Biosynthesis of eicosanoids

The essential individual steps are the following First, arachidonic acid bonds ionically to arginine-120 of prostaglandin-H2-synthase. The oxoiron(IV)-por-phyrin complex abstracts a hydrogen radical from tyrosine-385. This then cleaves off, regio- and stereo-selectively, the allylic (13-pro-S)-hydrogen atom of arachidonic acid, and thereby initiates the cycloaddition with oxygen. In the reaction centre of the hydroperoxidase, the hydroperoxide is then reduced to the alcohol in a second step (Fig. 5.97). [216] 

PGH2 is the key compound, from which the type-2 prostaglandins, prostacyclin and the thromboxanes are eventually generated by ring-opening of the endo-peroxide. 

A linear biosynthetic route, which is not influenced by acetylsalicylic acid, leads by means of lipoxygenase via a simple addition of oxygen to an epoxide, which is transformed by addition of water or glutathione into the various leukotrienes. 

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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. 

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. 

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. 

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. 

Inflammation is now recognized as a key process in atherogenesis [Libby, 2002]. The potential for dietary flavonoids to inhibit inflammatory activities is of particular interest. A potential anti-inflammatory feature of the flavonoids is the ability to inhibit the biosynthesis of eicosanoids. Selected phenolic acids and some flavonoids have been shown to inhibit both cyclooxygenase (COX) and 5-lipoxygenase (5-LO) pathways [Nijveldt et al., 2001 Takano-Ishikawa et al., 2006], Epicatechin and related flavonoids have been shown to inhibit the synthesis of pro-inflammatory cytokines in vitro [Sanbongi et al., 1997], and plasma metabolites of catechin and quercetin inhibit the adhesion of monocytes to cultured endothelial cells [Koga and Meydani, 2001]. Silymarin has been shown to inhibit the production of inflammatory cytokines, such as interleukin-1, interferon-, and tumor necrosis factor-a (TNFa), from macrophages and T-cells [Matsuda et al., 2005], Some flavonoids can inhibit neutrophil... 

Studying the biosynthesis of eicosanoids has led to other discoveries as well. For example, aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) inactivate the cyclooxygenase enzyme needed for prostaglandin synthesis. In this way, NSAIDs block the synthesis of the prostaglandins that cause inflammation (Section 19.6). 

The rate-limiting step in the biosynthesis of eicosanoids is the availabiUty of free precursor, unesterified AA (20 4, o)-6), for both cyclooxygenase (COX) and lipoxygenase en2ymes (13). The initial mobilization cellular AA (20 4, (0-6) is an essential step in the synthesis of eicosanoids (14, 15). Cellular AA is known to be exclusively associated with membrane phospholipids (16-18). It is also tigfrtly regulated through enzymes of the Lands cycle. The enzymes such as phospholipase Aj, arachidonoyl-CoA synthetase and lysophosphatidyl acyltransferases appear to be simultaneously active in order to maintain a steady turnover of AA (20 4, -6) (19). Platelets contain arachidonoyl CoA synthetase (20). 

Gryglewski, R.J. (1998) TransceUular Biosynthesis of Eicosanoids in Circulation, in Essential Fatty Acids and Eicosanoids Invited Papers from the Fourth International Conference (Riemersma, R.A., Armstrong, R., Kelly, R.W., Wilson, R., eds.) pp. 202-205, AOCS Press, Champaign, IL. 

Section 1 - Enzymes and factors involved in the biosynthesis of eicosanoids... 

This section deals primarily with the mechanisms of biosynthesis of eicosanoids and related compounds, in particular the nature of the enzymes and other factors involved. The first chapter briefly surveys the biosynthetic routes involved and the structure of the compounds produced. The proceedii chapters each deal with the diversity and evolution of cyclooxygenases, lipoxygenases and 5-lipoxygenaseactivating protein (FLAP). Each author was given a brief to produce a timely review of their particular subject, avoiding repetition of those areas already reviewed elsewhere. 

Biosynthesis of biologically active oxygenated derivatives of Cjg fatty adds in plants that are known as octadecanoids proceeds by similar mechanisms to the biosynthesis of eicosanoids (such as prostaglandins) in animals. The action of phospholipase Ap which hydrolyses linolenic acid in the membrane phospholipids and 13-hpoxygenase, which oxidises this acid, yields intermediates such as (9Z,llE,13S,15Z)-13-hydroperoxyoctadeca-... 

In addition, in vivo C MR spectroscopy has been applied to the study of adipose tissue composition in disease. Children with cystic fibrosis were shown to have lower levels of polyunsaturated adipose tissue fatty acids than healthy children, possibly owing to a disorder in essential fatty acid metabolism that may be partly responsible for the development of the disease. Further studies with in vivo MRS in disease have shown a significant increase in saturated adipose tissue fatty acids following transplantation and subsequent weight gain in malnourished patients with liver cirrhosis. It was suggested that this increase in saturated fatty acids may be secondary to a general repletion of membrane polyunsaturated fatty acids or the use of essential fatty acids for biosynthesis of eicosanoids in the postoperative period. 

Essential fatty acids and the biosynthesis of eicosanoids 103 = /= " COOH... 

In section 3.4 we described the biosynthesis of eicosanoids from polyunsaturated fatty acids of the n-3 and n-6 families and indicated in section 3.4.8 that the balance of eicosanoids produced was important in, for example, maintaining normal vascular function. Several studies have demonstrated that altering the amounts and types of n-6 and n-3 fatty acids in the diet can influence the spectrum of eicosanoids produced. For example, substitution of fish oils in which n-3 polyunsaturated fatty acids predominate for diets in which linoleic acid (n-6) is the main polyunsaturated fatty acid (as typified by the UK diet) results in changes in plasma and platelet fatty acid profiles from arachidonic to eicoasapentaenoic acid as the predominant polyunsaturated fatty acid and a reduction in the formation by platelets of thromboxane A2, an eicosanoid that stimulates their aggregation (Table 5.7). 

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