Enzymes of the cyclooxygenase pathways of prostanoid biosynthesis.

Prostanoids are cyclic, oxygenated products of ω3 and ω6 20- and 22-carbon essential fatty acids (FAs) that are formed enzymatically through “cyclooxygenases”. Prostaglandin endoperoxide synthases -1 and -2 (PGHS-1 and -2)a, which are also known as cyclooxygenases -1 and -2 (COX-1 and -2), catalyze the committed step in the biosynthesis of prostanoids (Figure 1). These compounds include what are sometimes referred to as the “classical” prostaglandins (PGs) PGD, PGE, and PGF as well as prostacyclins denoted as PGI's and the thromboxanes abbreviated Tx's; monohydroxy acids can also be formed via PGHSs, but information on the possible physiologic importance of such compounds is incomplete.1-3 The most abundant prostanoids are the “2-series” compounds (e.g. PGE2) that are formed from arachidonic acid (AA; 5Z, 8Z, 11Z, 14Z- eicosatetraenoic acid; 20:4 ω6; Figure 1). The “2” denotes the number of carbon-carbon double bonds in the product. Figure 1 Biosynthetic pathway for the formation of prostanoids PGHSs catalyze two distinct reactions that occur at physically distinct but functionally interacting sites. The cyclooxygenase (COX) reaction is a bis-oxygenation in which two O2 molecules are inserted into the carbon backbone of AA to yield PGG2 (Figure 1). The peroxidase (POX) reaction is a transformation in which the 15-hydroperoxyl group of PGG2 undergoes a net two electron reduction to PGH2 plus water. The POX reaction is important in the enzyme mechanism, but other peroxidases such as glutathione peroxidase may contribute importantly to the reduction of PGG2 to PGH2 in vivo. PGH2 is thought not to accumulate in cells but rather to be converted quickly to what are considered the biologically relevant, downstream products. There are specific synthases involved in forming PGD2, PGE2, PGF2α, PGI2 and TxA2 from PGH2. Except for the case of PGF2α, which is formed by a two electron reduction of PGH2, these enzymes catalyze non-oxidative rearrangements. Finally, there is a PGH 19-hydoxylase that converts PGHs to their corresponding 19-hydroxy derivatives which themselves are substrates for PGE synthase(s). There are one or more specific G protein-linked receptors for each prostanoid, and in some cases prostanoids may also act through nuclear peroxisome proliferator activated receptors. AA and other 20- and 22-carbon, highly unsaturated FAs are found esterified at the sn2 position of glycerophospholipids. Basal prostanoid formation generally occurs at a low rate relative to stimulated formation. A major factor limiting prostanoid formation is AA availability, which is controlled through the net rates of deacylation and reacylation of glycerophospholipids. Prostanoid formation is enhanced when phospholipase A2 (PLA2) activity is increased, and thus PLA2s play a substrate-limiting role in regulating prostanoid biosynthesis. Although reacylation may also be important, its possible role in regulating prostanoid biosynthesis is largely unexplored. In this chapter we review the biochemistry and the biochemical pharmacology of the enzymes involved in converting AA to various prostanoid products. These enzymes include PGHS-1, PGHS-2, hematopoietic PGD synthase (H-PGDS), lipocalin-type PGD synthase (L-PGDS), microsomal PGE synthase-1 (mPGES-1), microsomal PGE synthase-2 (mPGES-2), cytosolic PGE synthase (cPGES), PGF synthase (PGFS), PGI synthase (PGIS) and TXA synthase (TXAS). The PLA2s involved in mobilizing AA and the receptors through which prostanoids function are surveyed in other chapters of this volume.