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Introduction

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High-Yield Terms

  • ATP-citrate lyase (ACL): cytosolic enzyme involved in the transport of acetyl-CoA from the mitochondria to the cytosol; a nuclear ACL is involved in delivery of acetyl-CoA to histone acetyltransferases (HAT) involved in modulating gene expression at the level of epigenetic marking

  • Acetyl-CoA carboxylase (ACC): rate-limiting and highly regulated enzyme of de novo fatty acid synthesis

  • Fatty acid synthase (FAS): homodimeric enzyme that carries out all of the reactions of de novo fatty acid synthesis generating palmitic acid as the final product

  • Carbohydrate-response element-binding protein: major glucose-responsive transcription factor that is required for glucose-induced expression of L-PK and the lipogenic genes ACC and FAS

  • Steroyl-CoA desaturase (SCD): rate-limiting enzyme for the synthesis of monounsaturated fatty acids (MUFAs), primarily oleate (18:1) and palmitoleate (16:1), both of which represent the majority of MUFA present in membrane phospholipids, triglycerides, and cholesterol esters

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De Novo Fatty Acid Synthesis

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The pathway for fatty acid synthesis occurs in the cytoplasm, utilizes the oxidation of NADPH, and requires an activated intermediate. The activated intermediate is malonyl-CoA which is derived via carboxylation of acetyl-CoA. The synthesis of malonyl-CoA represents the first committed step as well as the rate-limiting and major regulated step of fatty acid synthesis (Figure 19-1). This reaction is catalyzed by the biotin-requiring enzyme, acetyl-CoA carboxylase (ACC). Human tissues express 2 distinct ACC genes identified as ACC1 and ACC2. The differential regulation of these 2 genes and the encoded enzymes is discussed in the Regulation of Fatty Acid Synthesis section.

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FIGURE 19-1:

Synthesis of malonyl-CoA catalyzed by acetyl-CoA carboxylase. Reproduced with permission of the medical biochemistry page, LLC.

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The reactions of fatty acid synthesis are catalyzed by fatty acid synthase (FAS) (Figure 19-2). All of the reactions of fatty acid synthesis take place in distinct reactive centers within the enzyme. These reactive centers are β-keto-ACP synthase, β-keto-ACP reductase, 3-OH acyl-ACP dehydratase and enoyl-CoA reductase. ACP is acyl-carrier protein but does not refer to a distinct protein but rather refers to a distinct domain of the enzyme which contains a phosphopantetheine group. The 2 reduction reactions require NADPH oxidation to NADP+. The acetyl-CoA and malonyl-CoA are transferred to ACP by the action of acetyl-CoA transacylase and malonyl-CoA transacylase, respectively. The attachment of these carbon atoms to ACP allows them to enter the fatty acid synthesis cycle. The primary fatty acid synthesized by FAS is palmitate. Palmitate is then released from the enzyme and can then undergo separate elongation and/or unsaturation to yield other fatty acid molecules.

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FIGURE 19-2:

Reactions of fatty acid synthesis catalyzed by FAS. Only half of the normal head-to-tail (head-to-foot) dimer of functional FAS is shown. Synthesis of malonyl-CoA from CO2 and acetyl-CoA is carried out by ACC as shown in Figure 19-1. The acetyl group is initially attached ...

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