Dc. Swinney et al., DIFFERENTIAL ALLOSTERIC REGULATION OF PROSTAGLANDIN-H SYNTHASE-1 AND SYNTHASE-2 BY ARACHIDONIC-ACID, The Journal of biological chemistry, 272(19), 1997, pp. 12393-12398
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.