Mechanism of selective inhibition of the inducible isoform of prostaglandin G/H synthase

摘要: Abstract Selective inhibition of the inducible isoform prostaglandin G/H synthase (cyclooxygenase-2; COX2; EC 1.14.99.1) can be achieved with compounds general form aryl methyl sulfonyls and sulfonamides. DuP 697 NS-398 are representative examples these compounds. Both inhibit constitute (COX1) (COX2) isoforms enzyme equal potency shortly after mixing, but their potencies increase time for COX2 selectively. This time-dependent follows first-order kinetics, rate constant inactivation is dose dependent both Kinetic analysis allows us to determine KI kinact (the maximal inactivation) each inhibitor. The substrate concentration dependent, as expected competitive inhibitors. that has been incubated inhibitors, then extensively dialyzed against buffer, shows no recovery activity, while complete activity seen COX1. Thus, inhibitors irreversibly inactivate time, showing minimal reversible We isolated long incubation excess subsequent denaturation enzyme. showed loss resulting from interactions COX2, suggesting not mediated by covalent modification These data suggest binding induces a slow structural transition results in its selective inactivation.