Arachidonic acid double bond positioning

Because the 12,15-diene has a 1,4-diene system, it oxidizes like linoleate to form two conjugated dienoic 12- and 16-hydroperoxides. However, in contrast to linoleate, the external 16-hydroperoxide is formed at a higher concentration than the internal 12-hydroperoxide, (with normalized concentrations of 58% and 42%) (Figure 2.12). Therefore, both the 9,15- and 12,15-dienes produce allylic radicals in which the terminal carbons 16 and 17, closest to the end of the fatty acid chain, are the most reactive with oxygen. The same preference of oxygen attack at the terminal double bond position is also observed in other polyunsaturated fatty acids with n-3 double bonds (linolenate, eicosapentaenoic and docosahexaenoic acids), and n-6 double bonds (arachidonic acid). Volatile decomposition products derived from hydroperoxides containing an n-3 double bond are particularly significant for their impact on flavor (Chapter 4). 

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. 

FIGURE 25.15 Arachidonic acid is synthesized from linoleic acid in enkaryotes. This is the only means by which animals can synthesize fatty acids with double bonds at positions beyond C-9. 

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... 

The omega (<0) numbering system is also used for unsaturated fatty acids. The co-family describes the position of the last double bond relative to the end of the chain. The omega designation identifies the major precursor fatty add, e.g., arachidonic add is formed from linoleic acid (co-6 family). Arachidonic acid is itself an important precursor for prostaglandins, thromboxanes, and leukotrienes. 

Arachidonic acid, illustrating position of double bonds. 

Lecithins and related phospholipids usually contain a saturated fatty acid in the C-l position but an unsaturated acid, which may contain from one to four double bonds, at C-2. Arachidonic acid is often present here. Hydrolysis of the ester linkage at C-2 yields a l-acyl-3-phosphoglycerol, better known as a Iysophosphatidylcholine. The name comes from the powerful detergent action of these substances which leads to lysis of cells. Some snake venoms contain phospholipases that form Iysophosphatidylcholine. Lysophosphatidic acid (l-acyl-glycerol-3-phosphate) is both an intermediate in phospholipid biosynthesis (Chapter 21) and also a signaling molecule released into the bloodstream by activated platelets.15... 

The conversion of oleoyl-CoA to linoleoyl-CoA is accomplished by some insects118 but does not take place in most animals. As a result of this biosynthetic deficiency, polyunsaturated fatty acids such as linoleic, linolenic, and the C20 arachidonic acid are necessary in the diet (Box 21-B). One essential function of linoleic acid is to serve as a precursor of prostaglandins and related prostanoids (Section D). Dietary linoleate is converted to its Co A derivative and then by sequential A6 desaturation,119 elongation, and then A5 desaturation, to the 20 4 (A5 8 11 14) arachidonoyl-CoA (Fig. 21-2, lower right). These acids are referred to as 0)6 because of the position of the last double bond. Linolenic acid can be converted in an analogous fashion to the CoA derivative of the 20 5 (A5 8 11 14 17 co6) eicosapentaenoic acid (EPA). The 22 6 docasahexaenoic acid (DHA Fig. 21-2) is apparently formed by elongation of the 22 5 acyl-CoA to 24 5, desaturation, transfer to a peroxisome or mitochondrion, and p oxidation to shorten the chain.953... 

Enzyme complexes occur in the endoplasmic reticulum of animal cells that desaturate at A5 if there is a double bond at the A8 position, or at A6 if there is a double bond at the A9 position. These enzymes are different from each other and from the A9-desaturase discussed in the previous section, but the A5 and A6 desaturases do appear to utilize the same cytochrome b5 reductase and cytochrome b5 mentioned previously. Also present in the endoplasmic reticulum are enzymes that elongate saturated and unsaturated fatty acids by two carbons. As in the biosynthesis of palmitic acid, the fatty acid elongation system uses malonyl-CoA as a donor of the two-carbon unit. A combination of the desaturation and elongation enzymes allows for the biosynthesis of arachidonic acid and docosahexaenoic acid in the mammalian liver. As an example, the pathway by which linoleic acid is converted to arachidonic acid is shown in figure 18.17. Interestingly, cats are unable to synthesize arachidonic acid from linoleic acid. This may be why cats are carnivores and depend on other animals to make arachidonic acid for them. Also note that the elongation system in the endoplasmic reticulum is important for the conversion of palmitoyl-CoA to stearoyl-CoA. 

Nomenclature Fatty acids are named according to the number of carbon atoms in the chain and the number and position of any double bonds. Some of the more common fatty acids are palmitate (06 0), stearate (08 0), oleate (08 1), linoleate (08 2), linolenate (08 3) and arachidonate (C20 4). The double bonds in a fatty acid are usually in the cis configuration. 

The products obtained from the co-6 fatty acids (linoleic acid, y-linolenic acid, and arachidonic acid) by in vivo reactions with strain ALA2 contain diepoxy bicyclic structures, tetrahydrofuranyl rings, and/or trihydroxy groups in their molecules. In contrast to these co-6 PUFAs, substrates classified as co-3 PUFAs (a-linolenic acid, EPA, and DHA) are only converted to hydroxyl THFAs by strain ALA2 with no diepoxy bicyclic or trihydroxy derivatives uncovered to date. Both the hydroxyl groups and cyclic structures derived there from appear to be placed at the same positions on the substrates from the co-carbon termini within each PUFA class, despite differences in carbon chain length and the number of double bonds in the specific PUFA substrates. 

Cyclization requires the presence of a c/i-double bond homoallylic to a hydroperoxide (230, 269), as shown in Reaction 45. In addition, cyclization of peroxyl radicals at internal positions is considerably faster than secondary oxidations of hydroperoxides at either external position. About 25% of peroxyl radicals in lino-lenic acid and 33% of peroxyl radicals in arachidonic acid are internal (Table 4). Thus, linolenic and arachidonic acids are particularly prone to formation of cyclic peroxides. These factors together make intramolecular cyclization 4—6 fold faster than p-scission in higher polyunsaturated fatty acids (247). 

Polyunsaturated fatty acids containing 20 carbons and three to five double bonds (e.g., arachidonic acid) are usually esterified to position 2 of the glycerol moiety of phospholipids in cell membranes. These fatty acids may require dietary linoleic acid (18 2,A9 12), an essential fatty acid, for their synthesis. 

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