Molecular identification of cytosolic prostaglandin E-2 synthase that is functionally coupled with cyclooxygenase-1 in immediate prostaglandin E-2 biosynthesis

Here we report the molecular identification of cytosolic glutathione (GSH)- dependent prostaglandin (PG) E-2 synthase (cPGES), a terminal enzyme of the cyclooxygenase (COX)-1-mediated PGE(2) biosynthetic pathway. GSH-dependent PGES activity in the cytosol of rat brains, but not of other tissues, incr eased 3-fold after lipopolysaccharide (LPS) challenge. Peptide microsequenc ing of purified enzyme revealed that it was identical to p23, which is repo rtedly the weakly bound component of the steroid hormone receptor/hsp90 com plex. Recombinant p23 expressed in Escherichia coli and 293 cells exhibited all the features of PGES activity detected in rat brain cytosol. A tyrosin e residue near the N terminus (Tyr(9)), which is known to be critical for t he activity of cytosolic GSH S-transferases, was essential for PGES activit y. The expression of cPGES/p23 was constitutive and was unaltered by proinf lammatory stimuli in various cells and tissues, except that it was increase d significantly in rat brain after LPS treatment, cPGES/p23 was functionall y linked with COX-1 in marked preference to COX-2 to produce PGE(2) from ex ogenous and endogenous arachidonic acid, the latter being supplied by cytos olic phospholipase A(2) in the immediate response. Thus, functional couplin g between COX-1 and cPGES/p23 may contribute to production of the PGE(2) th at plays a role in maintenance of tissue homeostasis.