Both COX-1 and COX-2 function as homodimers inserted into the membrane of the endoplasmic reticulum to promote the uptake of two molecules of oxygen by cyclization of AA to yield a C9–C11 endoperoxide C15 hydroperoxide (Figure 18–2). This product is PGG2, which is then rapidly modified by the peroxidase moiety of the COX enzyme to add a 15-hydroxyl group that is essential for biologic activity. This product is PGH2. Both endoperoxides are highly unstable. Analogous families—PGH1 and PGH3 and their subsequent 1-series and 3-series products— are derived from homo-γ-linolenic acid and eicosapentaenoic acid, respectively. In both COX-1 and COX-2 homodimers, one protomer acts as the catalytic unit binding AA for oxygenation, while the other acts as an allosteric modifier of catalytic activity.
The prostaglandins, thromboxane, and prostacyclin, collectively termed the prostanoids, are generated from PGH2 through the action of downstream isomerases and synthases. These terminal enzymes are expressed in a relatively cell-specific fashion, such that most cells make one or two dominant prostanoids. The prostaglandins differ from each other in two ways: (1) in the substituents of the pentane ring (indicated by the last letter, eg, E and F in PGE and PGF) and (2) in the number of double bonds in the side chains (indicated by the subscript, eg, PGE1, PGE2). PGH2 is metabolized by prostacyclin, thromboxane, and PGF synthases (PGIS, TXAS, and PGFS) to PGI2, TXA2, and PGF2α, respectively. Two additional enzymes, 9,11-endoperoxide reductase and 9-ketoreductase, provide for PGF2α synthesis from PGH2 and PGE2, respectively. At least three PGE2 synthases have been identified: microsomal (m) PGES-1, the more readily inducible mPGES-2, and cytosolic PGES. There are two distinct PGDS isoforms, the lipocalin-type PGDS and the hematopoietic PGDS.
Several products of the arachidonate series are of current clinical importance. Alprostadil (PGE1) may be used for its smooth muscle relaxing effects to maintain the ductus arteriosus patent in some neonates awaiting cardiac surgery and in the treatment of impotence. Misoprostol, a PGE1 derivative, is a cytoprotective prostaglandin used in preventing peptic ulcer and in combination with mifepristone (RU-486) for terminating early pregnancies. Dinoprostone (PGE2) and PGF2α are used in obstetrics to induce labor. Latanoprost and several similar compounds are topically active PGF2α derivatives used in ophthalmology to reduce intra-ocular pressure in open-angle glaucoma or ocular hypertension. Prostacyclin (PGI2) is synthesized mainly by the vascular endothelium and is a powerful vasodilator and inhibitor of platelet aggregation. Synthetic PGI2 (epoprostenol) and PGI2 analogs (iloprost, treprostinil) are used to treat pulmonary hypertension and portopulmonary hypertension. In contrast, thromboxane (TXA2) has undesirable properties (platelet aggregation, vasoconstriction). Therefore TXA2-receptor antagonists and synthesis inhibitors have been developed for cardiovascular indications, although these (except for aspirin) have yet to establish a place in clinical usage, and, in a recent large clinical trial, TXA2 receptor antagonism failed to show superiority over low-dose aspirin for secondary stroke protection.