There are two major classes of PUFA: n-6 and n-3. Unlike saturated and monounsaturated fatty acid, PUFA cannot be synthesized de novo by mammals because they lack the required enzymes and, therefore, PUFA must be obtained from the diet. The n-6 and n-3 PUFA also cannot be interconverted in mammals, but within each series, their metabolism can produce various lipids that differ in chain length and number of double bonds. Linoleic acid (LA, 18:2 n-6) is an n-6 PUFA found in high concentration in grains as well as many seeds and meats. LA serves as a substrate to be converted into a longer fatty acid, arachidonic acid (AA, 20:4 n-6), via a series of oxidative desaturation and elongation reactions. Of the n-3 fatty acids, alpha linolenic acid (ALA, 18:3 n-3) is found at moderate levels in plants, seeds, leafy vegetables, legumes, and nuts. ALA is not metabolized efficiently to longer-chain n-3 PUFA, such as EPA and DHA.
Although they belong to two distinct families, n-3 and n-6 PUFA are metabolized by some of the same enzymes, specifically, delta-5-desaturase and delta-6-desaturase. Excess in one family of fatty acid can interfere with the metabolism of the other and alter their overall biological effects [5
]. During n-6 PUFA conversion, delta-6-desaturase, or fatty acid desaturase 2 (FADS2), converts LA to gamma-linolenic acid (GLA, 18:3 n-6). This enzyme represents a rate-limiting step in the synthesis of AA from LA [6
]. GLA is elongated to dihomo-gamma-linolenic acid (DGLA, 20:3 n-6) through a chain reaction of four enzymes: a condensation reaction of the fatty acyl chain with malonyl-CoA, catalyzed by an enzyme encoded by the ELOVL5 gene (elongation of very long-chain fatty acids, family member 5); a reduction reaction mediated by 3-ketoacyl-CoA reductase (KAR); a dehydration reaction catalyzed by 3-hydroxyacyl-CoA dehydratase (HACD); and a second reduction reaction catalyzed by trans-2,3-enoyl-CoA reductase (TECR). Finally, DGLA is converted to AA by delta-5 desaturase, or fatty acid desaturase 1 (FADS1) [6
]. Interestingly, malonyl-CoA, which is necessary for fatty acid elongation, is derived from the rate-limiting enzyme of the de novo
fatty acid synthesis pathway, acetyl-CoA carboxylase. Fatty acid synthesis is well described as an overactive pathway in many cancers [8
], and its upregulation may also contribute to the elongation of PUFA.
In contrast to AA, the efficiency of ALA conversion to DHA appears to be very low, below 5% in humans. Most ingested ALA is subject to beta-oxidation to provide energy, and only a small fraction is converted to EPA [12
]. It was estimated that as low as 0.2% of ALA is converted to EPA, 64% of EPA to docosapentaenoic acid (DPA, 22:5 n-3), and 37% of DPA to DHA [14
]. Thus, the overall amount of DPA and DHA converted from ALA is about 0.13% and 0.05% of the starting ALA, respectively. These findings suggest that any contributions from the fatty acid synthesis pathway toward PUFA metabolism most likely favor n-6, rather than n-3, PUFA elongation. It is also very likely that synthesis of the longer n-3 fatty acids from ALA within the body is competitively hindered by the n-6 analogues. It has been reported that the n-3 conversion efficiency is greater in women, possibly because of the importance of meeting the DHA demands of the fetus and neonate [14