Polyunsaturated fatty acids, chain elongation desaturation

Fig. 1. Three biosynthetic pathways for major polyunsaturated fatty acids in mammals (desaturation, chain-elongation and chain-shortening steps). The site of desaturase action is shown by A9, A6, or A5. The major polyunsaturated fatty acids found in tissue lipids are linoleic (LA), arachidonic (ARA), docosapentaenoic (DPA), a-linolenic (ALA), eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids. Fatty acids are designated by the carbon chains the number of double bonds, and the position of the first double bond from the methyl terminus, as n-9, n-7, n-6, or n-3. Typical foods enriched with the indicated fatty acids are also shown.

FIGURE 3-7 Pathways for the interconversion of brain fatty acids. Palmitic acid (16 0) is the main end product of brain fatty acid synthesis. It may then be elongated, desaturated, and/or P-oxidized to form different long chain fatty acids. The monoenes (18 1 A7, 18 1 A9, 24 1 A15) are the main unsaturated fatty acids formed de novo by A9 desaturation and chain elongation. As shown, the very long chain fatty acids are a-oxidized to form a-hydroxy and odd numbered fatty acids. The polyunsaturated fatty acids are formed mainly from exogenous dietary fatty acids, such as linoleic (18 2, n-6) and a-linoleic (18 2, n-3) acids by chain elongation and desaturation at A5 and A6, as shown. A A4 desaturase has also been proposed, but its existence has been questioned. Instead, it has been shown that unsaturation at the A4 position is effected by retroconversion i.e. A6 unsaturation in the endoplasmic reticulum, followed by one cycle of P-oxidation (-C2) in peroxisomes [11], This is illustrated in the biosynthesis of DHA (22 6, n-3) above. In severe essential fatty acid deficiency, the abnormal polyenes, such as 20 3, n-9 are also synthesized de novo to substitute for the normal polyunsaturated acids. 

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... 

Arachidonic acid (5,8,11,14-eicosatetraenoic acid), a polyunsaturated fatty acid derived from dietary sources or by desaturation and chain elongation of the essential fatty acid linoleic acid, is found widely in the body. It is transported in a protein-bound state and stored in the phospholipids of cell membranes in all tissues of the body [108] from where it can be changed into biologically... 

On the other hand, some fish are able to synthesize long-chain polyenoic fatty acids (Kayama et al., 1963) from shorter carbon chains. Docosohexaenoic acid is laid down in coho salmon in quantities related to the size of the fish, rather than to its availability in the diet (Tinsley et al., 1973). Rainbow trout fed on 18 2 and 18 3 fatty acids can produce 20 3, 22 5 and 22 6 fatty acids in substantial quantities (Owen et al., 1975), but these workers noticed that the capacity of marine flatfish to elongate or desaturate the carbon chains was more limited. They found that 70% of the radioactivity of labelled 18 3 appeared later in the 22 6 fatty acid of rainbow trout, but that turbot converted only 3-15% of labelled precursors into polyunsaturated fatty acids of longer chain length. It was suggested that turbot in the wild probably received adequate polyunsaturated acids in their diet, which the fish therefore did not need to modify. The elongation of the carbon chains and the creation of more double bonds is also only slight in Atlantic cod, another marine teleost, presumably for the same reason (Ross, 1977). 

Figure 2-2 The n-3 Family Polyunsaturated Fatty Acids Based on Linolenic Acid. The heavy arrows show the relationship between the most important n-3 acids through desaturation (vertical arrows) and chain elongation (horizontal arrows)...

An unusual sphingolipid contains a 22-carbon, polyunsaturated fatty acid called du-panodonic acid, or 7,10,13,16,19-docosapentaenoic acid. In mammals, both the mitochondrial and endoplasmic reticular acyl-chain elongation and desaturation systems can synthesize clupanodonate from linolenate. 

A common chemical property of polyunsatured fatty acids, which are needed to maintain animals in healthy condition, seems to be cis double bonds at the w6 and w9 positions [14]. Important essential fatty acids in the diet are linoleic (18 2w6) and a-linoleic (18 3w3) acids, which both occur in plants. In the mammalian organism, these fatty acids can be desaturated and elongated to form the derived essential fatty acids, dihomo-y-linolenic acid (20 3w6), arachidonic acid (20 4 6) and timnodonic acid (20 5to3), the three precursor acids of prostaglandins (Fig. 2, see also Fig. 11). The derived essential fatty acids can also be obtained in the diet. Arachidonic and dihomo-y-linolenic acids occur in animal tissues timnodonic acid in fish. The mammalian organism cannot introduce double bonds at the co3 and <06 positions of long-chain fatty acids, which partly explains why fatty acids of the w3 and w6 series must be provided in the diet (see refs. 15-18 for reviews). These fatty acids are also essential to man, however, deficiency states can only be induced by... 

Animals are unable to synthesize linoleate or lino-lenate, which are therefore essential and must be supplied by the diet. Animals can desaturate stearo-yl-CoA to oleoyl-CoA. Starting from linoleoyl-CoA, animals are able to produce a variety of polyunsaturated fatty acids by desaturation and chain elongation, including the prostaglandin precursor, arachidonate (Fig.6). 

