Endoperoxide synthase

In the next step the —OOH group of PGG2 is reduced to an alcohol function Again prostaglandin endoperoxide synthase is the enzyme responsible The product of this step IS called PGH2... 

Studies of the biosynthesis of PGE2 from arachidonic acid have shown that all three oxygens come from O2. The enzyme involved, prostaglandin endoperoxide synthase, has cyclooxygenase (COX) activity and catalyzes the reaction of arachidonic acids with O2 to give an endoperoxide (PGG2). 

All prostaglandins are cyclopentanoic acids derived from arachidonic acid. The biosynthesis of prostaglandins is initiated by an enzyme associated with the endoplasmic reticulum, called prostaglandin endoperoxide synthase, also known as cyclooxygenase. The enzyme catalyzes simultaneous oxidation and cyclization of arachidonic acid. The enzyme is viewed as having two distinct activities, cyclooxygenase and peroxidase, as shown in Figure 25.28. 

FIGURE 25.29 (a) The structures of several commou analgesic agents. Acetaminophen is marketed under the tradename Tylenol. Ibuprofen is sold as Motrin, Nuprin, and Advil, (b) Acetylsalicylate (aspirin) inhibits the cyclooxygenase activity of endoperoxide synthase via acetylation (covalent modification) of Ser ... 

Patrignani P, Panara MR, Greco A et al (1994) Biochemical and pharmacological characterization of the cyclooxygenase activity of human blood prostaglandin endoperoxide synthases. J Pharmacol Exp Ther 271 1705-1712... 

F.a.b.-m.s. has contributed to a detailed analysis of the high-mannose carbohydrate chains of prostaglandin endoperoxide synthase from sheep. Oligosaccharides released by hydrazinolysis were analyzed after N-re-acetylation and reduction. The f.a.b. data defined the compositions of the oligosaccharides, and showed that hydrazinolysis had effected a partial fission of the chitobiose core. 

Smith, W.L. and Marnett, L.J. (1991). Prost andin endoperoxide synthase structure and catalysis. Biochem. Biophys. Acta 1083, 1-17. 

Tumorigenicity of tetrahydroepoxides. As yet, only Ch H -epoxide has been directly demonstrated to be tumorigenic (18). However, indirect evidence has been found in the high tumorigenicity of 3,4-dihydro BA, 9,10-dihydro BeP and 3,4-dihydrobenz[c]acridine (19-21), each of which is a likely metabolic precursor of a bay-region H -epoxide. In the case of 9,10-dihydro BeP, cis- and trans-9,10-dihydroxy -9,10,11,12-tetrahydro BeP were identified as products of metabolism of 9,10-dihydro BeP (22), and are the expected products of hydration of the epoxide. Diols are also formed from 7,8-dihydro BaP upon metabolism with prostaglandin endoperoxide synthase (23) or with rat liver homogenates (24). 

Marcheselli, V. L. and Bazan, N. G. Sustained induction of prostaglandin endoperoxide synthase-2 by seizures in hippocampus. Inhibition by a platelet-activating factor antagonist. / Biol. Chem. 271 24794-24799,1996. 

Tsujii M, DuBois RN. Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell 1995 83 493-501. 

A sensitive assay for lipid hydroperoxides is afforded by prostaglandin endoperoxide synthase, that in the presence of hydroperoxides is activated to liberate O2, which is measured with an oxygen electrode . Although it may be of advantage in certain cases, the procedure seems too complex to become of widespread application in practical analysis. 

Cyclooxygenase (COX), one of the two activities of prostaglandin endoperoxide synthase (PGHS), is the key enzyme in the conversion of arachidonic acid derived from lipids of the cell membrane to prostaglandins and other eicosanoids (Fig. 3). 

Patrignani, P., Panara, M. R., Sciulli, M. G., Santini, G., Renda, G., Patrono, C. Differential inhibition of human prostaglandin endoperoxide synthase-1 and -2 by nonsteroidal anti-inflammatory drugs, J. Physiol. Pharmacol. 1997, 48, 623-631. 

Oxidation and cyclization of arachidonic acid by the two catalytic activities of prostaglandin endoperoxide synthase. G-SH = reduced glutathione GS-SG = oxidized gluathione. 

Synthesis of prostaglandins and thromboxanes begins with the oxidative cyclization of free arachidonic acid to yield PGH2 by prostaglandin endoperoxide synthase—a microsomal protein that has two catalytic activities fatty acid cyclooxygenase (COX) and peroxidase. There are two isozymes of the synthase COX-1 and COX-2. Leukotrienes are produced by the 5-lipoxygenase pathway. 

Fig. (6). Vasoconstrictor mechanism of myricetin. PLA2 phospholipase A2 PL phospholipids AA arachidonic acid COX cyclooxygenase PGG2 prostaglandin G2 PGES prostaglandin endoperoxide synthase PGH2 prostaglandin Hi TXS Thromboxane synthase TXA2 Thromboxane A2 Tp Thromboxane receptor PKC protein kinase C.

Reaction catalyzed by prostaglandin endoperoxide synthase. This enzyme has two catalytic activities, as indicated next to the reaction arrows. 

Mamett LJ, Goodwin DC, Rowlinson SW, Kalgutkar AS and Landino LM (1999) Structure, function, and inhibition of prostaglandin endoperoxide synthases. Comprehensive Natural Products Chemistry, Vol 5. Elsevier, Amsterdam, pp 225-261. 

Kalgutkar, A. S. Crews, B. C. Mamett, L. J. Design, synthesis, and biochemical evaluation of N-substituted maleimides as inhibitors of prostaglandin endoperoxide synthase. /. Med. Chem. 1996, 39, 1692-1703. 

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