DIFFERENTIAL ALLOSTERIC REGULATION OF PROSTAGLANDIN-H SYNTHASE-1 AND SYNTHASE-2 BY ARACHIDONIC-ACID

Prostaglandins are synthesized by prostaglandin H synthase (PGHS) 1 an d 2. PGHS2 is regulated through inducible expression. We report here t he regulation of PGHS1 activity by substrate-dependent cooperative act ivation, The cooperativity is characterized by a Hill coefficient of 1 .29 +/- 0.06, a curved Eadie-Scatchard plot, and activation by low con centrations of competitive inhibitors, The activation also appears to induce a conformational change in the cyclooxygenase site. The coopera tivity produces a 2-4-fold greater rate of PGHS2-dependent prostagland in formation compared with PGHS1-dependent prostaglandin formation at arachidonic acid concentrations below 0.5 mu M. A consequence of the P GHS1 cooperativity is that the affinity of many cyclooxygenase inhibit ors for PGHS1 decreases in parallel to the activation by arachidonic a cid. In contrast, the affinity of these inhibitors for PGHS2 is unaffe cted by the changes in arachidonic acid concentration, This results in a dramatic difference in PGHS2/PGHS1 selectivity at different arachid onic acid concentrations.