Chemical structures and synthesis

Fatty acids are hydrocarbon chains with a carboxyl group (-COOH) at one end and a methyl group (CH3) at the other. Fatty acids vary in chain length, degree of unsaturation,1 and location of double bonds2 and can be classified as saturated (no double bonds), monounsaturated (single double bond), and polyunsaturated (several double bonds). Unsaturated fatty acids can be classified in two different ways: the delta (A) and the omega (ro) numbering system.1,3 In the delta system, the carboxyl carbon is denoted as carbon 1, while in the omega system carbon 1 is the methyl carbon.3 The number of double bonds in the fatty acid chain are counted from either the carboxyl or the methyl end. For instance, in the delta system the polyunsaturated fatty acid a-linolenic acid has the notation 18:3A9c12c15c or 18 carbons, and three double bonds occurring in the 9, 12, and 15 carbons. The same fatty acid in the omega system is 18:3ro3 or 18 carbons, with three double bonds and the first occurring at carbon 3.4 Fatty acids in which the first double bond occurs three carbons from the methyl end are called omega-3 fatty acids and are symbolized as ro-3 (or n-3) fatty acids. Fatty acids in which the first double bond occurs six carbons from the methyl end are named omega-6 fatty acids with the symbol of ro-6 (or n-6) fatty acids.2

Mammals do not have the capacity to completely synthesize either of these two types of polyunsaturated fatty acids because they cannot desaturate the 16- or 18-carbon products of fatty acid synthesis any further than nine carbons from the carboxyl end.3 Linoleic acid and a-linolenic acid are the two main representative compounds of the ro-6 and ro-3 fatty acids and are essential fatty acids because they prevent deficiency symptoms and cannot be synthesized by humans;5 therefore, they need to be obtained from the diet. These two types of polyunsaturated fatty acids cannot be interconverted, have different biochemical roles,3,5 and are precursors of other polyunsaturated fatty acids (Table 4.1). Linoleic acid is a precursor for arachi-donic acid and eicosanoids. a-Linolenic acid is a precursor for DHA. Linoleic acid,

TABLE 4.1

Primary ro-3 and ro-6 Polyunsaturated Fatty Acids

18:3 a-Linolenic acid 20:5 Eicosapentaenoic acid (EPA) 22:5 Docosapentaenoic acid 22:6 Docosahexaenoic acid (DHA)

18:2 Linoleic acid

18:3 y-Linolenic acid

20:3 Dihomo-y-linolenic acid

20:4 Arachidonic acid

22:4 Adrenic acid

22:5 Docosapentaenoic acid

Adapted from Institute of Medicine, Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids, National Academy Press, Washington, DC, 2005.

arachidonic acid, and DHA are found in cellular phospholipids.6 The more unsaturated and longer-chain ro-3 and ro-6 fatty acids, arachidonic acid (20:4ro-6), EPA (20:5ro-3), and docosahexaenoic acid (22:6ro-3) can be synthesized from linoleic and a-linolenic acids by alternating desaturation, elongation, and partial ^-oxidation process37 (Figure 4.1). Nonesterified fatty acids enter cells via fatty acid transporters and are converted to fatty acyl-CoA thioesters by acyl-CoA synthetases. Fatty acyl-CoA thioesters are the substrate for reactions of elongation, desaturation, and retroconversion8 that take place in the synthesis of ro-3 and ro-6 fatty acids in humans. The liver is the primary site for the metabolism of essential fatty acids; however, other tissues experience metabolism of these fatty acids.9 Dietary 18:2ro-6 and 18:3ro-3 are converted to long-chain highly unsaturated fatty acids by a series of desaturation and elongation reactions that take place in the endoplasmatic reticulum, and ^-oxidation, which occurs in the peroxisomes.8

