{"id":"1c41a153-ab16-52ea-a4bb-43e50daea1e7","stable_key":"db0fc92e-b5ef-5667-a4c5-3ef257edbc9b:glutathione-gclm-mutant-rescue","predicate":"improves_in_assay","statement":"Adding GCLM largely rescued impaired activity of recombinant GCLC Arg127Cys, His370Leu and Pro414Leu.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"context_dependent","is_public":true,"mechanism_event_id":"f1733d43-c679-50b5-89aa-911a9cd410b1","mechanism_event_label":"The partner subunit changed how a damaged catalytic subunit performed.","subject":{"id":"2be894ac-8d47-565b-94f3-f12fdc993c3f","slug":"gclm","display_name":"Human glutamate-cysteine ligase modifier subunit / GCLM","entity_type_key":"protein"},"object":{"id":"548262cb-9130-53a2-be88-06ef4ec7ec15","slug":"human-gcl-catalytic-activity","display_name":"Human glutamate-cysteine ligase catalytic activity","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"f1733d43-c679-50b5-89aa-911a9cd410b1","stable_key":"db0fc92e-b5ef-5667-a4c5-3ef257edbc9b:glutathione-gclm-mutant-rescue-event","event_type":"biochemical_relationship","label":"The partner subunit changed how a damaged catalytic subunit performed.","description":"Adding GCLM largely rescued impaired activity of recombinant GCLC Arg127Cys, His370Leu and Pro414Leu.","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":"variant_set","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"2be894ac-8d47-565b-94f3-f12fdc993c3f","slug":"gclm","display_name":"Human glutamate-cysteine ligase modifier subunit / GCLM","entity_type_key":"protein"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"548262cb-9130-53a2-be88-06ef4ec7ec15","slug":"human-gcl-catalytic-activity","display_name":"Human glutamate-cysteine ligase catalytic activity","entity_type_key":"cellular_process"},"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":"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":"The partner subunit changed how a damaged catalytic subunit performed.","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":"fe233d12-f7b7-59f9-9472-77004bd4c74d","evidence_kind":"source_excerpt","locator":"Lines 398-409","start_line":398,"end_line":409,"excerpt":"### glutathione-gclm-mutant-rescue\nAdding GCLM largely rescued impaired activity of recombinant GCLC Arg127Cys, His370Leu and Pro414Leu.\nCondition category: machinery_impairment\nnutrient_topic: Glutathione research collection; topical membership is not evidence of a direct dietary effect.\nplain_language: The partner subunit changed how a damaged catalytic subunit performed.\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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