BIOCHEMISTRY - L. Stryer - 1984

VOLUME 2

PART II GENERATION AND STORAGE OF METABOLIC ENERGY

CHAPTER 17. FATTY ACID METABOLISM

17.23. Elongation and Desaturation of Fatty Acids Are Carried Out by Additional Enzyme Systems

The primary product of the reaction catalyzed by fatty acid synthase is palmitate. In eukaryotes, longer-chain Fatty acids are produced through elongation Reactions Catalyzed by enzyme systems associated with the membranes of The Endoplasmic reticulum (also known as microsomal systems). Two-carbon units are added to the carboxyl end of both saturated and Unsaturated fatty acids. Microsomal systems also catalyze the Introduction of a double bond into long-chain fatty acyl-CoA derivatives. For example, The conversion of stearoyl-CoA to oleoyl-CoA involves the introduction of a cis-∆⁹ double bond by an oxidase that utilizes molecular oxygen and NADH (or NADPH):

Stearoyl-CoA + NADH + Н⁺ + O₂ → Oleoyl-CoA + NAD⁺ + 2Н₂O.

Various unsaturated fatty acids can be synthesized from oleate through a combination of elongation and desaturation reactions. For example, oleate can be elongated to a 20:1 cis-∆¹¹ acid. Alternatively, a second double bond may be introduced to yield an 18:2 cis-∆⁶, ∆⁹ acid. Similarly, palmitate (16:0) can undergo oxidation to palmitoleate (16:1 cis-∆⁹), which can be further elongated to cis-vaccenate (18:1 cis-∆¹¹).

Mammals lack Enzymes capable of introducing double bonds into fatty acid chains beyond the 9th carbon atom. Consequently, they cannot synthesize linoleate (18:2 cis-∆⁹, ∆¹²) and linolenate (18:3 cis-∆⁹, ∆¹², ∆¹⁵). Linoleate and linolenate are two Essential Fatty Acids. The term "essential" means that they are required by the Organism but cannot be synthesized endogenously, and therefore must be obtained from the diet. Dietary linoleate and linolenate serve as precursors for the synthesis of various other unsaturated fatty acids. Unsaturated fatty acids in mammals are derivatives of palmitoleate (16:1), oleate (18:1), linoleate (18:2), or linolenate (18:3). The precursor can be identified by the number of methylene carbons between the ω-CH₃ group of the unsaturated Fatty acid and the nearest double bond.

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17.24. Regulation of Fatty Acid Synthesis

Fatty acid synthesis reaches its peak under conditions of carbohydrate excess and low fatty acid levels. Both short-term and long-term control mechanisms play a major role in this process. The most important short-term regulator of fatty acid synthesis is the concentration of cytosolic citrate. As previously mentioned, citrate stimulates acetyl-CoA carboxylase, the enzyme that catalyzes the committed step in fatty acid synthesis. Citrate levels are high when both acetyl-CoA and ATP are present in excess. Recall that isocitrate dehydrogenase is inhibited by a high energy charge (Section 13.18). Consequently, a high citrate concentration signals the availability of two-carbon units and ATP for fatty acid synthesis. Palmitoyl-CoA, which accumulates when fatty acids are in excess, acts as an antagonist to citrate in its effect on acetyl-CoA carboxylase. Furthermore, palmitoyl-CoA inhibits the transporter protein responsible for moving citrate from the Cell/35.html">Mitochondria to the Cytosol, and also inhibits the generation of NADPH by glucose-6-phosphate dehydrogenase.

Long-term regulation is mediated by Changes in the rates of Synthesis and degradation of the enzymes involved in fatty acid synthesis. This type of regulation is also known as adaptive control. In animals subjected to a carbohydrate-rich, fat-poor diet for several days following starvation, There is a dramatic increase in the levels of acetyl-CoA carboxylase and fatty acid synthase in the Liver.