{"id":"5f42b11f-624b-569c-bee9-372ef11f193c","stable_key":"db0fc92e-b5ef-5667-a4c5-3ef257edbc9b:glutathione-gclc-mutant-gsh","predicate":"reduces_in_expression_assay","statement":"All four mutant GCLC transfectants had lower GSH than wild type in Gclc-null mouse fibroblasts; Pro414Leu was most impaired.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"context_dependent","is_public":true,"mechanism_event_id":"cb0ad2f3-e2f3-5839-9b31-f5e9f3118895","mechanism_event_label":"Supply can fail because the synthesis machinery is defective.","subject":{"id":"171d92a9-89a6-5315-a3c1-70c283f6cb28","slug":"gclc-clinical-mutants-2011","display_name":"Human GCLC Arg127Cys, Pro158Leu, His370Leu and Pro414Leu variants","entity_type_key":"protein_state"},"object":{"id":"5e8dd2eb-2ad7-519b-a0a1-0ff9ffa705da","slug":"cellular-glutathione-pool","display_name":"Cellular reduced-glutathione pool","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"cb0ad2f3-e2f3-5839-9b31-f5e9f3118895","stable_key":"db0fc92e-b5ef-5667-a4c5-3ef257edbc9b:glutathione-gclc-mutant-gsh-event","event_type":"biochemical_relationship","label":"Supply can fail because the synthesis machinery is defective.","description":"All four mutant GCLC transfectants had lower GSH than wild type in Gclc-null mouse fibroblasts; Pro414Leu was most impaired.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"171d92a9-89a6-5315-a3c1-70c283f6cb28","slug":"gclc-clinical-mutants-2011","display_name":"Human GCLC Arg127Cys, Pro158Leu, His370Leu and Pro414Leu variants","entity_type_key":"protein_state"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"5e8dd2eb-2ad7-519b-a0a1-0ff9ffa705da","slug":"cellular-glutathione-pool","display_name":"Cellular reduced-glutathione pool","entity_type_key":"cellular_process"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""}]},"contexts":[{"dimension":"availability_state","value_text":"machinery_impairment","comparator":null,"unit":null,"notes":"Imported condition classification; unverified.","entity":null},{"dimension":"evidence_span","value_text":"{\"source_cache\": \"artifacts/glutathione-research/21657237.abstract.txt\", \"locator\": \"Primary indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"d0ef7f04eacc64f48cee159ed630014f38163f2b848bf36b99c4d371786f55d7\", \"start_char\": 0, \"end_char\": 1854, \"text_sha256\": \"d0ef7f04eacc64f48cee159ed630014f38163f2b848bf36b99c4d371786f55d7\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Human variants in recombinant assays, mouse fibroblasts and yeast complementation","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Four clinical GCLC variants with or without GCLM","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"Expression-system rescue does not establish a clinical therapy; Pro158Leu retains near-wild-type isolated kinetics.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"Glutathione research collection; topical membership is not evidence of a direct dietary effect.","comparator":null,"unit":null,"notes":"","entity":{"slug":"glutathione","display_name":"GSH","entity_type_key":"small_molecule"}},{"dimension":"organism","value_text":"Human GCLC/GCLM; mouse and yeast hosts","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"Supply can fail because the synthesis machinery is defective.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[glutathione-p21657237] Enzymatic defects underlying hereditary glutamate cysteine ligase deficiency are mitigated by association of the catalytic and regulatory subunits. (2011). https://pubmed.ncbi.nlm.nih.gov/21657237/ DOI: 10.1021/bi200708w","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"GCL activity and cellular GSH","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":"e41c5dff-3763-5f2f-b393-9b65aa922b34","evidence_kind":"source_excerpt","locator":"Lines 385-396","start_line":385,"end_line":396,"excerpt":"### glutathione-gclc-mutant-gsh\nAll four mutant GCLC transfectants had lower GSH than wild type in Gclc-null mouse fibroblasts; Pro414Leu was most impaired.\nCondition category: machinery_impairment\nnutrient_topic: Glutathione research collection; topical membership is not evidence of a direct dietary effect.\nplain_language: Supply can fail because the synthesis machinery is defective.\norganism: Human GCLC/GCLM; mouse and yeast hosts\ntissue_or_cell_type: GCL activity and cellular GSH\nexperimental_model: Human variants in recombinant assays, mouse fibroblasts and yeast complementation\nlimitations: Expression-system rescue does not establish a clinical therapy; Pro158Leu retains near-wild-type isolated kinetics.\nexposure: Four clinical GCLC variants with or without GCLM\nevidence_span: {\"source_cache\": \"artifacts/glutathione-research/21657237.abstract.txt\", \"locator\": \"Primary indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"d0ef7f04eacc64f48cee159ed630014f38163f2b848bf36b99c4d371786f55d7\", \"start_char\": 0, \"end_char\": 1854, \"text_sha256\": \"d0ef7f04eacc64f48cee159ed630014f38163f2b848bf36b99c4d371786f55d7\"}\n[glutathione-p21657237] Enzymatic defects underlying hereditary glutamate cysteine ligase deficiency are mitigated by association of the catalytic and regulatory subunits. 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