Biosynthesis of Fatty Acids and Eicosanoids:- Eicosanoids Are Formed from 20-Carbon Polyunsaturated Fatty Acids
Eicosanoids are a family of very potent biological signaling molecules that act as short-range messengers, affecting tissues near the cells that produce them. In response to hormonal or other stimuli, phospholipase A2, present in most types of mammalian cells, attacks mem brane phospholipids, releasing arachidonate from the middle carbon of glycerol. Enzymes of the smooth ER then convert arachidonate to prostaglandins, beginning with the formation of prostaglandin H2 (PGH2), the immediate precursor of many other prostaglandins and of thromboxanes (Fig. 21–15a). The two reactions that lead to PGH2 are catalyzed by a bifunctional enzyme, cyclooxygenase (COX), also called prostaglandin H2 synthase. In the first of two steps, the cyclooxygenase activity introduces molecular oxygen to convert arachidonate to PGG2. The second step, catalyzed by the peroxidase activity of COX, converts PGG2 to PGH2. Aspirin (acetylsalicylate; Fig. 21–15b) irreversibly inactivates the cyclooxygenase activity of COX by acetylating a Ser residue and blocking the enzyme’s active site, thus inhibiting the synthesis of prostaglandins and thromboxanes. Ibuprofen, a widely used nonsteroidal antiinflammatory drug (NSAID; Fig. 21–15c), inhibits the same enzyme. The recent discovery that there are two isozymes of COX has led to the development of more precisely targeted NSAIDs with fewer undesirable side effects (Box 21–2). Thromboxane synthase, present in blood platelets (thrombocytes), converts PGH2 to thromboxane A2, from which other thromboxanes are derived (Fig. 21–15a). Thromboxanes induce constriction of blood vessels and platelet aggregation, early steps in blood clotting. Low doses of aspirin, taken regularly, re duce the probability of heart attacks and strokes by reducing thromboxane production.
Thromboxanes, like prostaglandins, contain a ring of five or six atoms; the pathway from arachidonate to these two classes of compounds is sometimes called the “cyclic” pathway, to distinguish it from the “linear” path way that leads from arachidonate to the leukotrienes, which are linear compounds (Fig. 21–16). Leukotriene synthesis begins with the action of several lipoxygenases that catalyze the incorporation of molecular oxygen into arachidonate. These enzymes, found in leukocytes and in heart, brain, lung, and spleen, are mixed-function oxidases that use cytochrome P-450 (Box 21–1). The various leukotrienes differ in the position of the peroxide group introduced by the lipoxygenases. This linear path way from arachidonate, unlike the cyclic pathway, is not inhibited by aspirin or other NSAIDs. Plants also derive important signaling molecules from fatty acids. As in animals, a key step in the initiation of signaling involves activation of a specific phospholipase. In plants, the fatty acid substrate that is released is -linolenate. A lipoxygenase then catalyzes the first step in a pathway that converts linolenate to jasmonate, a substance known to have signaling roles in insect defense, resistance to fungal pathogens, and pollen maturation. Jasmonate (see Fig. 12–28) also affects seed germination, root growth, and fruit and seed development.
FIGURE 21–15 The “cyclic” pathway from arachidonate to prostaglandins and thromboxanes. (a) After arachidonate is released from phospholipids by the action of phospholipase A2, the cyclooxygenase and peroxidase activities of COX (also called prostaglandin H2 synthase) catalyze the production of PGH2, the precursor of other prostaglandins and thromboxanes. (b) Aspirin inhibits the first reaction by acetylating an essential Ser residue on the enzyme. (c) Ibuprofen and naproxen inhibit the same step, probably by mimicking the structure of the substrate or an intermediate in the reaction.
