{"id":"51ac3e25-e6ca-5e09-a94e-2b965cdaadf5","stable_key":"db0fc92e-b5ef-5667-a4c5-3ef257edbc9b:glutathione-gss-variants","predicate":"reduces","statement":"Six tested GSS variants reduced Vmax to 2–27% of wild-type activity.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"context_dependent","is_public":true,"mechanism_event_id":"28032d54-e185-549b-b06e-653fac307302","mechanism_event_label":"The last assembly step can be the bottleneck.","subject":{"id":"4c7d9fc9-e054-5541-b11d-5aced53a4c66","slug":"gss-low-activity-2004","display_name":"Human GSS L188P, D219A, D219G, Y270C, Y270H and R283C variants","entity_type_key":"protein_state"},"object":{"id":"32ef3893-eb64-53de-8dc3-2498db7a0d41","slug":"human-gss-catalytic-activity","display_name":"Human glutathione synthetase catalytic activity","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"28032d54-e185-549b-b06e-653fac307302","stable_key":"db0fc92e-b5ef-5667-a4c5-3ef257edbc9b:glutathione-gss-variants-event","event_type":"biochemical_relationship","label":"The last assembly step can be the bottleneck.","description":"Six tested GSS variants reduced Vmax to 2–27% of wild-type activity.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"4c7d9fc9-e054-5541-b11d-5aced53a4c66","slug":"gss-low-activity-2004","display_name":"Human GSS L188P, D219A, D219G, Y270C, Y270H and R283C variants","entity_type_key":"protein_state"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"32ef3893-eb64-53de-8dc3-2498db7a0d41","slug":"human-gss-catalytic-activity","display_name":"Human glutathione synthetase catalytic activity","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/15056072.abstract.txt\", \"locator\": \"Primary indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"eba1361a80a1f5021b9ca1c841eb5a6f8cc0e79302f68d30a09273debe3f6ee1\", \"start_char\": 0, \"end_char\": 1151, \"text_sha256\": \"eba1361a80a1f5021b9ca1c841eb5a6f8cc0e79302f68d30a09273debe3f6ee1\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Recombinant patient-associated variant kinetics","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Seven missense variants versus wild type","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"Variants differ; P314L was kinetically neutral in this assay. Clinical severity cannot be read directly from Vmax.","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 GSS expressed in E. coli","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"The last assembly step can be the bottleneck.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[glutathione-p15056072] Human hereditary glutathione synthetase deficiency: kinetic properties of mutant enzymes. (2004). https://pubmed.ncbi.nlm.nih.gov/15056072/ DOI: 10.1042/bj20040114","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Purified enzymes","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":"f74f77c5-a1f1-52cd-b96c-ec0e97986357","evidence_kind":"source_excerpt","locator":"Lines 411-422","start_line":411,"end_line":422,"excerpt":"### glutathione-gss-variants\nSix tested GSS variants reduced Vmax to 2–27% of wild-type activity.\nCondition category: machinery_impairment\nnutrient_topic: Glutathione research collection; topical membership is not evidence of a direct dietary effect.\nplain_language: The last assembly step can be the bottleneck.\norganism: Human GSS expressed in E. coli\ntissue_or_cell_type: Purified enzymes\nexperimental_model: Recombinant patient-associated variant kinetics\nlimitations: Variants differ; P314L was kinetically neutral in this assay. Clinical severity cannot be read directly from Vmax.\nexposure: Seven missense variants versus wild type\nevidence_span: {\"source_cache\": \"artifacts/glutathione-research/15056072.abstract.txt\", \"locator\": \"Primary indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"eba1361a80a1f5021b9ca1c841eb5a6f8cc0e79302f68d30a09273debe3f6ee1\", \"start_char\": 0, \"end_char\": 1151, \"text_sha256\": \"eba1361a80a1f5021b9ca1c841eb5a6f8cc0e79302f68d30a09273debe3f6ee1\"}\n[glutathione-p15056072] Human hereditary glutathione synthetase deficiency: kinetic properties of mutant enzymes. (2004). https://pubmed.ncbi.nlm.nih.gov/15056072/ DOI: 10.1042/bj20040114","model_system":"Recombinant patient-associated variant kinetics","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. 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