Arachidonic acid leukotrienes derived from

Lipoxygenases catalyse the regio-specific and stereoselective oxygenation of unsaturated fatty acids. The mammalian enzymes have been detected in human platelets, lung, kidney, testes and white blood cells. The leukotrienes, derived from the enzymatic action of the enzyme on arachidonic acid, have effects on neutrophil migration and aggregation, release of lysosomal enzymes, capillary permeability, induction of pain and smooth muscle contraction (Salmon, 1986). 

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). 

The fatty acid-like leukotrienes derived from the addition of glutathione to products of the lipoxygenase branch of the arachidonic cascade are closely associated with manifestations of asthma. Many compounds designed to antagonize leukotrienes at the receptor level incorporate long alkyl chains to mimic the leukotrienes backbone in addition to the sulfur-containing moieties that stand in for glutathione. The reaction... 

EIA enzyme immunoassay. See ELISA, eicosanoids A family of fatty acid mediators derived from arachidonic acid, and which includes prostaglandins, thromboxanes and leukotrienes. 

Enzymic lipid peroxidation reactions are a common reaction in mammalian cells as response to stress from outside. In contrast to plants mammalian cell membranes contain arachidonic acid instead of linolenic acid. The latter is known to generate by LPO processes physiological potent compounds prostaglandines, prostacyclines, thromboxanes and leukotrienes [221]. In addition a great number of other LPO products derived not only from arachidonic acid but also from linoleic acid have been detected in blood, especially low density lipoprotein (LDL) and tissue samples of humans [222-227]. These are increased especially in diseases combined with cell degradation [228], indicating that cell death in plant and mammalian cells is connected with a similar cascade of events. 

Mammals can add additional double bonds to unsaturated fatty acids in their diets. Their ability to make arachidonic acid from linoleic acid is one example (Figure 25.15). This fatty acid is the precursor for prostaglandins and other biologically active derivatives such as leukotrienes. Synthesis involves formation of a linoleoyl ester of CoA from dietary linoleic acid, followed by introduction of a double bond at the 6-position. The triply unsaturated product is then elongated (by malonyl-CoA with a decarboxylation step) to yield a 20-carbon fatty acid with double bonds at the 8-, 11-, and 14-positions. A second desaturation reaction at the 5-position followed by an acyl-CoA synthetase reaction (Chapter 24) liberates the product, a 20-carbon fatty acid with double bonds at the 5-, 8-, IT, and ITpositions. 

Eicosanoid (Section 27.4) A lipid derived biologically from 5,8.11,14-eicosatetraenoic acid, or arachidonic acid. Prostaglandins, thromboxanes and leukotrienes are examples. 

Figure 9.5 Prostaglandins (PG) and leukotrienes (LT) derived from arachidonic (n - 6) and eicosapentaenoic acid...

Fatty acid derivatives include a large and diverse group of compounds named eicosanoids, which includes thromboxanes, prostaglandins and leukotrienes, all of which are biochemically derived from arachidonic acid (a long-chain polyunsaturated fatty acid). 

Prostaglandins, thromboxane, and the leukotrienes are lipids that are collectively called eicosanoids, since they are all derived from the C20 fatty acid, arachidonic acid [eicosa (Gr.) = twenty]. Over the past twenty years, the eicosanoids have emerged as important molecules around which to target drug design and development. 

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.

Apart from histamine, leukotiienes liberated during inflammation are more powerful bronchoconstrictor and longer acting. Leukotrienes also increase bronchial mucus secretion and increase vascular permeability. All the leukotrienes are derived from 5-lipoxygenase pathway of arachidonic acid and are synthesized by a variety of inflammatory cells in the airways e.g. eosinophils, mast cells, basophils and macrophages. The LTB, exert many... 

Prostanoid mediators derived from arachidonic acid and sites of drug action. ASA, acetylsalicylic acid (aspirin) LT, leukotriene NSAID, nonsteroidal... 

Eicosanoids The eicosanoid hormones (prostaglandins, thromboxanes, and leukotrienes) are derived from the 20-carbon polyunsaturated fatty acid arachidonate. 

Arachidonic acid released from membrane phospholipids or other sources is metabolized by the LO pathway to the smooth muscle contractile and vasoactive leukotrienes (LT), LTC4, and LTD4, as well as to the potent chemoattractant LTB4. These molecules are intimately involved in inflammation, asthma, and allergy, as well as in other multiple physiological and pathological processes. For example, cirsiliol (3, 4, 5-trihydroxy-6,7-dimethoxyflavone) proved to be a potent inhibitor of 5-LO (IC50, 0.1 pM) derived from basophilic leukemia cells and peritoneal polymorphonuclear leukocytes. 

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