Even when rats are raised on a fat free diet the liver lipids do not contain high levels of polyunsaturated fatty acids derived from palmitoleate. On the basis of structure this is somewhat surprising since the metabolites from 18 2 to 20 4 in the palmitoleate sequence differ from those in the linoleate sequence only in that the double bond is shifted one position closer to the carboxyl carbon. The rates of desaturation and chain elongation of acids in the palmitoleate sequence are shown in Figure 4,... 

Certain biochemical indices are available for determining the presence of either total EFA deficiency or -3 fatty acid deficiency. Linoleic, linolenic and oleic (18 l -9) acids compete for the same desaturation and elongation enzymes that convert these fatty acids to long chain polyunsaturated fatty acids (see Figure 2.3). The desaturases prefer co-3 over -6 over -9 fatty acids (Tinoco et al., 1979). Normally, with sufficient EFA in the diet, tissue levels of eicosatrienoic acid (20 3 -9) are very minor despite the abundance in tissues of its precursor, oleic acid. With total EFA deficiency, tissue levels of eicosatrienoic acid rise concomitant with decreased levels of AA. An increase in this triene/tetraene ratio (20 3 -9/20 4 -6) in blood and tissues is characteristic of total EFA deficiency, but not of -3 fatty acid deficiency (Holman et al., 1964). 

The polyunsaturated fatty acids of fish oils are often said to be -3 , since the most obvious components are 18 4/i-3, 20 5/j-3 and 22 6n-3. The corresponding popular usages for the latter two fatty acids are EPA for eicosapentaenoic and DHA for docosahexaenoic. At one time, it was accepted that these were all based on plant 18 3/i-3 and were formed by chain elongation and desaturation steps taking place in the hsh. Examina-... 

Fatty acid desaturation, a second major source of variation in the phylogenetic distribution of fatty acids, has been reviewed in detail (294-302). Some bacteria have a unique anaerobic system for production of monounsaturated fatty acids. This mechanism is involved in elongation of medium-chain length c/.r-3-unsaturated fatty acyl intermediates, and functions via P,y-dehydration of P-OH intermediates. It should be noted that this process cannot generate methylene-interrupted polyunsaturated fatty acids. 

The enzymatic reactions involved in the biosynthesis of arachidonic acid in mammalian cells are shown in Figure 2.1. As in the case with other polyunsaturated fatty acids, they consist of alternating steps of chain elongation (i.e., addition of an acetyl unit to the carboxyl-terminal end) and desaturation (i.e., formation of a new double bond). In mammals, linoleic acid is the ultimate precursor for arachidonic acid an essential fatty acid, linoleic acid cannot be synthesized and must be obtained from plants, in which it is usually very abundant. 

Polyunsaturated fatty acids are ultimately derived from plants, seed, leaves, and phytoplankton. Terrestrial food chains (i.e., edible plants and animal fat) contain primarily linoleic acid (Table 3, Fig. 2), an polyunsaturated fatty acid, and only very small amounts of cu-3 polyunsaturated fatty acids (nearly exclusively CK-linolenic acid). Fatty acids in land plants are not chain-elongated above the 18-carbon level. In mammalians, the polyunsaturated 18-carbon eu-6 linoleic acid will be converted to arachidonic acid (20 4, (o-6) by chain elongation and desaturation. As the three major families of unsaturated fatty acids (oleic acid, (o-9 linoleic acid, cu-6 and linolenic acid, cu-3) (Table 3) are metabolically nearly inconvertible in mammalians, phytoplankton and algae, which synthesize eicosapentaenoic acid (20 5, cu-3) and docosahexaenoic acid (22 6, cu-3), are the principal sources of the major cu-3 fatty acids. Only a-linolenic acid from vegetable oils is in principle able to be partially converted to eicosapentaenoic acid ([26] Fig. 2). 

The three major families of unsaturated fatty acids are those of oleic acid (n-9), linoleic acid (n-6) and hnolenic acid (n-3). Linoleic and linolenic acid, the 18-carbon essential fatty acids obtained from the diet, are converted through desaturation and elongation steps to the long-chain polyunsaturated fatty adds (PUFAs). The 20-carbon PUFAs, dihomogammalinoleni acid (DHGLA 20 3 n-6), arachidonic acid (AA 20 4 n-6) and eicosapentaenoic acid (EPA 20 5 n-3), derived from linolenic acid, are the precursors of the prostaglandin series 1,2 and 3, respectively. 

The more extensive formation of unsaturates (including longer-chain polyunsaturates) observed in cel could result from several factors. Substrates derived from the supplement may be more available for elongation and desaturation due to the limited flux of substrates formed de novo from the impaired fatty acid synthase. Alternatively, the regulation of 18 0 desaturation may differ in the cd mutant, to compensate for the normally more restricted conversion of exogenous 16 0 to 18.TA9. 

Once fatty acids have been made de novo they can either be modified by elongation (above), by desaturation or by other reactions. Desaturation usually takes place by an aerobic mechanism - an exception being in the E. coli fatty acid synthetase. Aerobic desaturases differ from each other by the nature of the acyl substrate they use, the type of reduced cofactor and the position at which the double bond is introduced into the acyl chain. Particularly notable are the desaturases which produce the polyunsaturated linoleic and a-linolenic acids. These enzymes use complex lipid substrates rather than acyl-thioesters. 

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