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FATTY ACIDS SYNTHESIS A large proportion of the fatty acids used by the body are supplied by the diet. Carbohydrates, protein, and other molecules obtained from the diet in excess of the body's needs for these compounds can be converted to fatty acids, which are stored as triacylglycerols. In humans, fatty acid synthesis occurs primarily in the liver and lactating mammary glands and, to a lesser extent, in adipose tissue, the process incorporates carbons from acetyl CoA into the growing fatty acid chain, using ATP and reduced nicotinamide adenine dinucleotide phosphate (NADPH). Three stages of fatty acid synthesis: 1. Transport of acetyl CoA into cytosol 2. Carboxylation of acetyl CoA 3. Assembly of fatty acid chain The reactions of fatty acid synthesis all take place in the cytosol, the starting material for synthesis of fatty acid is acetyl CoA which is made in the mitochondria and can't cross the inner membrane .Note that the acetyl-CoA is first joined to oxaloacetate to make citrate which is readily transported out of the mitochondria using a co-transporter. The citrate is then cleaved to acetyl-CoA and oxaloacetate by the enzyme citrate lyase. The oxaloacetate can return to the mitochondria as malate or pyruvate. Acetyl-CoA for fatty acid synthesis is now available in the cytosol. The first committed step of fatty acid biosynthesis is Carboxylation of acetyl CoA to form malonyl CoA catalyzed by Acetyl-CoA carboxylase (ACC). 1 The enzyme adds a CO2 to acetyl CoA. Note that this reaction is an energy requiring process (1 ATP per Malonyl-CoA formed). This carboxylation is both the rate-limiting and the regulated step in fatty acid synthesis. The enzyme undergoes allosteric activation by citrate, and inactivated by long-chain fatty acyl CoA (the end product of the pathway), second mechanism of regulation is by reversible phosphorylation. In the presence of counter regulatory hormones, such as epinephrine and glucagon, acetyl CoA carboxylase is phosphorylated and, thereby, inactivated.in the presence of insulin, acetyl CoA carboxylase is dephosphorylated and, thereby, activated. The remaining series of reactions of fatty acid synthesis is catalyzed by the multifunctional dimer enzyme, fatty acid synthase. Each fatty acid synthase monomer is a polypeptide with different enzymatic activities plus a domain referred to as the acyl carrier protein (ACP). The reactions are as follow: A. Loading of precursors Transfer of the acetyl group of Acetyl-CoA to ACP by acetyl-CoA ACPtransacylase. 2 Now ACP accepts a three-carbon from malonyl CoA by Malonyl CoAACP-transacylase B. Condensation of the precursors The malonyl group loses HCO3 originally added by acetyl CoA carboxlyase, the result is a four-carbon unit attached to the ACP this achieve by 3-Ketoacyl-ACP synthase. The next three reactions convert the 3-ketoacyl group to the corresponding saturated acyl group by a pair of reductions requiring NADPH and a dehydration step. The keto group is reduced to form beta-hydroxyacyl ACP by 3KetoacylACP reductase. A molecule of water is removed to introduce a double bond by 3Hydroxyacyl-ACP dehydratase. A second reduction step occurs by Enoyl-ACP reductase The result of these steps is production of a four-carbon compound (butyryl) whose three terminal carbons are fully saturated, and which remains attached to ACP. These steps are repeated. When the fatty acid reaches a length of sixteen carbons, the synthetic process is terminated with thioesterase which releases palmitate from the multienzyme complex, producing a fully saturated molecule of palmitate (16:0). [Note: All the carbons in palmitic acid have passed through malonyl CoA except the two donated by the original acetyl CoA, which are found at the methyl-group end of the fatty acid.] .The major fatty acid synthesized de novo is palmitic acid. Summary of fatty acid synthesis acetyl CoA+7malonylCoA+14NADPH 1palmitate+7CO2+14 NADP +8CoA 3 Fatty acid synthesis pathway Elongation of fatty acid chains Although palmitate, is the primary end-product of fatty acid synthase activity, it can be further elongated by the addition of two-carbon units in the endoblasmic reticulum (ER) and the mitochondria. These organelles use separate enzymic processes. The brain has additional elongation capabilities, allowing it to produce the very-long-chain fatty acids (up to 24 carbons) that are required for synthesis of brain lipids. Desaturations of fatty acid chains Enzymes present in the ER are responsible for desaturating fatty acids (that is, adding cis double bonds). Termed mixed-function oxidases, the 4 desaturation reactions require NADPH .a variety of polyunsaturated fatty acids (PUFA) can be made through additional desaturation combined with elongation.[Note: Humans lack the ability to introduce double bonds at carbon 9 therefore, must have the polyunsaturated linoleic and linolenic acids provided in the diet . Storage of fatty acids as components of triacylglycerols Mono-, di-, and triacylglycerols consist of one, two, or three molecules of fatty acid esterified to a molecule of glycerol. Fatty acids are esterified through their carboxyl groups, resulting in a loss of negative charge and formation of "neutral fat." The three fatty acids esterified to a glycerol are usually not of the same type. A fatty acid must be converted to its activated form (attached to coenzyme A) before it can participate in TAG synthesis. This reaction is catalyzed by a family of fatty acyl Co A synthetases (thiokinases). Synthesis of a molecule of TAG from glycerol phosphate and fatty acyl CoA involves four reactions; include the sequential addition of two fatty acids from fatty acyl CoA, the removal of phosphate, and the addition of the third fatty acid. 5