Sarah K. Orr, BSc, Chuck T. Chen, BSc, Arthur A. Spector, MD and Richard P. Bazinet, PhD The synthesis of the longer, more highly unsaturated derivatives from the 18-carbon members of the n−3 and n−6 classes occurs through the pathway illustrated in Figure 18-2. Three types of reactions are involved: fatty acid chain elongation, desaturation, and β-oxidation (Sprecher, 2000). These reactions occur with both n−6 and n−3 PUFAs, but the two classes cannot be interconverted. Therefore an n−6 PUFA can be converted only to another n−6 PUFA, and likewise, an n−3 PUFA can be converted only to another n−3 PUFA. Therefore both classes of essential fatty acids are necessary in the diet. Of related interest, a gene from Caenorhabditis elegans encoding an n−3 desaturase, capable of converting n−6 PUFAs into n−3 PUFAs, has been isolated and transfected into mice and pigs, allowing them to synthesize n−3 PUFAs from n−6 PUFAs (Kang et al., 2004; Lai et al., 2006). Although several genes may encode the FADS enzymes, in terms of PUFA metabolism, FADS1 and FADS2 are the most studied. FADS1 is the fatty acid Δ5-desaturase, and FADS2 is the fatty acid Δ6-desaturase. The genes coding for FADS1 and FADS2 are located on human chromosome 11q12-q13.1 in reverse orientation, separated by about 10,000 bp (Marquardt et al., 2000). The expression of these two genes is coordinately regulated. In addition, a third desaturase gene, FADS3, is located in the 11q12-q13.1 region, but the function of its gene product is unknown (Lattka et al., 2010). Figure 18-2 illustrates where the fatty acid Δ5- and Δ6-desaturases act in essential fatty acid metabolism. Both fatty acid desaturases can utilize either n−3 or n−6 polyunsaturated fatty acyl-CoA substrates, and they both require O2, NADH, cytochrome b5, and cytochrome b5 reductase. Figure 18-4 illustrates the two reactions. The desaturases act on the segment of the acyl-CoA chain between the carboxyl group and the first existing double bond. The Δ5-desaturase acts on polyunsaturated acyl-CoAs that have the first double bond at C8, inserting the new double bond at C5. This enzyme acts at only one point in the metabolic pathway, converting 20:3n−6 to ARA in n−6 PUFA metabolism and 20:4n−3 to EPA in n−3 PUFA metabolism. The Δ6-desaturase acts on polyunsaturated fatty acyl-CoA substrates that have the first double bond at C9, and inserts the new double bond at C6. There is only one fatty acid Δ6-desaturase, and this enzyme functions twice in n−3 PUFA metabolism, converting α-linolenic acid to 18:4n−3 and 24:5n−3 to 24:6n−3 (Sprecher, 2000). The Δ6-desaturase ordinarily functions only once in n−6 PUFA metabolism, converting linoleic acid to 18:3n−6. It also is capable of converting 24:4n−6 to 24:5n−6, but this occurs to an appreciable extent only if there is a deficiency of n−3 PUFAs. Conversion of the 24-carbon acyl-CoA intermediates to the 22-carbon end products is thought to occur through peroxisomal fatty acid oxidation, a β-oxidation system that shortens very-long-chain fatty acids. This process requires transport of the 24-carbon intermediate from the ER to the peroxisomes and, subsequently, transport of the 22-carbon product back to the ER where it is incorporated into tissue lipids. As shown in Figure 18-5, the retroconversion reaction requires O2, FAD, NAD+, and CoA, and it removes two carbons in the form of acetyl-CoA from the carboxyl end of the fatty acyl-CoA. The peroxisomal enzymes that catalyze this β-oxidation process are straight-chain acyl-CoA oxidase, D-bifunctional protein, and either 3-ketoacyl-CoA thiolase or sterol carrier protein X (SCP-X) (Ferdinandusse et al., 2001). The levels of PUFAs present in the plasma lipids of human subjects who consumed western diets are shown in Table 18-1 (Edelstein, 1986). These data show that n−6 PUFAs accounted for 17% of the fatty acids in the plasma free fatty acid fraction, 37% of the fatty acids in phospholipids, 22% of the fatty acids in triacylglycerols, and 59% of the fatty acids in cholesteryl esters. Linoleic acid and ARA comprised most of the n−6 PUFAs contained in these plasma lipids. In contrast to the high n−6 PUFA content, n−3 PUFAs comprised only 1% to 3% of the total fatty acids in any of the plasma lipid fractions. TABLE 18-1 Essential Fatty Acid Composition of Normal Human Plasma Lipids ∗Abbreviated as ratio of number of carbons to number of double bonds. †Phospholipids contain 0.65 ± 0.08% 20:5n−3 and 0.77 ± 0.03% 22:5n−3. The other lipid fractions contain only trace amounts (<0.3%) of these n−3 fatty acids. ‡Cholesteryl esters contain 1.07 ± 0.07% 18:3n−6, but the other lipid fractions contain only trace amounts. §The lipids contain only trace amounts (<0.5%) of 22:4n−6 and 22:5n−6. Modified from data compiled by Edelstein, C. (1986). General properties of plasma lipoproteins and apoproteins. In A. M. Scanu & A. A. Spector (Eds.), Biochemistry and biology of the plasma lipoproteins (pp. 495–505). New York: Marcel Dekker.
Lipid Metabolism
Polyunsaturated Fatty Acids
Structure of Polyunsaturated Fatty Acids
Essential Fatty Acid Metabolism
Synthesis of 20- And 22-Carbon Pufas
Fatty Acid Desaturation
Retroconversion in the Peroxisomes
Essential Fatty Acid Composition of Plasma and Tissue Lipids
Lipoprotein Lipids
FATTY ACID∗
FREE FATTY ACID
PHOSPHOLIPIDS†
TRIACYLGLYCEROLS
CHOLESTERYL ESTERS‡
(FRACTION OF TOTAL FATTY ACIDS, % BY WEIGHT)
n−3
18:3
0.71 ± 0.11
0.21 ± 0.03
1.18 ± 0.08
0.50 ± 0.06
22:6
0.34 ± 0.06
2.23 ± 0.14
0.35 ± 0.04
0.49 ± 0.08
n−6§
18:2
15.60 ± 0.63
22.94 ± 0.57
19.54 ± 0.84
49.82 ± 1.79
20:3
0.14 ± 0.04
3.11 ± 0.12
0.36 ± 0.05
0.91 ± 0.06
20:4
1.25 ± 0.17
10.95 ± 0.45
1.64 ± 0.14
8.08 ± 0.39
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Lipid Metabolism: Polyunsaturated Fatty Acids
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