Eicosanoid Synthesis

The fatty acid 20:4n-6 (arachidonic acid) is the precursor of most eicosanoids, which include the pros-taglandins, leukotrienes, and thromboxanes. Because it is an n-6 fatty acid, 20:4 must be derived from dietary lipids or synthesized by elongation and unsaturation of the essential fatty acid 18:2n-6. As with other fatty acids, cellular concentrations of unesterified 20:4 are low. Conversion of 20:4 to eicosanoids begins with an agonist-induced release of the fatty acid from the sn-2 position of membrane phospholipids via the action of phospholipase A2. Unlike most reactions of fatty acids, eicosanoid synthesis appears to use free 20:4 rather than its CoA derivative as the substrate. Cyclooxygenases (COX1 and COX2) catalyze a complex molecular oxygen-requiring reaction that converts 20:4 to prostaglandin G2. This reaction involves carbon atoms in the middle of the acyl chain, rather than the methyl carbon (such as occurs in !-oxidation) or the carboxyl carbon (such as occurs in nearly all other reactions of fatty acids). Prostaglandin G2 can subsequently be converted to other prostaglandins or to thromboxanes. As these compounds have potent biological effects, including mediation of inflammation, COX inhibitors are an important class of anti-inflammatory drugs. Free 20:4 is also the primary substrate for the enzyme 5-lipoxygen-ase, which is the first step in the synthesis of leukotrienes.

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