Synthases prostacyclin

Fig. 2. Interplay among superoxide anion, nitric oxide, and eicosanoids in high oxidative stress. The biological function of nitric oxide in target cells is influenced by the cellular redox state. In increased oxidative stress, which results in an oxidizing environment, NO readily form free radicals, including the highly reactive peroxynitrite (OONO ). Peroxynitrite can influence eicosanoid synthesis by interfering with different enzyme systems of the arachidonic acid cascade. Increased free radicals may also catalyze nonenzymic peroxidation of membrane PUFA (e.g., arachidonic acid), resulting in increased production of isoprostanes that possess potent vasoconstrictor activity. PLA, phospholipase NO, nitric oxide NOS, nitric oxide synthase NADPH oxidase, vascular NAD(P)H oxidase 02 , superoxide anion PUFA, polyunsaturated fatty acids EPA, eicosapentaenoic acid DHA, docosahexaenoic acid COX, cyclooxygenase PGI2 synthase, prostacyclin 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). 

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.)...

PGHS, prostaglandin endoperoxide H synthase PGI2, prostacycline synthase... 

Peroxynitrite reacts with heme proteins such as prostacycline synthase (PGI2), microperoxidase, and the heme thiolate protein P450 to form a ferryl nitrogen dioxide complex as an intermediate [120]. Peroxynitrite also reacts with acetaldehyde with the rate constant of 680 1 mol 1 s" 1 forming a hypothetical adduct, which is decomposed into acetate, formate, and methyl radicals [121]. The oxidation of NADH and NADPH by peroxynitrite most certainly occurs by free radical mechanism [122,123], Kirsch and de Groot [122] concluded that peroxynitrite oxidized NADH by a one-electron transfer mechanism to form NAD and superoxide ... 

Todaka T, Yokoyama C, Yanamoto H, Hashimoto N, Nagata I, Tsukahara T, Hara S, Hatae T, Morishita R, Aoki M, Ogihara T, Kaneda Y, Tanabe T (1999) Gene transfer of human prostacyclin synthase prevents neointimal formation after carotid balloon injury in rats. Stroke 30 419-426... 

Besides cholesterol efflux from arterial wall and its role in RCT, additional properties of HDL have been proposed for its protective anti-atherogenic activities. HDL protects vascular function by a number of potential alternative mechanisms, including inhibition of LDL oxidation [8,9], platelet aggregation and coagulation [10], and endothelial monocyte adhesion [11], as well as promotion of endothelial nitric oxide synthase (eNOS) [12], and prostacyclin synthesis [13-15]. The proposed alternate protective mechanisms for HDL are attractive but many of them lack validation under in vivo conditions. 

E. Spisni, C. Griffoni, S. Santi, M. Riccio, R. Maulli, G. Bartolini, M. Toni, V. Ullrich, and V. Tomasi. Colocalization prostacycline (PGI2) synthase - caveolin-1 in endothelial cells and new roles for PGI2 in angiogenesis. Exp. Cell Res. 266 31—43 (2001). 

Mehl M, Bidmon HJ, Hilbig H, ZiUes K, Dringen R, et al. 1999. Prostacyclin synthase is localized in rat, bovine and human neuronal brain cells. Neurosci Fett 271 187-190. 

Siegle I, Klein T, Zou MH, Fritz P, Komhoff M. 2000. Distribution and cellular localization of prostacyclin synthase in human brain. J Histochem Cytochem 48 631-641. 

Tone Y, Inoue H, Hara S, Yokoyama C, Hatae T, et al. 1997. The regional distribution and cellular localization of mRNA encoding rat prostacyclin synthase. Eur J Cell Biol... 

Poole EM, Bigler J, Whitton J, Sibert JG, Potter JD, Ulrich CM. (2006) Prostacyclin synthase and arachidonate 5-hpoxygenase polymorphisms and risk of colorectal polyps. Cancer Epidemiol Biomarkers Prev. 15, 502-508. 

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). 

Figure 10. Scheme illustrating the main locations and functional role of H3 receptors in the vessels. H3 receptors coupled with inhibitory G proteins (Gj) occur as prejunctional receptors in the adrenergic varicosities, where they negatively modulate noradrenaline (NA) release. Moreover, their activation in endothelial cells can induce muscle relaxation, by the release of inhibitory factors, such as nitric oxide (NO) and prostacyclin (PGI2). In some districts, excitatory H3 receptors were found in muscle cells and they mediate muscle contraction. MC = mast cell NOS = NO synthase COX = cyclooxygenase. 

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