Linoleic acid desaturation

The question arises whether inhibition of the desaturase for this particular pathway can be overcome. The answer is yes. The product of the A desaturase when desaturating linoleic acid is y-linolenic acid. Supplementation of the diet with y-linolenic acid, which bypasses the A desaturase reaction, has been used to increase the formation of dihomo-y-linolenic acid and arachidonic acid (Figure... 

Hassam AG. Rivers JPW, Crawford MA. The failure of the cat to desaturate linoleic acid its nutrient implications. Br J Nutr 1977 39 227-231. 

The metabolic transformation of the C,s essential fatty acids to their longer chain fatty acid derivatives has been studied mainly in the liver and to some extent in the brain. Animals and tissues vary greatly in their efficiency of desaturation and chain elongation [18,414,415]. Thus young rats have a particularly active system whereas cats are unable to perform this metabolic reaction. The failure of the cat family to desaturate linoleic acid has been suggested to be a possible reason behind the cats evolution to carnivorous animals [416] (e.g. eating rats). Humans occupy an intermediate position. 

The potency of the different fractions obtained in the purification steps to reactivate the capacity of extracted microsomes (Me) to desaturate linoleic acid was measured using the same procedure, except that the amount of Me used was the remainder after the extraction of 2.5 mg of complete microsomes (M). 

Arachidonic acid biosynthesis does not occur in all cell types in the mammals body. Neurons, for instance, can neither elongate nor desaturate linoleic acid and must rely therefore on other cells for their supply of free arachidonate. What type of cells Three complementary sources have been identified hepatocytes, which... 

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. 

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. 

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. 

Figure 11.11 Outline of the pathway consisting of desaturation and elongation reactions that convert linoleic acid into arachidonic acid.

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. 

Dietary intake is of great importance. Linoleic acid (C18 2o)6) and a-linolenic acid (C18 3o)3) are the parent essential fatty acids for humans. Both fatty acids derive from vegetable oils. Higher fatty acids are then produced by chain elongation and desaturation. In addition, some of the prime essential fatty acids, AA (C20 4o)6), EPA (C20 5w3) and DHA (C22 6w3), can be obtained directly from the diet. Meat and eggs are rich in AA, whereas fish is a rich source of EPA and DHA [14]. 

The dietary precursor of the prostaglandins is the essential fatty acid, linoleic acid. It is elongated and desaturated to arachidonic acid, the immediate precursor of the predominant class of prostaglandins (those with two double bonds) in humans (Figure 17.22). [Note Arachidonic acid is released from membrane-bound phospholipids by phospholipase Ap in response to a variety of signals (Figure 17.23).]... 

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. 

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... 

Emken, E.A., Adlof, R.O., and Gulley, R.M. 1994. Dietary linoleic acid influences desaturation and acylation of deuterium-labeled linoleic and linolenic acids in young adult males. Biochim. Bio-phys. Acta 1213, 277-288. 

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). 

Guiet et al. (2003) demonstrated that deuterium (2H) distribution in fatty acids was non-statistical and could be related to isotopic discrimination during chain extension and desaturation. Petroselinic acid (C18 1A6) (Fig. 21.4), a fatty acid characteristic of the seeds of the Apiaceae, has been shown to be biosynthesized from palmitoyl-ACP (C16 0) by two steps, catalysed by a dedicated A4-desaturase and an elongase. The isotopic profile resulting from this pathway is similar to the classical plant fatty acid pathway, but the isotopic fingerprint from both the desaturase and elongase steps shows important differences relative to oleic and linoleic acid biosynthesis. 

In humans, the conversion of ALA to EPA and DHA is extremely slow, with only about 15% and 5% of ALA converted to EPA and DHA, respectively (Cunnane, 1995). This conversion appears to be affected by a number of dietary factors. For example, a diet rich in linoleic acid has been found to reduce this conversion by as much as 40% (Emken, 1995). In addition, saturated and lruns fatty acids also interfere with ALA desaturation and elongation steps (Ackman and Cunnane, 1992 HouwelingenandHornstra, 1994). DHA can be reconverted back to EPA, although in humans it appears to be a very minor pathway (Brossard et al., 1996). DHA appears to play an important in the brain and retina and was found to be incorporated during the last trimester of pregnancy and the first year of life. Visual acuity was shown to develop much faster in preterm infants fed formulas rich in DHA compared with standard infant formulas low in long chain n-3 fatty acids (Jorgensen et al., 1996). 

The mammalian organism is unable to introduce double bonds at fatty acids, and this is probably why these families must be present in the diet. These fatty acids can be desaturated and elongated (see Chapter 19) to form derived essential fatty acids, dihomo-T-linoleic acid (20 3o>6), arachidonic acid (20 4ft)6), and eicosapentaenoic acid (20 5ft>3), the three direct precursor acids of PGs. Dihomo-r-linoleic acid, an intermediate in the biosynthesis of arachidonic acid from linoleic acid, is the precursor of PGs of the 1 series. Arachidonic acid and eicosapentaenoic acid are precursors of PGs of the 2 series and 3 series, respectively. 

Bretillon, L., Chardigny, J.M., Gregoire, S., Berdeaux, O., Sebedio, J.-L. 1999. Effects of conjugated linoleic acid isomers on the hepatic microsomal desaturation activities in vitro. Lipids. 34, 965-969. 

Santora, J.E., Palmquist, D.L., Roehrig, K.L. 2000. / raws -vacccnic acid is desaturated to conjugated linoleic acid in mice. J. Nutr. 130, 208-215. 

Palmitic acid may be converted to stearic acid (C1K 0) by elongation of the carbon chain. Desaturation of stearic acid produces oleic acid (C18 1 A9). Linoleic acid (Ci8 2A9,12), however, cannot be synthesized in mammalian tissues. Therefore, it is an essential fatty acid for animals and must be obtained from the diet it has two important metabolic roles. One is to maintain the fluid state of membrane lipids, lipoproteins, and storage lipids. The other role is as a precursor of arachidonic acid, which has a specialized role in the formation of prostaglandins (Sec. 13.9). 

See Fig. 13-9. The carbon chain of linoleic acid is desaturated at position 6. y-Linolenic acid is elongated by two carbon units, and then another double bond is introduced in the C2o chain at position 5. 

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. 

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