Cyclooxygenase synthase

The enzyme system responsible for the biosynthesis of PGs is widely distributed in mammalian tissues and has been extensively studied (2). It is referred to as prostaglandin H synthase (PGHS) and exhibits both cyclooxygenase and peroxidase activity. In addition to the classical PGs two other prostanoid products, thromboxane [57576-52-0] (TxA ) (3) and prostacyclin [35121 -78-9] (PGI2) (4) are also derived from the action of the enzyme system on arachidonic acid (Fig. 1). 

In order for the cyclooxygenase to function, a source of hydroperoxide (R—O—O—H) appears to be required. The hydroperoxide oxidizes a heme prosthetic group at the peroxidase active site of PGH synthase. This in turn leads to the oxidation of a tyrosine residue producing a tyrosine radical which is apparendy involved in the abstraction of the 13-pro-(5)-hydrogen of AA (25). The cyclooxygenase is inactivated during catalysis by the nonproductive breakdown of an active enzyme intermediate. This suicide inactivation occurs, on average, every 1400 catalytic turnovers. 

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 ... 

TXA2 is produced by activated platelets via the sequential conversion of arachidonic acid by phospholipase A2, cyclooxygenase-1 (COX-1), and thromboxane synthase. Similar to ADP, TXA2 acts as a... 

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... 

Fu JY, Masferrer JL, Seibert K et al (1990) The induction and suppression of prostaglandin H2 synthase (cyclooxygenase) in human monocytes. J Biol Chem 265 16737-16740... 

Hong CH, Sun KH, Jin O, Sun SK, Kyung AN, Sang KL. Evaluation of natural products on inhibition of inducible cyclooxygenase (COX-2) and nitric oxide synthase (iNOS) in cultured mouse macrophage cells. J Ethnopharmacol 2002 83 153-159. 

Red wine contains quercetin, rutin, catechin, and epicatechin, among other flavonoids (Frankel and others 1993). Quercetin and other phenolic compounds isolated from wines were found to be more effective than a-tocopherol in inhibiting copper-catalyzed LDL oxidation. It has been determined that quercetin has also several anti-inflammatory effects it inhibits inflammatory cytokine production (Boots and others 2008), inducible NO synthase expression and activation of inflammatory transcription factors (Hamalainen and others 2007), and activity of cyclooxygenase and lipooxygenase (Issa 2006), among others. 

Sakata K, Hirose Y, Qiao Z, Tanaka T and Mori H. 2003. Inhibition of inducible isoforms of cyclooxygenase and nitric oxide synthase by flavonoid hesperidin in mouse macrophage cell line. Cancer Lett 199(2)439-145. 

O Donnell et al. [70] found that LOX and not cyclooxygenase, cytochrome P-450, NO synthase, NADPH oxidase, xanthine oxidase, ribonucleotide reductase, or mitochondrial respiratory chain is responsible for TNF-a-mediated apoptosis of murine fibrosarcoma cells. 15-LOX activity was found to increase sharply in heart, lung, and vascular tissues of rabbits by hypercholesterolemia [71], Schnurr et al. [72] demonstrated that there is an inverse regulation of 12/15-LOXs and phospholipid hydroperoxide glutathione peroxidases in cells, which balanced the intracellular concentration of oxidized lipids. 

It has been suggested that only one tyrosine residue, tyrosine 385, is oxidized into tyrosyl free radical in cyclooxygenase cycle. This suggestion was confirmed by NO trapping of this tyrosyl radical generated by prostaglandin H synthase [81]. It was found that the stoichiometry of AA oxidation by prostaglandin H synthase AA/02 is equal to ca. 2 [82,83],... 

Similar to LOXs, cyclooxygenases may catalyze superoxide production in the presence of NADH and NADPH [49]. It has been shown [88] that prostaglandin H synthase produced oxygen radicals and hydrogen peroxide during the transformation of 2(3)-tcrt-butyl-4-... 

Schreiber, J., Eling, T. E. and Mason, R. P. The oxidation of arachidonic acid by the cyclooxygenase activity of purified prostaglandin H synthase spin trapping of a carbon-centered free radical intermediate. Arch. Biochem. Biophys. 249 126-136,1986. 

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