Prostaglandins enzymic formation

More than 50 years ago a compound was discovered in the seminal fluid and in the prostate which caused contraction of smooth muscle cells [12]. Although the chemical structure of this factor remained unclear for many years, it was named prostaglandin because of its organ source. Since then the chemical structures of a variety of prostanoids have been identified, and we also know that the prostate is not the only, and not even the major, source of prostaglandin (PG) formation. Moreover, most enzymes involved in prostaglandin biosynthesis have been well characterized. 

The widely used platelet inhibitor aspirin or acetylsalicylic acid, by acetylating the enzyme cyclooxygenase, inhibits platelet function by preventing the formation of thromboxane A2 and the synthesis of prostaglandin I2 (PGI2) (68). Aspirin has been used in combination with other antiplatelet agents such as ticlopidine, which inhibits ADP-induced platelet aggregation (69). 

Enzyme systems produce prostaglandins these are substances involved with formation of platelet plugs as well as limitation of clot growth. 

Recently, Gunther et al. [41] proposed that nitric oxide may directly react with enzymes without intermediate formation of peroxynitrite. It is known that the oxidation of arachido-nic acid by prostaglandin H oxidase is mediated by the formation of enzyme tyrosyl radical (see Chapter 26). Correspondingly, it has been suggested that NO is able to react with this radical to form the tyrosine iminoxyl radical and then nitrotyrosine. Therefore, the NO-dependent nitration of protein tyrosine residue may occur without the formation of peroxynitrite or other nitrogen oxides. 

Dietary polyunsaturated fatty acids (PUFAs), especially the n-3 series that are found in marine fish oils, modulate a variety of normal and disease processes, and consequently affect human health. PUFAs are classified based on the position of double bonds in their lipid structure and include the n-3 and n-6 series. Dietary n-3 PUFAs include a-linolenic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) whereas the most common n-6 PUFAs are linoleic acid, y-linolenic acid, and arachidonic acid (AA). AA is the primary precursor of eicosanoids, which includes the prostaglandins, leukotrienes, and thromboxanes. Collectively, these AA-derived mediators can exert profound effects on immune and inflammatory processes. Mammals can neither synthesize n-3 and n-6 PUFAs nor convert one variety to the other as they do not possess the appropriate enzymes. PUFAs are required for membrane formation and function... 

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. 

An irreversible enzyme inhibitor of clinical value is aspirin, which inhibits cyclooxygenase and dierefore prostaglandin formation (Chapter 11). 

Bradykinin is a small peptide that is released from a precursor, kininogen, by the action of the proteolytic enzyme kallikrein, which itself is formed from a precursor, prekallikrein, by the action of the blood clotting factor, Xlla (Figure 17.4). Bradykinin is responsible for the pain, vasodilation and increased permeability of the blood vessels by stimulating formation and release of prostaglandins and prostacyclins from the endothelial cells (see Chapter 11). 

The cells in the hypothalamus that control body temperature respond to the cytokines by stimulating the activity of the membrane bound phospholipase, which results in the formation of arachidonic acid, the substrate for the enzyme cyclooxygenase-2 (COX-2) which is the rate-limiting step in the pathway for synthesis of prostaglandins. Prostaglandins influence cells in the hypothalamus that are responsible for temperature regulation. 

The discovery that a subtype cycloxygenase enzyme, COX-2, does not inhibit the formation of stomach-protecting prostaglandins paved the way for a series of NSAIDS whose stracmres depart markedly from the carboxylic acid-based drugs... 

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