Essential fatty acids metabolic pathway

Linoleic acid and ot-linolenic acid are essential fatty acids and are the important fatty acids involved in the metabolic pathway of prostaglandin synthesis. 

Fig. (4). Metabolic pathway of essential fatty acids of the n-6 and n-3 series via elongation-desaturation steps.

Cunnane SC, Menard CR, Likhodii SS, Brenna JT, Crawford MA. Carbon recycling into de novo lipogenesis is a major pathway in neonatal metabolism of linoleate and a-linolenate. Prostaglandins Leukotrienes Essential Fatty Acids 1999 60 387. 

Fig. 1. Metabolic pathway of essential fatty acids. Recent evidence indicated that 22 6n-3 are produced by [l-oxidation of 24 6n-3, which is desaturated from 24 5n-3, after elongation from 22 5n-3. Very long-chain fatty acids in the box are found in the retina however, the metabolism and function is not known.

Once ingested, these essential fatty acids can be metabolized into longer, more unsaturated products (Holman, 1968). This process involves sequential desaturation (adding double bonds) and chain elongation (adding carbon atoms), as shown in Fig. 1. The important aspect of Fig. 1 is that the n-6 and n-3 families compete for the enzymes responsible for desaturation (Sinclair, 1993). The main metabolite of the n-6 series is arachidonic acid (20 4n-6, AA), whereas eicosapentaenoic acid (20 5n-3, EPA) and docosahexaenoic acid (22 6n-3, DHA) are the main metabolites ofthe n-3 series (Holman, 1968). The metabolic pathways leading to DHA are complicated by involving retroconversion from 24 6n-3 to 22 6n-3 (DHA) (Voss et al., 1991). 

The metabolic pathways for synthesis of n-6 and n-3 families of polyunsaturated fatty acids from the essential fatty acids, linoleic acid (LA) (18 2 [n-6]) and a-linolenic acid (18 3 [n-3]), respectively, are showninFig. 2. Conversion of LA to arachidonic acid (AA) occurs via A6 desaturation to yield y-linolenic acid (GLA), then an elongation step to produce dihomo-y-linolenic acid (DHGL A) and A5 desaturation, to form AA. The A6 and A5 microsomal desaturases have been reported to utilize both NADH and NADPH as cofactors in vitro (Brenner 1977). Whether there is a more stringent pyridine nucleotide requirement in vivo is not known with certainty. Desaturase activities are especially abundant in the liver. 

Many of the biological actions of essential fatty acids are the result of their metabolic products, the eicosanoids. These are oxidized derivatives of AA and include prostaglandins and thromboxanes that are formed via the cyclo-oxygenase (COX) pathway, as well as hydroxy fatty acids and leukotrienes that arise by means of the lipoxygenase pathway. Another series of AA-derived products, the epoxy fatty acids, are produced by the cytochrome P450 epoxygenase pathway. The AA that serves as precursor for these reactions... 

In earlier sections of this chapter we focused on the distribution and physical properties of CE and on several intra- and extracellular enzymes and proteins that mediate CE formation, hydrolysis, and transfer. We turn now to a discussion of the major pathways of CE metabolism in plasma, and in cells such as fibroblasts, steroid hormone-forming cells, macrophages, and hepatocytes. These pathways seem to be integrated in such a way as to effect not only the transport and storage of cholesterol, but possibly also the transport of essential fatty acids. It can be argued in addition that the pathways of CE metabolism in plasma and in tissues provide a critical mechanism for buffering the content of UC in cell membranes and maintaining cholesterol homeostasis in the body (see Chapter 2). 

An alcohol can react with phosphoric acid to produce a phosphate ester iphosphoester). When two phosphate groups are joined, the resulting bond is a phosphoric anhydride bond. These two functional groups are important to the structure and fimction o( adenosine triphosphate (ATP), the universal energy currency of all cells. Cellular enzymes can carry out a reaction between a thiol and a carboxylic acid to produce a thioester. This reaction is essential for the activation of acyl groups in carbohydrate and fatty acid metabolism. Coenz)une A is the most important thiol involved in these pathways. 

Fukao, T., G. D. Lopaschuk, and G. A. Mitchell. 2004. Pathways and control of ketone body metabolism On the fringes of lipid metabolism. Prostaglandins Leukotrienes and Essential Fatty Acids 70 243-251. 

Approaches other than the use of pharmacological inhibitors have also been tried. Dietary manipulations leading to essential fatty acid deficiency and various drug trials have led to inconclusive results. Cook and co-workers demonstrated decreased mortality from endotoxin shock in rats raised on an essential fatty acid-deficient diet ". Although the decreased mortality was associated with a failure of plasma TxB levels to rise after endotoxin, one cannot conclude that thromboxane was instrumental in causing this syndrome since arachidonic acid deficiency may affect other metabolic pathways and... 

An extremely important approach to blocking all arachidonate metabolism is the use of 5,8,11,14-eicosatetraynoic acid [19], This acetylenic analogue of arachidonate was first used to inhibit cyclooxygenase in 1970 and was replaced in 1971 by the non steroidal anti-inflammatory drugs. Later it returned to favor when it was realized that tetraynoic acid blocks the lipoxygenase pathways too. Consequently eico-satetraynoic acid treatment does not involve the complications involved in the use of either eicosapentaenoic acid or other essential fatty acids. 

Several aspects of eicosanoid metabolism and function, however, need urgent research. These include (a) the mechanism by which the relative proportions of the different eicosanoids are regulated (b) the significance of changes of dietary fatty acid composition for whole body eicosanoid production (c) the quantitative significance of the different pathways and sites of synthesis and (d) the quantitative relationships between the requirements for essential fatty acids, which are measured in grams and the daily production of eicosanoids, which is measured in micrograms. 

The 4-phosphopantetheine group of CoA is also utilized (for essentially the same purposes) in acyl carrier proteins (ACPs) involved in fatty acid biosynthesis (see Chapter 25). In acyl carrier proteins, the 4-phosphopantetheine is covalently linked to a serine hydroxyl group. Pantothenic acid is an essential factor for the metabolism of fat, protein, and carbohydrates in the tricarboxylic acid cycle and other pathways. In view of its universal importance in metabolism, it is surprising that pantothenic acid deficiencies are not a more serious problem in humans, but this vitamin is abundant in almost all foods, so that deficiencies are rarely observed. 

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