Prostaglandin H-synthase

Prostaglandin H synthase (EC 1.14.99.1), also called cyclooxygenase, is the rate-limiting enzyme in the conversion of arachidonic acid to prostanoids. To 

Non-steroidal anti-inflammatory drugs inhibit cyclooxygenases and thus the conversion of arachi-donic acid to prostanoids. 

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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). 

Figure 23-6. Conversion of arachidonicacid to prostaglandins and thromboxanes of series 2. (PG, prostaglandin TX, thromboxane PGI, prostacyclin HHT, hydroxyheptadecatrienoate.) (Asterisk Both of these starred activities are attributed to one enzyme prostaglandin H synthase. Similar conversions occur in prostaglandins and thromboxanes of series 1 and 3.)...

The first line of evidence derives from the predominant formation of quinones when metabolism of BP is conducted under peroxi-datic conditions, namely by prostaglandin H synthase (21) or by cytochrome P-450 with cumene hydroperoxide as cofactor T22). Under these metabolic conditions one-electron oxidation is the preponderant mechanism of activation. 

Lipid Peroxidation and Free Radical Production Catalyzed by Prostaglandin H Synthases... 

LOX-dependent superoxide production was also registered under ex vivo conditions [55]. It has been shown that the intravenous administration of lipopolysaccharide to rats stimulated superoxide production by alveolar and peritoneal macrophages. O Donnell and Azzi [56] proposed that a relatively high rate of superoxide production by cultured human fibroblasts in the presence of NADH was relevant to 15-LOX-catalyzed oxidation of unsaturated acids and was independent of NADPH oxidase, prostaglandin H synthase, xanthine oxidase, and cytochrome P-450 activation or mitochondrial respiration. LOX might also be involved in the superoxide production by epidermal growth factor-stimulated pheochromo-cytoma cells [57]. 

LIPID PEROXIDATION AND FREE RADICAL PRODUCTION CATALYZED BY PROSTAGLANDIN H SYNTHASES... 

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-... 

It has already been mentioned earlier that similar to LOXs, prostaglandin H synthases can be activated or inhibited by reactive nitrogen species. Nitric oxide may exhibit the inhibitory [58,65,86,101 104] or stimulatory effects [105 110] on PGHSs. Inhibitory effects depend on the ability of nitric oxide to reduce the ferric enzyme to the inactive ferrous form, competition... 

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. 

The realization of the widespread occurrence of amino acid radicals in enzyme catalysis is recent and has been documented in several reviews (52-61). Among the catalytically essential redox-active amino acids glycyl [e.g., anaerobic class III ribonucleotide reductase (62) and pyruvate formate lyase (63-65)], tryptophanyl [e.g., cytochrome peroxidase (66-68)], cysteinyl [class I and II ribonucleotide reductase (60)], tyrosyl [e.g., class I ribonucleotide reductase (69-71), photosystem II (72, 73), prostaglandin H synthase (74-78)], and modified tyrosyl [e.g., cytochrome c oxidase (79, 80), galactose oxidase (81), glyoxal oxidase (82)] are the most prevalent. The redox potentials of these protein residues are well within the realm of those achievable by biological oxidants. These redox enzymes have emerged as a distinct class of proteins of considerable interest and research activity. 

FIGURE 4.22 Prostaglandin H synthase-mediated conversion of arachidonic acid to PGH2. 

Marnett LJ, Maddipati KR. Prostaglandin H synthase. In Everse J, Everse KE, Grisham MB, eds. Peroxidases in Chemistry and Biology. Boca Raton, FL CRC Press 1991 293-334. 

Parman T, Chen G, Wells PG. Free radical intermediates of phenytoin and related teratogens. Prostaglandin H synthase-catalyzed bioactivation, electron paramagnetic resonance spectrometry, and photochemical product analysis. J Biol Chem 1998 273(39) 25079-25088. 

Parman T, Wells PG. Embryonic prostaglandin H synthase-2 (PHS-2) expression and benzo[a]pyrene teratogenicity in PHS-2 knockout mice. FASEB J 2002 16(9) 1001-1009. 

Eling TE, Mason RP, Sivarajah K. The formation of aminopyrine cation radical by peroxidase activity of prostaglandin H synthase and subsequent reactions of the radical. J Biol Chem 1985 260(3) 1601—1607. 

PROLYL 3-HYDROXYLASE PROSTAGLANDIN H SYNTHASE PROTOCATECHUATE 3,4-DIOXYGENASE PROTOCATECHUATE 4,5-DIOXYGENASE... 

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