Eicosanoids phospholipases

Phospholipases other than phospholipase C are also stimulated by G proteins. Arachidonic acid, released from phosphatidylcholine, is the major metabolic precursor to eicosanoids. Phospholipase A2, which releases fatty acids from glycerophospholipids, also interacts with G proteins, and phospholipase D (see here) is thought to participate in signal transduction via diacylglycerol formation. In addition, some phospholipases are controlled by Ca. ... 

See also Eicosanoids, Phospholipases, Phosphatidylcholine, Phosphatidylethanolamine, Phosphatidylinositol, PGH Synthase, Ibuprofen... 

Eicosanoids, so named because they are all derived from 20-carbon fatty acids, are ubiquitous breakdown products of phospholipids. In response to appropriate stimuli, cells activate the breakdown of selected phospholipids (Figure 25.27). Phospholipase Ag (Chapter 8) selectively cleaves fatty acids from the C-2 position of phospholipids. Often these are unsaturated fatty acids, among which is arachidonic acid. Arachidonic acid may also be released from phospholipids by the combined actions of phospholipase C (which yields diacyl-glycerols) and diacylglycerol lipase (which releases fatty acids). 

There are three groups of eicosanoids that are synthesized from C20 eicosanoic acids derived from the essential fatty acids linoleate and a-linolenate, or directly from dietary arachidonate and eicosapentaenoate (Figure 23-5). Arachidonate, usually derived from the 2 position of phospholipids in the plasma membrane by the action of phospholipase Aj (Figure 24-6)—but also from the diet—is the substrate for the synthesis of the PG2, 1X2 series (prostanoids) by the cyclooxygenase pathway, or the LT4 and LX4 series by the lipoxygenase pathway, with the two pathways competing for the arachidonate substrate (Figure 23-5). 

Recknagel, R.O. and Glende, E.A. (1992). Calcium, phospholipase Az and eicosanoids in toxigenic liver cell injury. In Free Radicals and Liver (eds. G. Csomos and J. Feher) pp. 43-62. Springer-Verlag, Berlin. 

Chronic changes in the type of fat in the diet can change the type of polyunsaturated fatty acids in the phospholipids that are components of membranes and hence change fluidity of the membrane. This might change the activity of the phospholipase and/or the type of eicosanoid produced from... 

Figure 11.30 Mechanisms of regulation of phospholipase A2. In all these processes described above, it is phospholipase A that carries out the hydrolysis of membrane phospholipid. Cytokines are local hormones produced by immune cells, T-lymphocytes and macrophages (Chapter 17). Other factors relate to shear stress in endothelial cells and those that stimulate release of granules from mast cells. Eicosanoids are present in the granules and they must be re-synthesised after degranulation in the mast cells. Here the enzymes described above must be present in mast cells.

The eicosanoids, so called because of their derivation from a 20-carbon unsaturated fatty acid, arachidonic acid (eicosatetraenoic acid), are obtained from membrane phospholipids and synthesized de novo at the time of cellular stimulation. Arachidonic acid is cleaved from membrane-bound phosphatidylcholine by the enzyme phospholipase A2. Alternatively, arachidonic acid may be derived by the sequential actions of phospholipase C and diacylglyceryl lipase. Arachidonic acid can then follow either of two enzymatic pathways that result in the production of inflammatory mediators. The pathway initiated by cyclooxygenase (COX) produces prostaglandins the lipoxygenase pathway generates leukotrienes (Fig. 36.2). 

Metabolites of arachidonic acid, including prostaglandins (PG), thromboxanes, and leukotrienes, are considered strong candidates as mediators of the inflammatory process. Steroids may exert a primary effect at the inflammatory site by inducing the synthesis of a group of proteins called lipocortins. These proteins suppress the activation of phospholipase A2, thereby decreasing the release of arachidonic acid and the production of proinflammatory eicosanoids (Fig. 60.6). 

Figure 8.9 Prostaglandins and leukotrienes are potent eicosanoid lipid mediators, derived from phospholipase-released arachidonic acids, that are involved in numerous homeostatic biological functions and inflammation. They are generated by cyclooxygenase isozymes and 5-lipoxygenase, respectively, and their biosynthesis and pharmacological actions are inhibited by clinically relevant nonsteroidal anti-inflammatory drugs.

Corticosteroids block all the known pathways of eicosanoid synthesis, perhaps in part by stimulating the synthesis of several inhibitory proteins collectively called annexins or lipocortins. They inhibit phospholipase A2 activity, probably by interfering with... 

T FIGURE 10-18 Arachidonic acid and some eicosanoid derivatives. (a) In response to hormonal signals, phospholipase A2 cleaves arachidonic acid-containing membrane phospholipids to release arachidonic acid (arachidonate at pH 7), the precursor to various eicosanoids. (b) These compounds include prostaglandins such as PCE, in which C-8 and C-12 of arachidonate are joined to form the characteristic five-membered ring. In thromboxane A2/ the C-8 and... 

The dietary precursor of the eicosanoids is the essential fatty acid, linoleic acid. It is elongated and desaturated to arachidonic acid, the immediate precursor of prostaglandins, which is stored in the membrane as a component of a phospholipid—generally phosphatidyl-inositol (PI). Arachidonic acid is released from PI by phospholipase A2. 

Arachidonic acid is not present in significant amounts in tissues as the free acid but is stored as a fatty acid at the sn-2 position of phospholipids. Prostaglandin biosynthesis is initiated by the interaction of a stimulus with the cell surface. Depending on the cell type, the stimulus can take the form of a hormone, such as angiotensin II or antidiuretic hormone, or a protease such as thrombin (involved in blood clotting), or both hormone and protease. These agents bind to a specific receptor that activates a phospholipase A2 that specifically releases the arachidonic acid from a phospholipid such as phosphatidylcholine. The release of arachidonic acid by phospholipase A2 is believed to be the rate-limiting step for the biosynthesis of eicosanoids. 

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