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Fatty Acid Biosynthesis

In animals, fatty acids represent a major storage form of energy. When caloric intake exceeds energy demand and glycogen stores are saturated, excess dietary carbohydrate is converted to fatty acid and stored in adipose tissue as triglyceride, together with excess dietary fat. When energy demand cannot be met by the utilization of stored glycogen, fat is mobilized from adipose and transported to tissues such as muscle, where it is taken up and oxidized for energy production. Thus, the rate of de novo fatty acid synthesis is rapid in well-fed animals and slow in fasted animals. Critical to the regulation of fatty acid synthesis and oxidation are the opposing actions of insulin and glucagon. Glucagon, via its intracellular messenger, cAMP, activates protein kinases involved in the phosphorylation of key enzymes and transforms the liver from a glycogenic, glycolytic, lipogenic tissue to a glycogenolytic, gluconeogenic, fatty acid oxidizing tissue. Initially, when the food supply is stopped, serum insulin concentration falls, and glucagon concentration rises, triggering the short-term regulatory mechanism. On refeeding, insulin concentration rises, glucagon falls and these changes are reversed, and the liver reverts to its role as a glycogenic, glycolytic, lipogenic tissue. The antagonism between insulin and glucagon may also serve in long-term regulation of these pathways by controlling transcription of key genes.

The Animal Fatty Acid Synthase
The fatty acid synthase consists of two identical 272 kDa polypeptides, each containing seven functional components: KS, b-ketoacyl synthase; MAT, malonyl/acetyl transferase; DH, dehydrase; ER, enoyl reductase; KR, Ketoreductase; ACP, acyl carrier protein; TE, thioesterase. The exact role of the central core is uncertain; it may provide a structural scaffold for proper orientation of the catalytic components.

The major sites of synthesis of saturated fatty acids are in the soluble cytoplasm of liver adipose tissue and, during lactation, the mammary gland. Acetyl-CoA carboxylase catalyzes the initial conversion of acetyl-CoA to malonyl-CoA, which subsequently is utilized as the carbon source for the elongation of an acetyl primer moiety to a long chain fatty acid in a series of iterative condensation and reductive reactions catalyzed by a single protein, the fatty acid synthase. This multifunctional polypeptide form of molecular architecture offers unique advantages for the compartmentalization of a complex anabolic pathway that ensures efficient synthesis of palmitic acid, without significant accumulation or leakage of intermediates.The kinetics and specificities of the component enzymes are well adapted to ensure that the iterative condensation of an acetyl moiety with successive malonyl moieties and complete reduction of the intermediates normally results in the formation of palmitic acid as the major product. Unraveling the details as to how these reactions are coupled together in a single protein represents a major challenge in structural and biochemical analysis and is the subject of current research in Dr. Smith’s laboratory.

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