-3346435f0f72","stable_key":"46d15d9e-d3b5-544d-ba01-b785aa3e4f42:b1-lias-defect-reduces-pdh","predicate":"is-associated-with-reduced-activity-of","statement":"The LIAS Arg249His patient had depleted protein-bound lipoyl signal and reduced PDH activity/pyruvate oxidation in investigated muscle and fibroblast preparations.","claim_class":"observational","status":"source_derived_draft","evidence_grade":"ungraded","direction":"negative","is_public":true,"mechanism_event_id":"a4c11178-45ca-593b-b2bc-fb8206c72551","mechanism_event_label":"A B1-dependent pathway can fail because its lipoyl machinery is defective. This case does not show that adding thiamine corrects the defect.","subject":{"id":"127ab782-1d2e-54c3-a766-60383303ae57","slug":"lias-r249h","display_name":"LIAS Arg249His","entity_type_key":"protein_state"},"object":{"id":"6d908873-0745-523a-96bf-9cf25bda2676","slug":"pyruvate-dehydrogenase-complex","display_name":"Human pyruvate dehydrogenase complex","entity_type_key":"protein_complex"},"evidence_count":1,"mechanism_event":{"id":"a4c11178-45ca-593b-b2bc-fb8206c72551","stable_key":"46d15d9e-d3b5-544d-ba01-b785aa3e4f42:b1-lias-defect-reduces-pdh-event","event_type":"observed_intervention","label":"A B1-dependent pathway can fail because its lipoyl machinery is defective. This case does not show that adding thiamine corrects the defect.","description":"The LIAS Arg249His patient had depleted protein-bound lipoyl signal and reduced PDH activity/pyruvate oxidation in investigated muscle and fibroblast preparations.","status":"provisional","compartment":{"slug":"mitochondrial-matrix","display_name":"Mitochondrial matrix"},"participants":[{"entity":{"id":"f9fc9417-ca4f-5e0c-b01d-60b337493d34","slug":"lias","display_name":"Lipoic acid synthetase / LIAS","entity_type_key":"protein"},"role":"affected synthesis enzyme","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"fd2197c3-5a63-55f4-8bb1-bfc1e91a0e1e","slug":"protein-bound-lipoamide","display_name":"Protein-bound oxidized lipoyl-lysine","entity_type_key":"chemical_species"},"role":"depleted prosthetic group","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"12e22bc4-4bc8-5a45-87bc-9274656e9dab","slug":"dlat","display_name":"Dihydrolipoyl acetyltransferase / DLAT","entity_type_key":"protein"},"role":"lipoyl-containing PDC subunit","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"91e6d4f5-fba1-542d-b68a-57cc28e1e425","slug":"pyruvate","display_name":"Pyruvate","entity_type_key":"small_molecule"},"role":"tested oxidative substrate","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""},{"entity":{"id":"127ab782-1d2e-54c3-a766-60383303ae57","slug":"lias-r249h","display_name":"LIAS Arg249His","entity_type_key":"protein_state"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":4,"notes":""},{"entity":{"id":"6d908873-0745-523a-96bf-9cf25bda2676","slug":"pyruvate-dehydrogenase-complex","display_name":"Human pyruvate dehydrogenase complex","entity_type_key":"protein_complex"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":5,"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":"Endogenous lipoate synthesis is a separate requirement of the thiamine-dependent PDH pathway.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"evidence","value_text":"[{\"paper_key\": \"mayr-2011-lias\", \"source_bundle\": \"artifacts/thiamine_metabolism_sources.json\", \"passage_ids\": [\"abstract\"], \"locator\": \"Primary publication abstract\", \"preservation\": \"Exact text retained in the source bundle; full source document retained when openly retrievable.\"}]","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Patient biochemical analysis.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"Single patient; no proof of thiamine-treatment failure mechanism.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient","value_text":"Thiamine (vitamin B1)","comparator":null,"unit":null,"notes":"","entity":{"slug":"thiamine","display_name":"Thiamine (vitamin B1)","entity_type_key":"small_molecule"}},{"dimension":"nutrient_topic","value_text":"Thiamine research collection; topical membership is not evidence of a direct dietary effect.","comparator":null,"unit":null,"notes":"","entity":{"slug":"thiamine","display_name":"Thiamine (vitamin B1)","entity_type_key":"small_molecule"}},{"dimension":"organism","value_text":"Homo sapiens","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"A B1-dependent pathway can fail because its lipoyl machinery is defective. This case does not show that adding thiamine corrects the defect.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[mayr-2011-lias] Lipoic acid synthetase deficiency causes neonatal-onset epilepsy, defective mitochondrial energy metabolism, and glycine elevation (2011). https://pubmed.ncbi.nlm.nih.gov/22152680/ DOI: 10.1016/j.ajhg.2011.11.011","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Muscle and cultured fibroblasts","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":"77405bd2-29cb-57bd-95f5-1c466b22159b","evidence_kind":"source_excerpt","locator":"Lines 759-771","start_line":759,"end_line":771,"excerpt":"### b1-lias-defect-reduces-pdh\nThe LIAS Arg249His patient had depleted protein-bound lipoyl signal and reduced PDH activity/pyruvate oxidation in investigated muscle and fibroblast preparations.\nCondition category: machinery_impairment\nnutrient_topic: Thiamine research collection; topical membership is not evidence of a direct dietary effect.\nplain_language: A B1-dependent pathway can fail because its lipoyl machinery is defective. This case does not show that adding thiamine corrects the defect.\norganism: Homo sapiens\ntissue_or_cell_type: Muscle and cultured fibroblasts\nexperimental_model: Patient biochemical analysis.\nlimitations: Single patient; no proof of thiamine-treatment failure mechanism.\nevidence: [{\"paper_key\": \"mayr-2011-lias\", \"source_bundle\": \"artifacts/thiamine_metabolism_sources.json\", \"passage_ids\": [\"abstract\"], \"locator\": \"Primary publication abstract\", \"preservation\": \"Exact text retained in the source bundle; full source document retained when openly retrievable.\"}]\ncross_nutrient: Endogenous lipoate synthesis is a separate requirement of the thiamine-dependent PDH pathway.\nnutrient: Thiamine (vitamin B1)\n[mayr-2011-lias] Lipoic acid synthetase deficiency causes neonatal-onset epilepsy, defective mitochondrial energy metabolism, and glycine elevation (2011). https://pubmed.ncbi.nlm.nih.gov/22152680/ DOI: 10.1016/j.ajhg.2011.11.011","model_system":"Patient biochemical analysis.","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. Study references: [mayr-2011-lias] Lipoic acid synthetase deficiency causes neonatal-onset epilepsy, defective mitochondrial energy metabolism, and glycine elevation (2011). https://pubmed.ncbi.nlm.nih.gov/22152680/ DOI: 10.1016/j.ajhg.2011.11.011","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"158d2c03-ac8c-589f-8270-c468165ae346","stable_key":"import-46d15d9e-d3b5-544d-ba01-b785aa3e4f42","title":"Thiamine: 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":"f376512fb3310141315548015b387833e3af45146e73fb73cd02cee20e4ddb9c","revision_id":"53bc5eda-dec8-58cc-a56f-a9eb4ab036ef","review_status":"unverified_draft","notes":""}}],"relations":[],"conflicts":[],"corrections":[],"research":null}