Prostaglandins synthases

Despite considerable efforts very few membrane proteins have yielded crystals that diffract x-rays to high resolution. In fact, only about a dozen such proteins are currently known, among which are porins (which are outer membrane proteins from bacteria), the enzymes cytochrome c oxidase and prostaglandin synthase, and the light-harvesting complexes and photosynthetic reaction centers involved in photosynthesis. In contrast, many other membrane proteins have yielded small crystals that diffract poorly, or not at all, using conventional x-ray sources. However, using the most advanced synchrotron sources (see Chapter 18) it is now possible to determine x-ray structures from protein crystals as small as 20 pm wide which will permit more membrane protein structures to be elucidated. 

Herschman, R. W. Prostaglandin synthase 2. Biochim. Biophys. Acta. 1299 125-140,1996. 

Bazan, N. G., Fletcher, B. S., Herschman, H. R. and Mukherjee, P. K. Platelet-activating factor and retinoic acid synergistically activate the inducible prostaglandin synthase gene. Proc. Natl Acad. Sci. U.S.A. 91 5252-5256,1994. 

Another location with high prostaglandin-synthase activity and low P450 levels is the fetus, and it has been proposed that the teratogenicities of benzo[a]pyrene and phenytoin are due to cyclooxygenase-mediated bioactivation of these agents (45,46). 

Prostaglandin synthase is also present in the skin where it may make a significant contribution to the oxidation of carcinogens and the pathogenesis of skin cancer (47). 

Marnett LJ. Prostaglandin synthase-mediated metabolism of carcinogens and a potential role for peroxyl radicals as reactive intermediates. Environ Health Perspect 1990 88 5-12. 

Pharmacotherapy. Acute relief of inflammatory symptoms can be achieved by prostaglandin synthase inhibitors nonsteroidal anti-inflammatory drugs, or NSAlDs, such as diclofenac, indomethacin, piroxicam, p. 200), and glucocorticoids (p. 248). The inevitably chronic use of NSAlDs is likely to cause adverse effects. Neither NSAlDs nor glucocorticoids can halt the progressive destruction of joints. 

Two different pathways lead from arachidonate to prostaglandins, prostacyclins, and thromboxanes, on the one hand, or leuko-trienes on the other. The key enzyme for the first pathway is prostaglandin synthase [2]. Using up O2, it catalyzes in a two-step reaction the cyclization of arachidonate to prostaglandin H2, the parent substance for the prostaglandins, prostacyclins, and thromboxanes. Acetylsalicylic acid (aspirin) irreversibly ace-tylates a serine residue near the active center of prostaglandin synthase, so that access for substrates is blocked (see below). 

Acetylsalicylic acid and related non-steroidal anti-inflammatory drugs (NSAIDs) selectively inhibit the cyclooxygenase activity of prostaglandin synthase [2] and consequently the synthesis of most eicosanoids. This explains their analgesic, antipyretic, and antirheumatic effects. Frequent side effects of NSAIDs also result from inhibition of eicosanoid synthesis. For example, they impair hemostasis because the synthesis of thromboxanes by thrombocytes is inhibited. In the stomach, NSAIDs increase HCl secretion and at the same time inhibit the formation of protective mucus. Long-term NSAID use can therefore damage the gastric mucosa. 

Prostanoids, which consist of prostaglandins (PCs) and thromboxanes (TXs), are biologically synthesized in the body from arachidonic acid by cyclooxygenase, PG hydroperoxydase, and a family of prostaglandin synthases (Fig. 1). They exert a variety of actions as hormones produced locally in various tissues and cells to maintain homeostasis. 

In addition to aconitases, nitric oxide is an inhibitor of many other enzymes such as ribonucleotide reductase [71], glutathione peroxidase [72,73], cytochrome c oxidase [74], NADPH oxidase [75], xanthine oxidase [76], and lipoxygenase [77] but not prostaglandin synthase [78]. (Mechanism of lipoxygenase inhibition by nitric oxide is considered in Chapter... 

Peroxidases. Another group of enzymes, which is involved in the oxidation of xenobiotics, is the peroxidase. There are a number of these enzymes in mammalian tissues prostaglandin synthase found in many tissues, but especially seminal vesicles and also the kidney, the lung, the intestine spleen, and blood vessels lactoperoxidase found in mammary glands myeloperoxidase found in neutrophils, macrophages, liver Kupffer cells, and bone marrow cells. 

Helliwell RJ, Adams LF, Mitchell MD. Prostaglandin synthases recent developments and a novel hypothesis. Prostaglandins Leukot Essent Fatty Acids. 2004 70 101-113. 

Morimitsu et al. (2000) have shown that after incubation with MS-ITC (5 or 10 min), the treated platelets were washed two times with phosphate-buffered saline, and MS-ITC potently inhibited platelet aggregation induced by thrombin. Then, MS-ITC could not show any effects on arachidonic acid cascade (phospholipase A prostaglandin synthase, and thromboxane synthase) in human platelets. 

In addition to inhibiting prostaglandin synthase, indomethacin and other NSAIDs also inhibit urate crystal phagocytosis. Indomethacin is commonly used as initial treatment of gout as the replacement for colchicine. Three or four doses of 50 mg every 6 hours are given when a response occurs, the dosage is reduced to 25 mg three or four times daily for about 5 days. 

Prostaglandin synthase Histidine Dioxygenation of arachidonic acid... 

Roth GJ, Stanford N, Majerus PW. Acetylation of prostaglandin synthase by aspirin. Proc Natl Acad Sci USA 1975 72 3073-3077. 

Prostaglandins Prostaglandins and the other eicosanoids (prostacyclins, thromboxanes and leukotrienes) are derived from arachidonate. These compounds all act as local hormones. Aspirin reduces inflammation by inhibiting prostaglandin synthase, the enzyme that catalyzes the first step in prostaglandin synthesis. 

Kubow S, Wells P. In vitro bioactivation of phenytoin to a reactive free radical intermediate by prostaglandin synthase, horseradish peroxidase and thyroid peroxidase. Mol Pharmacol 1989 35 1-8. 

Prostaglandins are mediators of the inflammatory response and are produced by the action of two activities of the enzyme prostaglandin synthase. The first activity is a cyclooxygenase activity, which adds two oxygen molecules the arachidonic acid. Secondly, the peroxide group from the first step is reduced to a hydroxyl group. 

Gossypol has been isolated from the roots, stems, and seeds of the cotton plant and reported as a COX inhibitor based on in vitro assay in neutrophils [165] and an inhibitor of LOX and prostaglandin synthase from rat basophilic leukemia cells [166]. Gossypol showed as a potent inhibitor of leukotrienes B4 and D4 production and also reduced PTF-induced contraction of guinea-pig lung parenchyma [167]. 

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