Linolenic acid desaturation, elongation

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. 

Synthesis of docosahexaenoic acid from a-linolenic acid. Desaturation and chain elongation are similar to the use described in Figure 18-13. 

Arachidonic acid is present in high concentrations in ester form in most animal fats and so can be assimilated by man directly in his diet. Alternatively, mammals may biosynthesize arachidonic acid from linoleic acid via desaturation to y-linolenic acid, chain elongation to dihomo-y-linolenic acid, and then further desaturation to arachidonic acid. 

Figure 2.1. Biosynthetic relationships between unsaturated fatty acids, (a) Elongation and retroconversion of oleic acid (b) elongation and desaturation of linoleic acid (c) biosynthesis of prostaglandin E2 from arachidonic acid (d) elongation and desaturation of a-linolenic acid (e) elongation and desaturation of oleic 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 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... 

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). 

EPA and DHA in fish is derived primarily from ingesting marine algae where it is synthesized by desaturation and elongation of a-linolenic acid (ALA, C18 3n-3) (Figure 4.2). 

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)...

Fatty acids are elongated and desaturated by enzyme systems in the endoplasmic reticulum membrane. Desaturation requires NADH and O2 and is carried out by a complex consisting of a flavoprotein, a cytochrome, and a nonheme iron protein. Mammals lack the enzymes to introduce double bonds distal to C-9, and so they require linoleate and linolenate in their diets. 

An alternative route to EPA and DHA can come from elongation and further desaturation of stearidonic acid (18 4A ). Certain plants, including blackberry, borage, and evening primrose, contain up to 25% of y-linolenic acid (18 3A ) in their seed oil, with considerably smaller amounts of stearidonic acid. The y-linolenate arises from the action of a A6-desaturase on linoleate. Small amounts of co-3-desaturase present in these seeds account for the stearidonate produced. When A6-desaturase from borage was introduced into soy, plants producing up to 29% y-linolenate (precursor to arachidonate), with up to 4% stearidonate in oil, resulted (32). Further desaturation to stearidonate could be promoted with high expression of an co-3-desaturase. 

The RDA for the essential fatty acids is 1 to 2% of total energy intake. Generally, between 5 and 10% of our energy intake consists of EFAs. Because of our ample intake of fat, a deficiency in EFAs is quite rare. The biochemical steps in the modification of nonessential fatty acids, such as oleic add, and essential fatty adds (linoleic add and linolenic acid) are generally the same. These steps include elongation and desaturation. Modification of fatty adds by their repeated desatu-... 

Fig. (4). Instead, the alternative A8-route begins with the elongation of Ci8 to C20, followed by two desaturations. Fig. (4). There also exists another unusual pathway to produce DHA which has been characterised in mammals and fish, called the Sprecher s pathway, this route is characterized by a lack of desaturation reaction at A4-position, but successive A5 and A6-desaturations of ALA (a-linolenic acid, 18 3 ) generating a C24 intermediate which is finally shortened by peroxisomal -oxidation forming DHA, Fig. (4).

Linoleic acid can be converted in mammalian liver to y-linolenic acid and arachidonic acid by the microsomal desaturation and chain elongation process (Figure 18-14). Thus, the requirement for arachidonic acid may be dispensed with when the diet contains adequate amounts of linoleic acid. Similarly, a-linolenic acid is converted by desaturation and chain elongation to EPA and DCHA (Figure 18-15). 

The answer is c. (Klurray, pp 505-626. Scriver, pp 4029-4240. Sack, pp 121-138. Wilson, pp 287-320.) In mammals, arachidonic (5,8,11,15-eicosatetraenoic) acid can only be synthesized from essential fatty acids derived from the diet. Linoleic (9,12-octadecadienoic) acid produces arachidonic acid following two desaturations and chain elongation. While linolenic (9,12,15-octadecatrienoic) acid also is an essential fatty acid, desaturation and elongation produce 8,11,14,17-eicosatetraenoic acid, which is distinct from arachidonic acid. Oleic, palmitic, and stearic acids are all nonessential fatty acids that cannot give rise to arachidonic acids in mammals. 

The answer is b. (Murray, pp 505-626. Scriver, pp 5029-5250. Sack, pp 121-138. Wilson, pp 287-320.) The essential fatty acid linoleic acid, with 18 carbons and two double bonds at carbons 9 and 18 (C-18 2-A ) is desaturated to form a-linolenic acid (C-18 3-A ), which is sequentially elongated and desaturated to form eicosatrienoic acid (C-20 3-2 8,11,1+) arachidonic acid (C-20 4-A " ), respectively. Many of the eicosanoids (20-carbon compounds)—prostaglandins, thromboxanes, and leukotrienes—are derived from arachidonic acid. The scientific name of arachidonic acid is eicosatetraenoic acid. Arachidonic acid can only be synthesized from essential fatty acids obtained from the diet. Palmitic acid (C-16 0) and oleic acid (C-18 l-A" ) can be synthesized by the tissues. 

Pawlosky RJ, Sprecher HW, Salem N Jr. High sensitivity negative ion GC-MS method for the detection of desaturated and chain elongated products of deuterium-labeled hnoleic and linolenic acids. J Lipid Res 1992 33 1711-1717. 

Fig. 1. The n-3/n-6 metabolic pathways. Precursors of the n-3 (18 3n-3, linolenic acid) and n-6 (18 2n-6, (/.-linoleic acid) are converted by a series of desaturation and (adding double bonds) and elongation (adding carbon atoms to the hydrocarbon backbone) reactions. Note that the same enzymes catalyze n-3 and n-6 desaturation and elongation reactions. Major metabolites are indicated. PUFAs with 20-carbon backbones (20 4n-6, arachidonic acid, and 20 5n-3, eicosapentaenoic acid) are precursors to the eicosanoids (prostaglandins, leukotrienes, thromboxanes). Docosahexaenoic acid (22 6n-3) is also indicated. Note that only a limited part of the metabolic pathway is shown in this figure.

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. 

Linoleic acid (LA or 18 2n-6) An 18-carbon, two double-bond fatty acid. It is the most predominant PUFA in the Western diet. It is found in mayoimaise, salad dressings, and in the seeds and oils of most plants, with the exception of coconut, cocoa, and palm. Linoleic acid is metabolized into longer-chain fatty acids, such as arachidonic acid and gamma-linolenic acid, in animals through a process of chain elongation and desaturations. 

C-16) is formed. By elongation and desaturation, palmitic acid can be used as precursor for the production of most natural fatty acids in the human body. Humans lack enzymes to synthesize linoleic and linolenic acid. Hence, these two fatty acids are essential and must be supplied to the body in the diet. 

Fig. 4. Synthesis of n - 6 and n-3 series of PUFA from dietary essential fatty acids linoleic and a-linolenic acids, respectively, by elongation and desaturation.

---