Fatty acid desaturation is accomplished by the enzymes A6-desaturase and A5-desaturase.3'5'78 A6-Desaturase is now considered to be the rate-limiting step of the pathway.5 Earlier it was thought that an acyl-CoA-dependent 4-desaturase was responsible for the desaturation of the ro-3 and ro-6 fatty acids; however, it was later found that the endoplasmatic reticulum does not contain this type of desaturase.10 These two desaturases are membrane-bound enzymes that occur in the endoplasmatic reticulum of tissues in the liver, intestinal mucosa, brain, and retina.1116 The work of Okayasu et al.17 showed that cytochrome b5 and cytochrome b5 reductase were required to desaturate 18:2ro-6 to 18:3ro-6. Later, it was accepted that the desaturase reactions require O2, NADH, cytochrome b5, and cytochrome b5 reductase for the desaturation of both linoleic and a-linolenic acid.37 Hormonal and dietary factors such as insulin and fatty acid-deficient diets have been observed to increase the activity of the A6-desaturase, while glucose, epinephrine, and glucagon decrease desaturase activity.18 A6-Desaturase utilizes the fatty acyl chain that has a double bond at carbon 9 and inserts a new double bond at carbon 6. This desaturase converts a-linolenic acid to 18:4, and 24:5 to 24:6; and linoleic acid to 18:3, and 24:4 to 24:5. A5-Desaturase operates on a fatty acyl chain that has a double bond at carbon

18:2 (Linoleic acid)

^ A6-desaturase

elongase 20:3 (DGLA)

\ A5-desaturase

22:4

24:4

24:5

elongase elongase A6-desaturase

18:3 (a-linolenic acid)

18:4

20:4

24:5

24:6

peroxisomal oxidation

FIGURE 4.1 Pathway for the synthesis of ro-6 and ro-3 fatty acids. Note: GLA = y-linolenic acid, DGLA = dihomo-y-linolenic acid, AA = arachidonic acid, EPA = eicosapentaenoic acid, DPA = docosapentaenoic acid, DHA = docosohexanoic acid. Source: Adapted from Arterburn et al. (2006).118

8 and adds a new double bond at carbon 5. It converts 20:4 to 20:5 (EPA) and 20:3 to 20:4 (arachidonic acid).3

Fatty acid elongation occurs with only one type of elongase. During the elongation process, the chain is lengthened by the addition of two carbons to the carbonyl group by malonyl CoA. The carbonyl group of the fatty acyl CoA is reduced to a methylene group in reactions that need NADPH. During the elongation of the fatty acids the double bonds do not move.3 Three elongation steps occur in the synthesis of the ro-3 and ro-6 fatty acids.

Retroconversion is the final step in the synthesis of these polyunsaturated fatty acids. The retroconversion step of peroxisomal ^-oxidation is also called the Sprecher pathway.19 The role of peroxisomes takes place when the synthesis of 22:5 and 22:6 requires intracellular communication between the endoplasmic reticulum and a site where a partial ^-oxidation could occur.10 In the retroconversion process, two carbons are removed from the carboxyl end of the fatty acid as acetyl CoA. Then the 24-carbon intermediaries are retroconverted to 22:5 and 22:6. The retroconver-sion process requires O2, FAD, and NAD+.3

TABLE 4.2

Selected Physical Properties of Some ro-3 and ro-6 Polyunsaturated Fatty Acids

Fatty Acid

Linoleic acid

Chemical Name

Formula Formula MW

Melting Point

14c,17c

Solubility i.H2O, ^EtOH, eth., CHCl3

All cis-9,12-octadecadienoic y-Linolenic acid All cis-6,9,12-

octadecatrienoic a-Linolenic acid All cis-9,12,15-

octadecatrienoic Arachidonic acid All cis-5,8,11,14-eicosatetraenoic Eicosapentaenoic All cis-5,8,11,14,17-

acid eicosapentaenoic

Docosahexaenoic All cis-4,7,10,13,16,19- 22:6A4c'7c10c' 22:6ro3 328.50 acid docosahexaenoic Bd&jfc

Note: MW = molecular weight; i. = insoluble; «> = completely miscible; eth. = diethyl ether; s. = soluble.

Adapted from Small, D.M., in Biochemical and Physiological Aspects of Human Nutrition, Stipanuk, M.H., Ed., W.B. Saunders Company, Philadelphia, PA, 2000, pp. 43-71; and Dawson, R.C. et al., in Data for Biochemical Research, Dawson, R.C. et al., Eds., Oxford University Press, New York, 1986, pp. 167-189.

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