Polyunsaturated desaturation

Organisms differ with respect to formation, processing, and utilization of polyunsaturated fatty acids. E. coli, for example, does not have any polyunsaturated fatty acids. Eukaryotes do synthesize a variety of polyunsaturated fatty acids, certain organisms more than others. For example, plants manufacture double bonds between the A and the methyl end of the chain, but mammals cannot. Plants readily desaturate oleic acid at the 12-position (to give linoleic acid) or at both the 12- and 15-positions (producing linolenic acid). Mammals require polyunsaturated fatty acids, but must acquire them in their diet. As such, they are referred to as essential fatty acids. On the other hand, mammals can introduce double bonds between the double bond at the 8- or 9-posi-tion and the carboxyl group. Enzyme complexes in the endoplasmic reticulum desaturate the 5-position, provided a double bond exists at the 8-position, and form a double bond at the 6-position if one already exists at the 9-position. Thus, oleate can be unsaturated at the 6,7-position to give an 18 2 d5-A ,A fatty acid. 

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. 

Particularly in the metabolism of the polyunsaturated fatty acids, the process of elongation occurs in sequence with desaturation to produce the specific acids required by the tissues in the body. 

Although these are termed essential fatty acids, they are, in fact, precursors for the major polyunsaturated fatty acids that have essential roles in the body but are present only in small amounts in the diet. Linoleic acid is converted, via elongation and desaturation reactions, to dihomo-y-linolenic (20 3n-6) and then to arachidonic (20 4n-6) acid. a-Linolenic is converted to eicosapentaenoic (20 5n-3) and then docosahexae-noic (22 6n-3). The pathways for formation of these latter fatty acids, from their dietary precursors, are presented in Figures 11.11 and 11.12. Full details of one pathway are provided, as an example, in Appendix 11.4. For comparison of the two pathways, they are presented side by side in Figure 11.13. 

Enzymes present in the ER are responsible for desaturating fatlyj j acids (that is, adding cis double bonds). Termed mixed-function oxidases, the desaturation reactions require NADPH and 02. A van-l ety of polyunsaturated fatty acids (PUFA) can be made through addi-l tional desaturation combined with elongation. [Note Humans laal the ability to introduce double bonds between carbon 9 and the col... 

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). 

Saturated fatty acids or unsaturated fatty acids, such as oleic acid (18 1, n-9), can be synthesized by normal mammalian cells that posses elongation and desaturation enzymes (Rosenthal, 1987). However, the polyunsaturated fatty acids of the n-3 and n-6 group, such as linoleic acid (18 2, n-6) or linolenic acid (18 3, n-3), are essential nutrients for animals because they are precursors for the synthesis of eicosanoid hormones such as prostaglandins (Needleman et al., 1986). 

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)...

Although polyunsaturated fatty acids are biohydrogenated to stearic acid (Cl8 0) in the rumen, they are desaturated to oleic acid in the small intestine, mucosa adipose tissue, and mammary gland. Thus the ratio of C18 l to C18 0 is greater in the fatty tissue and the milk lipids than in plasma triacylglycerols. Ruminant milk also contains 40-50% C4 0-C14 0 fatty acids by weight synthesized in the mammary glands from acetate (52). 

Experiences in cat nutrition underscore the fallacy of assuming that metabolic pathways found in one species are automatically present in others. Early studies on metabolism of PUFA were conducted on rats, which have high A6 and A5 desa-turase abilities to convert linoleic acid (18 2n-6) to the prostaglandin precursors dihomo-y-linolenic acid (20 3 -6) and arachidonic acid (20 4 -6), respectively. This led to the assumption that other species can desaturate polyunsaturated fatty acids equally well. Over a period of time, it was shown that cats are not able to convert 18 2 -6 to 20 3n-6 or 20 4 -6. The NRC currently recommends the inclusion of 5 g linoleic acid and 0.2 g arachidonic acid/kg diet dry matter. 

Polyunsaturated fatty acid synthesis is catalyzed by acyl-lipid-desaturases, also named front-end desaturases due to their action mechanism, which proceeds via introduction of double bonds into preformed acyl chains by oxygen and electron-donor dependent desaturation, between the carboxyl group and the pre-existing unsaturation which acts as substrate. For many microsomal desaturases, the electron donors are cytochrome b5, and a small hemoprotein that operates in numerous redox reactions in plants, involving NADH-dependent acyl-group desaturation [200]. 

Cook HW. In vitro formation of polyunsaturated fatty acids by desaturation in rat brain some properties of the enzymes in developing brain and comparisons with liver. J Neurochem 1978 30 1327-1334. Cowan WM. The development of the brain. In The Brain. New York Scientific American 241 (3) 113—133. Crastes de Paulet P, Sarda P, Boulot P, Crastes de Paulet A. Fatty acids blood composition in fetal and... 

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.

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. 

Because elongation and desaturation systems are in close proximity to each other in microsomal membrane, a variety of long-chain polyunsaturated acids are typically produced. A prominent example of this interaction is the synthesis of arachidonic acid (20 4A5,8 11,14) from linoleic acid (18 2A9,12). 

The endoplasmic reticulum (ER) has traditionally been viewed as the primary source of phospholipids in plant cells. With the exception of cardiolipin, all of the common phospholipids can be produced by microsomal fractions. The ER also serves as the major site of fatty acid diversification. Although plastids do have the ability to synthesize polyunsaturated fatty acids, they are formed on acyl lipid substrates and are not typically exported. Thus, the ER desaturation pathways are of particular importance for developing seeds that store large quantities of 18 2 and 18 3. Pathways for the production of unusual fatty acids found primarily in seed oils have likewise been described in microsomes. Not surprisingly, the ER also appears to be instrumental in the formation of TGs and the lipid bodies in which they are stored (Section 7). 

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