Polyunsaturated fatty acids leukotriene

Animal cells can modify arachidonic acid and other polyunsaturated fatty acids, in processes often involving cyclization and oxygenation, to produce so-called local hormones that (1) exert their effects at very low concentrations and (2) usually act near their sites of synthesis. These substances include the prostaglandins (PG) (Figure 25.27) as well as thromboxanes (Tx), leukotrienes, and other hydroxyeicosanoic acids. Thromboxanes, discovered in blood platelets (thrombocytes), are cyclic ethers (TxBg is actually a hemiacetal see Figure 25.27) with a hydroxyl group at C-15. 

Eicosanoids are formed from 20-carbon polyunsaturated fatty acids and make up an important group of physiologically and pharmacologically active compounds known as prostaglandins, thromboxanes, leukotrienes, and lipoxins. 

Dietary polyunsaturated fatty acids (PUFAs), especially the n-3 series that are found in marine fish oils, modulate a variety of normal and disease processes, and consequently affect human health. PUFAs are classified based on the position of double bonds in their lipid structure and include the n-3 and n-6 series. Dietary n-3 PUFAs include a-linolenic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) whereas the most common n-6 PUFAs are linoleic acid, y-linolenic acid, and arachidonic acid (AA). AA is the primary precursor of eicosanoids, which includes the prostaglandins, leukotrienes, and thromboxanes. Collectively, these AA-derived mediators can exert profound effects on immune and inflammatory processes. Mammals can neither synthesize n-3 and n-6 PUFAs nor convert one variety to the other as they do not possess the appropriate enzymes. PUFAs are required for membrane formation and function... 

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). 

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

Forms of prostaglandins (PG), thromboxanes (TX), and leukotrienes synthesized from n-6 and n-3 polyunsaturated fatty acids. [Note the positions of the first double bonds in the n-6 and the n-3 polyunsaturated fatty acids (red circles).]... 

When a diet is rich in polyunsaturated fatty acids, the inflammatory response and production of free radicals appear to be strengthened. Arachidonic acid is held responsible for this reaction, as it is used by lipoxygenases of the immune system cells to produce, via biochemical transformations, leukotrienes, compounds which function as mediators and perform an important function in the immune system (Szponar and Respondek 1998, Fimmel and Zouboulis 2005). 

Free radicals through lipid peroxidation can cause membrane damage, induce electrolyte imbalance and edema. Indeed, children with kwashiorkor display low levels of polyunsaturated fatty acids (e.g., linoleic acid) in the erythrocyte membrane compared to the marasmic children, presumably due to increased lipid peroxidation (Leichsenring et al., 1995). Interestingly, cysteinyl leukotrienes, which can cause edema by altering capillary permeability, are also enhanced in those with kwashiorkor but not marasmic children (Mayatepek et al., 1993). 

Lipoxygenases (LOs) are nonheme, mononuclear iron enzymes that catalyze the regio- and stereoselective conversion of polyunsaturated fatty acids with a di.di-1,4-diene functionality into products having a l-hydroperoxy-tra 5, cM-2,4-diene functionality. The mammalian LOs typically act on arachidonic acid and produce alkyl hydroperoxides that are converted into leukotrienes and lipoxins, which are involved as messengers in the inflammatory response. Plant enzymes act on linoleic acid, but the role of the product alkyl hydroperoxide is less well understood. 

Omega-3 fatty acids are long-chain polyunsaturated fatty acids. The parent fatty acid of this group is alpha-linolenic acid, an essential fatty acid that the body is unable to synthesize alpha-linolenic acid can be converted in the body to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). In animals and man, these acids reduce the production of several compounds that are involved in inflammation and thrombosis, such as eicosanoids (prostaglandins, thromboxanes, prostacyclin, and leukotrienes) and cytokines (interleukin II-l) (1). The extent of the conversion of alpha-linolenic acid to EPA and DHA is unclear. The conversion process appears to be inhibited by a high intake of linoleic acid, another essential fatty acid (2). In addition, alpha-linolenic acid is found in dark green vegetables and the oils of certain nuts and seeds, especially rape seeds and soya beans. 

