Arachidonic acid, conversion prostaglandin

Fig. 35.8. Formation of prostaglandins (including the prostacyclin PGIj) and thromboxane TXAj from arachidonic acid. The conversion of arachidonic acid to PGHj is catalyzed by a membrane-bound enzyme, prostaglandin endoperoxide synthase, which has cyclooxygenase and peroxidase activities. The reducing agent is glutathione (GSH), which is oxidized to GSSG.

Free radicals are by-products of prostaglandin metabolism and may even regulate the activity of the arachidonate pathway. Arachidonic acid, released from lipids as a result of activation of phospholipases by tissue injury or by hormones, may be metabolized by the prostaglandin or leu-kotriene pathways. The peroxidase-catalysed conversion of prostaglandin G2 to prostaglandin H2 (unstable prostanoids) and the mechanism of hydroperoxy fatty acid to the hydroxy fatty acid conversion both yield oxygen radicals, which can be detected by e.s.r. (Rice-Evans et al., 1991). 

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

Cyclooxygenase converts arachidonic acid first to prostaglandin G (PGG) and then to PGH prior to formation of prostaglandins, thromboxanes and prostacyclins. The structures of the intermediates and some of the end-products of these conversions are provided in Figure 11.28. 

Lipoxygenases (LOX), cycloxygenases (COXs), and xanthine oxidase (XO) are metalloen-zymes whose catalytic cycle involves ROS such as lipid peroxyl radicals, superoxide, and hydrogen peroxide. LOXs and COXs catalyze important steps in the biosynthesis of leuco-trienes and prostaglandins from arachidonic acid, which is an important cascade in the development of inflammatory responses. XO catalyzes the ultimate step in purine biosynthesis, the conversion of xanthine into uric acid. XO inhibition is an important issue in the... 

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). 

The conversion of oleoyl-CoA to linoleoyl-CoA is accomplished by some insects118 but does not take place in most animals. As a result of this biosynthetic deficiency, polyunsaturated fatty acids such as linoleic, linolenic, and the C20 arachidonic acid are necessary in the diet (Box 21-B). One essential function of linoleic acid is to serve as a precursor of prostaglandins and related prostanoids (Section D). Dietary linoleate is converted to its Co A derivative and then by sequential A6 desaturation,119 elongation, and then A5 desaturation, to the 20 4 (A5 8 11 14) arachidonoyl-CoA (Fig. 21-2, lower right). These acids are referred to as 0)6 because of the position of the last double bond. Linolenic acid can be converted in an analogous fashion to the CoA derivative of the 20 5 (A5 8 11 14 17 co6) eicosapentaenoic acid (EPA). The 22 6 docasahexaenoic acid (DHA Fig. 21-2) is apparently formed by elongation of the 22 5 acyl-CoA to 24 5, desaturation, transfer to a peroxisome or mitochondrion, and p oxidation to shorten the chain.953... 

Although the arylpropionic acids contain a stereogenic center they are generally marketed as racemic mixtures. The only exception is naproxen, which is marketed as its (S)-enantiomer. NSAIDs produce their antiinflammatory effects by inhibiting cyclooxygenase (COX), the enzyme which catalyzes the first transformation in the biosynthetic conversion of arachidonic acid to the 20 carbon prostaglandins. 

Another group of compounds that are chemically related to the prostaglandins are the leukotrienes. These compounds are also derived from arachidonic acid and are linear oxidation products found in leukocytes (white blood cells). Leukotrienes are distinguished by containing a conjugated triene double-bond arrangement. The conversion of arachidonic acid to leukotrienes is as shown in Fig. 13-19. 

Lipoxygenase is the first enzyme in a series involved in the conversion of arachidonic acid to the family of leukotrienes. The inhibition of this enzyme therefore decreases leukotriene production without adversely influencing cyclooxygenase-based prostaglandin production [94],... 

---