Fatty Acid Unsaturation and the Essential Fatty Acids

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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