Arachidonic acid desaturation, elongation

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.

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 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. 

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... 

Fig. 15. Proposed biosynthetic pathways for PUFA biosynthesis in an arachidonic acid-producing fungus, M. alpina 1S-4 Broken arrows show by-paths through which co9 fatty acids and nonmethylene-interrupted PUFAs are formed by mutants of M. alpina 1S-4, Mut48 and Mut49, respectively. An, An desaturation EL, elongation...

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. 

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). 

A. Arachidonic acid is produced from linoleic acid (an essential fatty acid) by a series of elongation and desaturation reactions. Arachidonic acid is stored in membrane phospholipids, released, and oxidized by a cyclooxygenase (which is inhibited by aspirin) in the first step in the synthesis of prostaglandins, prostacyclins, and thromboxanes. Leukotrienes require a lipoxygenase, rather than a cyclooxygenase, for their synthesis from arachidonic acid. 

Synthesis of arachidonic acid from linoleic acid. The desaturation and chain elongation occur in microsomes. 

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. 

Once ingested, these essential fatty acids can be metabolized into longer, more unsaturated products (Holman, 1968). This process involves sequential desaturation (adding double bonds) and chain elongation (adding carbon atoms), as shown in Fig. 1. The important aspect of Fig. 1 is that the n-6 and n-3 families compete for the enzymes responsible for desaturation (Sinclair, 1993). The main metabolite of the n-6 series is arachidonic acid (20 4n-6, AA), whereas eicosapentaenoic acid (20 5n-3, EPA) and docosahexaenoic acid (22 6n-3, DHA) are the main metabolites ofthe n-3 series (Holman, 1968). The metabolic pathways leading to DHA are complicated by involving retroconversion from 24 6n-3 to 22 6n-3 (DHA) (Voss et al., 1991). 

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. 

There are other cases of inhibition of lipid enzymatic pathways by trans fatty acid isomers. The above reported mono-14 -trans isomer of arachidonic acid is inhibitor of the synthesis of thromboxane B2 and, therefore, can prevent rat platelet aggregation [52]. The transformation of mono-trans isomers of linoleic acid by rat liver microsomes showed that the 9-cis,12-trans isomer is better desaturated, whereas the 9-trans, 2-cis isomer (Scheme 6.1) is better elongated [53]. 

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). 

A substantial body of literature exists reporting the inflammatory (or anti-inflammatory) effects of n-6 and n-3 PUFA. LA and ALA undergo a series of desaturation and elongation steps that yield arachidonic acid (AA, 20 4n-6) and EPA (20 5n-3), respectively. Additional metabolism of EPA produces the n-3 PUFA DHA (22 6n-3). However, the conversion of ALA to EPA, and especially DHA, is limited in humans (Goyens et al., 2005 Hussein et al., 2005 Pawlosky et al., 2001). Based on a metabolic model, Goyens et al. (2005) estimated that 7% of dietary ALA is converted to long-chain PUFA 99% is converted to EPA and 1% to docosapentaenoic acid (DPA). DHA is subsequently produced via elongation and desaturation of DPA. Ilierefore,... 

Fig. 33.19. Conversion of linoleic acid to arachidonic acid. Dietary linoleic acid (as linoleoyl CoA) is desaturated at carbon 6, elongated by 2 carbons, and then desaturated at carbon 5 to produce arachidonyl CoA.

Cultured heart cells responded rapidly to fatty acids administered to the medium. Heated fat produced lower levels of unsaturated fatty acids in the PL fractions, and a greatly increased level of arachidonic acid in the TG fractions (15) In the livers of rats fed heated fats, Rao et al. (50) showed a rapid rate of elongation and desaturation of fatty acid chains. 

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