PGE synthase

Prostaglandin E (PGE) is the most common prostanoid with a variety of bioactivities and has been implicated in various pathologies. PGE is produced via three sequential enzymatic reactions: release of arachidonic acid (AA) from membrane glycerophospholipids by phospholipase A2 (PLA2), conversion of AA to the unstable intermediate prostanoid PGH2 by cyclooxygenase (COX), and isomerization of PGH2 to PGE by prostaglandin E synthase (PGES). Despite a rapidly expanding body of information on the structures, expression and regulatory functions of various eicosanoidbiosyntheticenzymes during the last decade, little has been learned about the molecular identity of PGES until very recently. The membrane-bound and cytosolic forms of PGES are now designated as mPGES-1 and cPGES, respectively. The primary structures of mPGES-1 proteins from several species show a high degree of sequence homology. mPGES-1 also shows significant homology with other MAPEG superfamily proteins, including MGST-1, MGST-2, MGST-3, 5-lipoxygenase-activating protein (FLAP) and leukotriene C4 synthase (LTCS), with the highest homology being found with MGST-1 (~40%). 
In the immediate response elicited by Ca2+ agonists, AA rapidly released by cPLA2a is metabolized to PGE2 via the constitutive enzymes COX-1 and cPGES, which forms a tertiary complex with Hsp90 and CK2. In the delayed response induced by proinflammatory stimuli (plain arrows), AA slowly and continuously released by cPLA2a is metabolized to PGE2 via the two inducible enzymes COX-2 and mPGES-1. mPGES-1 is capable of producing PGE2 via COX-1 when explosive activation of cPLA2a occurs (i.e. large amounts of AA are released). mPGES-2, a constitutive enzyme that is initially associated with the Golgi membrane and is released into the cytoplasm after N-terminal proteolysis, is coupled with both COX-1 and COX-2.  mPGES-1 play important roles in the febrile and pain responses in the CNS, inflammatory arthritis, granulation, angiogenesis and edema, and the development of cancer. In addition, spatiotemporal expression of mPGES-1 supports the involvement of this enzyme in the reproduction, gastrointestinal and renal homeostasis, and DA closure. Transcript for mPGES-2 is more abundantly distributed in the brain, heart, skeletal muscle, kidney and liver than in other tissues, which differs from the expression profile of that for mPGES-1. In contrast to the marked inducibility of mPGES-1 (see above), mPGES-2 is constitutively expressed in various cells and tissues and is not increased appreciably during tissue inflammation or damage.


1.Murakami M, Kudo I. Curr Pharm Des. 2006;12(8):943–954.