Eicosanoid biosynthesis

Eicosanoid Biosynthesis Eicosanoids Exert Their Action Locally... 

Detailed accounts of the biosynthesis of the prostanoids have been pubUshed (14—17). Under normal circumstances arachidonic acid (AA) is the most abundant C-20 fatty acid m vivo (18—21) which accounts for the predominance of the prostanoids containing two double bonds eg, PGE2 (see Fig. 1). Prostanoids of the one and three series are biosynthesized from dihomo-S-linolenic and eicosapentaenoic acids, respectively. Concentrations ia human tissue of the one-series precursor, dihomo-S-linolenic acid, are about one-fourth those of AA (22) and the presence of PGE has been noted ia a variety of tissues (23). The biosynthesis of the two-series prostaglandins from AA is shown ia Eigure 1. These reactions make up a portion of what is known as the arachidonic acid cascade. Other Hpid products of the cascade iaclude the leukotrienes, lipoxins, and the hydroxyeicosatetraenoic acids (HETEs). Collectively, these substances are termed eicosanoids. 

The first step in the biosynthesis of eicosanoids from arachidonic acid is generally a lipoxygenation reaction. The resulting hydroperoxides (HPETE s) can undergo reduction to the corresponding alcohols (HETE s). Preparative routes to the 5-, 11-, and 15-HETE s and HPETE s have been developed as oudine below. 

We turn now to the biosynthesis of lipid structures. We begin with a discussion of the biosynthesis of fatty acids, stressing the basic pathways, additional means of elongation, mechanisms for the introduction of double bonds, and regulation of fatty acid synthesis. Sections then follow on the biosynthesis of glyc-erophospholipids, sphingolipids, eicosanoids, and cholesterol. The transport of lipids through the body in lipoprotein complexes is described, and the chapter closes with discussions of the biosynthesis of bile salts and steroid hormones. 

Compounds 111 having structural features of the dual cyclooxygenase (COX)/5-lipooxygenase (5-LO) inhibitor tepoxalin and the 5-LO inhibitor ABT-761 were prepared. Many of these hybrid compounds are potent COX and 5-LO inhibitors two compounds (111, r =McO, R = R" = R = H, R = NH2, R = Me and r = MeO, R = R = Me, R" = R = H, R = Cl) inhibited eicosanoid biosynthesis in an ex vivo assay, but neither improved on the main deficiency of tepoxalin, duration of 5-LO inhibitory activity (99BMCL979). Compounds 111 inhibit the production of arachidonic acid products associated with 5-lipoxygenase and cyclooxygenase and are useful in the treatment of inflammatory disorders (99USP5925769). 

The biosynthesis of eicosanoids utilizes several enzymes till the ultimate bioactive ligand is obtained. The literature is very rich in PAL studies on these enzymes and the local hormone receptors therefore only some major results on the key biotransformations and receptors are represented here. 

Srivastava KC. (1986). Isolation and effects of some ginger components of platelet aggregation and eicosanoid biosynthesis. Prostaglandins Leukot Med. 25(2-3) 187-98. 

Epoxide ring-opening with transfer of an sp carbon moiety was applied in a short synthesis [44] of eicosanoid 56 [45], relevant in marine prostanoid biosynthesis (Scheme 9.13). Homoallyl alcohol 55 was obtained in good yield from 54 by use of a cyano-Gilman alkenylcuprate [46]. 

Cyt P450 systems are also involved in many other metabolic processes—e.g., the biosynthesis of steroid hormones (see p. 172), bile acids (see p. 314), and eicosanoids (see p. 390), as well as the formation of unsaturated fatty acids (see p. 409). The liver s reddish-brown color is mainly due to the large amounts of P450 enzymes it contains. 

Biosynthesis. Almost all of the body s cells form eicosanoids. Membrane phospholipids that contain the polyunsaturated fatty acid arachidonic acid (20 4 see p.48) provide the starting material. 

Nicosia S, Patrona C. Eicosanoid biosynthesis and action novel opportunities for pharmacological intervention. EASEB J 1989 3 1941-8. 

A convenient approach to the synthesis of 2-aryl-4-alkyl-13 -triazino[l,2-ajbenzimidazoles 113 from 2-aminobenzimidazole has been reported <98IJC(B)1283>. New 8-cyanopyridothieno[l,23]triazines 114 as inhibitors of nitric oxide and eicosanoid biosynthesis have been described <99JMC4720>. Synthesis of pyridodithienotriazines 115, from dithienopyrimidine derivatives, and their antihistaminic and cytotoxic activities have been reported <98EJM887>. 

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.

In human being, arachidonic acid is the most important precursor for the biosynthesis of eicosanoids. Arachidonic acid is formed from linoleic acid in most mammalians by desaturation and carbon elongation to dihomog-linolenic acid and subsequent desaturation. 

Cells of the immune system contribute substantially to eicosanoid biosynthesis during an immune reaction. T and lymphocytes are not primary synthetic sources however, they may supply arachidonic acid to monocyte-macrophages for eicosanoid synthesis. In addition, there is evidence for eicosanoid-mediated cell-cell interaction by platelets, erythrocytes, leukocytes, and endothelial cells. 

We focus first on the pathway of fatty acid synthesis, then turn our attention to regulation of the pathway and to the biosynthesis of longer-chain fatty acids, unsaturated fatty acids, and their eicosanoid derivatives. 

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