Monounsaturated and polyunsaturated fatty acids are extraordinarily important in human health and nutrition. Thus, the insertion of double bonds into the carbon skeleton of a fatty acid is a vital metabolic function. However, humans are in general not capable of inserting double bonds closer than nine carbon atoms from the methyl end of a fatty acid. Thus, we are incapable of the de novo synthesis of two important classes of fatty acids, the n-3 fatty acids such as docosahexaenoic acid (22:6n-3) and the n-6 fatty acids such as arachidonic acid (20:4n-6). The n-3 fatty acids have proven to be beneficial in the prevention of coronary artery disease. The fatty acid 22:6n-3 has been shown to be important for the normal development of the brain and retina, leading some manufacturers to include this fatty acid in their infant formula preparations. The n-6 fatty acids are important constituents of membrane lipids. The fatty acid 20:4 is also the well-known precursor of prostaglandins and other bioactive eicosanoids. Since we cannot synthesize these fatty acids de novo, we are dependent on the presence of at least some n-3 and some n-6 fatty acids in the diet. Linoleic acid (18:2n-6) and a-linolenic acid (18:3n-3) are the precursors of most biologically important n-3 and n-6 fatty acids; thus, they are referred to as essential fatty acids.
As noted earlier, the most abundant fatty acids in humans include a saturated fatty acid (16:0) and a monounsaturated fatty acid (18:1n-9). Humans can readily insert a ds-double bond nine carbons from the carboxyl carbon atom of a fatty acid (A9) in a reaction catalyzed by stearoyl-CoA desaturase (SCD1; so-named because the preferred substrate is the CoA derivative of 18:0, stearic acid). Because SCD1 is involved in the synthesis of such an abundant fatty acid, 18:1, the importance of this enzyme in metabolism was initially overlooked. However, 18:1 produced by SCD1 appears to be directed specifically towards triacylglycerol synthesis. Mice in which the SCD1 gene is disrupted have decreased adiposity. Furthermore, genetically obese leptin-deficient (ob-/ob-) mice in which the SCD1 gene is also disrupted have significantly reduced body weight compared with ob-/ob- mice, leading to the hypothesis that leptin regulates the synthesis of SCD1. Interestingly, dietary 18:1 seems to be more readily incorporated into lipids other than triacylgly-cerols, implying that the dietary and the SCD1-pro-duced pools of this fatty acid are metabolically distinct. As with the n-3 fatty acids, dietary ingestion of monounsaturated fatty acids such as 18:1 has been associated with benefits to cardiovascular health.
Humans are also capable of inserting cis-double bonds either five or six carbon atoms from the car-boxyl carbon atom of a fatty acid (A5 desaturase and A6 desaturase activity, respectively). These activities, when combined with the elongation pathways described above, form a powerful mechanism for synthesis of highly polyunsaturated fatty acids such as 20:4n-6 and 22:6n-3 from the dietary essential fatty acids. Previously, it was thought that humans also had the ability to insert a double bond four carbon atoms from the carboxyl carbon (A4 desaturase activity), as this activity was thought to be necessary for the conversion of 18:3n-3 to 22:6n-3. However, attempts to measure A4 desaturase activity experimentally were not successful. It is now thought that, through a series of elongation and desaturation reactions, 18:3n-3 is converted to the penultimate intermediate, 22:5n-3. Rather than using a A4 desaturase to complete the synthesis, 22:5n-3 is elongated to 24:5n-3, converted to 24:6n-3 by A6 desaturase, and finally chain-shortened to 22:6n-3 by one cycle of peroxisomal ^-oxidation.
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