Which one of the following best represents de novo fatty acid biosynthesis starting with cytosolic citrate?
Correct Answer: NADH is Required - no; Major Product is - Palmitic acid; Occurs at a Glucagon-to-insulin Ratio Best Described as - low; Required Cofactors - Biotin and Coenzyme A
Description: This enzyme contains a phosphopantetheine residue, derived from the vitamin pantothenic acid, and a cysteine residue; both contain sulfhydryl groups that can form thioesters with acyl groups. The growing fatty acyl chain moves from one to the other of these sulfhydryl residues as it is elongated.a. Addition of C-2 units(1). Initially, acetyl-CoA reacts with the phosphopantetheinyl residue and then the acetyl group is transferred to the cysteinyl residue. This acetyl group provides the o-carbon of the fatty acid produced by the fatty acid synthase complex.(2). A malonyl group from malonyl-CoA forms a thioester with the phosphopantetheinyl sulfhydryl group.(a). Malonyl-CoA is formed from acetyl-CoA by a carboxylation reaction that requires biotin and ATP.(b). The enzyme is acetyl-CoA carboxylase, a regulatory enzyme that is inhibited by phosphorylation, activated by dephosphorylation and citrate, and induced by insulin. The enzyme that phosphorylates acetyl-CoA carboxylase is the AMP-activated protein kinase (not protein kinase A ).(3). The acetyl group on the fatty acid synthase complex condenses with the malonyl group; the CO2 that was added to the malonyl group by acetyl-CoA carboxylase is released; and a b-ketoacyl group, containing four carbons, is produced.b. Reduction of the b-ketoacyl group(1). The b-keto group is reduced by NADPH to a b- hydroxy group.(2). Then, dehydration occurs, producing an enoyl group with the double bond between carbons 2 and 3.(3). Finally, the double bond is reduced by NADPH, and a C-4 acyl group is generated.(a). The NADPH for these reactions is produced by the pentose phosphate pathway and by the malic enzyme.c. Elongation of the growing fatty acyl chain(1). The acyl group is transferred to the cysteinyl sulfhydryl group, and malonyl-CoA reacts with the phosphopantetheinyl group. Condensation of the acyl and malonyl groups occurs with the release of CO2, followed by the three reactions that reduce the b-keto group. The chain is now longer by two carbons.(2). This sequence of reactions repeats until the growing chain is 16 carbons in length.(3). Palmitate, a C-16 saturated fatty acid, is the final product released by hydrolysis from the fatty acid synthase complex.Fatty acid synthesis is maximal in the fed state when insulin is elevated and the glucagon-to-insulin ratio is low. Glucose is converted to citrate, which moves from the mitochondrion to the cytosol, where it is cleaved to oxaloacetate and acetyl-CoA. The regulatory enzyme acetyl-CoA carboxylase requires biotin and converts acetyl-CoA to malonyl-CoA, which provides the 2-carbon units for the elongation of the fatty acyl chain by the fatty acid synthase complex. Thus, biotin (for the carboxylation reaction) and coenzyme A (to produce acetyl-CoA) are the required cofactors for fatty acid synthesis. NADPH provides reducing equivalents. The major product of the fatty acid synthase complex is palmitic acid.
Category:
Biochemistry
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