{"id":"1e533f14-adab-5689-bbc5-2f3ca2158218","stable_key":"f8641d02-8413-5bd8-92e9-62ad49286e81:asa-the-new-activity-is-efficient","predicate":"produces","statement":"Both the S516M mutant and the aspirin-acetylated form of cyclooxygenase-2 synthesise 15(R)-HETE with apparent Km values for arachidonic acid within tenfold of untreated enzyme and with similar time courses of turnover-dependent inactivation, and the conversion of arachidonic acid to 15-HETE by acetylated cyclooxygenase-2 is an efficient process providing a unique mechanism among non-steroidal anti-inflammatory drugs that will not lead to arachidonic acid accumulation or shunting to other biosynthetic pathways.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"positive","is_public":true,"mechanism_event_id":"2d2d39ed-cdda-5e32-b8ce-25ab0bb76728","mechanism_event_label":"The rerouted enzyme works well enough that arachidonate does not pile up and spill into other pathways.","subject":{"id":"cda05399-1c07-5459-b8e2-0edcf5066e94","slug":"acetylated-cox2","display_name":"Aspirin-acetylated cyclooxygenase-2","entity_type_key":"protein_state"},"object":{"id":"a8fa3506-620f-5c71-a0f1-226962e93b69","slug":"15r-hete","display_name":"15(R)-hydroxyeicosatetraenoic acid","entity_type_key":"small_molecule"},"evidence_count":1,"mechanism_event":{"id":"2d2d39ed-cdda-5e32-b8ce-25ab0bb76728","stable_key":"f8641d02-8413-5bd8-92e9-62ad49286e81:asa-the-new-activity-is-efficient-event","event_type":"biochemical_relationship","label":"The rerouted enzyme works well enough that arachidonate does not pile up and spill into other pathways.","description":"Both the S516M mutant and the aspirin-acetylated form of cyclooxygenase-2 synthesise 15(R)-HETE with apparent Km values for arachidonic acid within tenfold of untreated enzyme and with similar time courses of turnover-dependent inactivation, and the conversion of arachidonic acid to 15-HETE by acetylated cyclooxygenase-2 is an efficient process providing a unique mechanism among non-steroidal anti-inflammatory drugs that will not lead to arachidonic acid accumulation or shunting to other biosynthetic pathways.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"11741820-6c04-50a2-bed5-2926a56bb930","slug":"cox2-s516m","display_name":"Cyclooxygenase-2 with methionine substituted at position 516","entity_type_key":"protein_state"},"role":"mimicking_mutant","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"48bd3537-336a-512d-be9e-69faf8a45b1a","slug":"arachidonate-shunting","display_name":"Diversion of unmetabolised arachidonate into the 5-lipoxygenase pathway","entity_type_key":"cellular_process"},"role":"avoided_process","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"39f9446f-52a6-502d-b507-91137726f82c","slug":"arachidonic-acid","display_name":"AA","entity_type_key":"small_molecule"},"role":"substrate","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"cda05399-1c07-5459-b8e2-0edcf5066e94","slug":"acetylated-cox2","display_name":"Aspirin-acetylated cyclooxygenase-2","entity_type_key":"protein_state"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""},{"entity":{"id":"a8fa3506-620f-5c71-a0f1-226962e93b69","slug":"15r-hete","display_name":"15(R)-hydroxyeicosatetraenoic acid","entity_type_key":"small_molecule"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":4,"notes":""}]},"contexts":[{"dimension":"evidence_span","value_text":"{\"source_cache\": \"artifacts/aspirin-research/9016346.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"2cc2efefceabbee7bb4f1052db8fc86ee218409fe56981cf92b707c7b0ef531b\", \"start_char\": 0, \"end_char\": 1899, \"text_sha256\": \"2cc2efefceabbee7bb4f1052db8fc86ee218409fe56981cf92b707c7b0ef531b\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Kinetic characterisation of aspirin-acetylated cyclooxygenase-2 and the S516M mutant against a panel of non-steroidal anti-inflammatory drugs","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Aspirin acetylation and the methionine mutant, tested with indomethacin, diclofenac, meclofenamic acid and selective inhibitors","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"Quantifies how efficient the new activity is, which most descriptions of the switch do not. 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Purified and recombinant enzyme rather than intact cells.\nexposure: Aspirin acetylation and the methionine mutant, tested with indomethacin, diclofenac, meclofenamic acid and selective inhibitors\nevidence_span: {\"source_cache\": \"artifacts/aspirin-research/9016346.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"2cc2efefceabbee7bb4f1052db8fc86ee218409fe56981cf92b707c7b0ef531b\", \"start_char\": 0, \"end_char\": 1899, \"text_sha256\": \"2cc2efefceabbee7bb4f1052db8fc86ee218409fe56981cf92b707c7b0ef531b\"}\n[asa-p9016346] Altered sensitivity of aspirin-acetylated prostaglandin G/H synthase-2 to inhibition by nonsteroidal anti-inflammatory drugs. 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