Prostaglandins, thromboxanes, and leukotrienes are synthesized from 20-carbon polyunsaturated fatty acids (e.g., arachidonic acid) that are released from membrane phospholipids by phospholipase A2, which is inhibited by glucocorticoids and other steroidal anti-inflammatory agents. 

Figure 6-16. Prostaglandins, thromboxanes, and leukotrienes. For each of the classes of prostaglandins (H, E, F, A), the ring contains hydroxyl and keto groups at different positions. Only the ring portions of PGE2, PGF2ct, and PGA2 are shown. The remainder of the molecule (not shown) is the same as PGH2. The subscript refers to the number of double bonds in the nonring portion. The class with two double bonds is derived from arachido-nate. Other classes (with one or three double bonds) are derived from other polyunsaturated fatty acids.

Recently Liu and Weller [84] have reviewed the arachidonic acid metabolism in filarial parasites and other helminths. Arachidonic acid (AA) is a 20 carbon polyunsaturated fatty acid derived from dietary fatty acids. In human tissues, AA is usually present in the esterified form such as glycerolipids, phospholipids and neutral lipids. The free AA, released by phospholipases, undergoes various enzymatic oxygenations to form local mediators such as prostaglandins and leukotrienes, which are collectively known as eicosanoids (Chart 9). These eicosanoids are associated with platelet aggregation, vasodilation, leukocyte inflammatory and immune functions and cellular adhesion [85]. 

Arachidonate, an essential precursor of prostaglandins and other signal molecules, is derived from linoleate. This 20 4 polyunsaturated fatty acid is the precursor of several classes of signal molecules— prostaglandins, prostacyclins, thromboxanes, and leukotrienes— that act as messengers and local hormones because of their transience. They are called eicosanoids because they contain 20 carbon atoms. Aspirin (acetylsalicylate), an anti-inflammatory and antithrombotic drug, irreversibly blocks the synthesis of these eicosanoids. 

Sellmayer A, Danesh U, Weber PC. Modulation of the expression of early genes by polyunsaturated fatty acids. Prostagladins Leukotrienes Essential Fatty Acids 1997 57 353-357. 

Bourre JM, Bonneil M. Clement M, Dumont O, Durand G, Lafont H, et al. Function of dietary polyunsaturated fatty acids in the nervous system. Prostaglandins Leukotrienes Essential Fatty Acids 1993 48 5-15. Bridge EM, lob LV. The mechanism of the ketogenic diet in epilepsy. Bull Johns Hopkins Hosp 1931 ... 

Leaf A, Kang JX, Xiao Y-F, Billman GE, Voskuyl RA. Functional and electrophysiologic effects of polyunsaturated fatty acids on excitable tissues heart and brain. Prostaglandins Leukotrienes Essential Fatty Acids 1999 60 307-312. 

Eicosanoids Oxygenated lipid signaling molecules containing 20 carbons derived from polyunsaturated fatty acids released from membrane phospholipids by the action of phospholipase A. These include the prostanoids produced by the cyclooxygenase pathway and the leukotrienes produced by the lipoxygenase pathway. 

Abbreviations AA arachidonic acid AFA alpha-linolenic acid AP-1 activator protein 1 COX cyclooxygenase DFIA docosahexaenoic acid EPA eicosapentaenoic acid IF interleukin FA linoleic acid FOX lipoxygenase EPS lipopolysaccaride FT leukotriene NF-kB nuclear factor-kappa B, PG prostaglandin PPARs peroxisome proliferator-activated receptors PUFA polyunsaturated fatty acids, RvEl resolvin El, TNFa tumor necrosis factor alpha, TX thromboxane... 

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