Fatty acyl synthase complex

Malonyl-CoA is converted into new fatty acids by a remarkable enzyme system, the fatty acyl synthase complex. This consists of several individual active sites on the same polypeptide chain, with the intermediates that are involved in the process being positioned sequentially in the correct temporal order in these different sites. 

FIGURE 21-5 Sequence of events during synthesis of a fatty acid. The fatty acid synthase complex is shown schematically. Each segment of the disk represents one of the six enzymatic activities of the complex. At the center is acyl carrier protein (ACP), with its phosphopantetheine arm ending in an —SH. The enzyme shown in blue is the one that will act in the next step. As in Figure 21-3, the initial acetyl group is shaded yellow, C-1 and C-2 of malonate are shaded pink, and the carbon released as C02 is shaded green. Steps (T) to (7) are described in the text. 

Overview Fatty acid synthesis involves the condensation of two-carbon units, in the form of acetyl CoA, to form long hydrocarbon chains in a series of reactions. These reactions are carried out on the fatty acid synthase complex using NADPH as reductant. The fatty acids are covalently linked to acyl carrier protein (ACP) during their synthesis. 

In prokaryotes, each of the reactions of fatty acid synthesis is catalyzed by a separate enzyme. However, in eukaryotes, the enzymes of the fatty acid synthesis elongation cycle are present in a single polypeptide chain, multifunctional enzyme complex, called fatty acid synthase. The fatty acid synthase complex exists as a dimer, with the ACP moiety shuttling the fatty acyl chain between successive catalytic sites, and from one subunit of the dimer to the other. It is, in effect, a highly efficient production line for fatty acid biosynthesis. 

The most important functions of pantothenic acid are its incorporation in coenzyme A and acyl carrier protein (AGP). Both CoA and AGP/4-phosphopantetheine function metabolically as carriers of acyl groups. Coenzyme A forms high-eneigy thioester bonds with carboxylic acids. The most important coenzyme is acetyl CoA. Acetic acid is produced during the metabolism of fatty acids, amino acids, or carbohydrates. The active acetate group of acetyl CoA can enter the Krebs cycle and is used in the synthesis of fatty acids or cholesterol. AGP is a component of the fatty acid synthase multienzyme complex. This complex catalyzes several reactions of fatty acid synthesis (condensation and reduction). The nature of the fatty acid synthase complex varies considerably among different species (91). 

Palmitate, the product released by the fatty acid synthase complex, is converted to a series of other fatty acyl CoAs by elongation and desaturation reactions. 

Figure 6-7. Fatty acid synthesis. Malonyl CoA provides the 2-carbon units that are added to the growing fatty acyl chain. The addition and reduction steps are repeated until palmitic acid is produced. P = a phosphopantetheinyl group attached to the fatty acid synthase complex Cys-SH = a cys-teinyl residue.

The answer is e. (Murray, pp 230-267. Scriver, pp 2297-2326. Sack, pp 121-138. Wilson, pp 287-320.) The fatty acid synthase complex of mammals is composed of two identical subunits. Each of the subunits is a multienzyme complex of seven enzymes and the acyl carrier protein component. All the components are covalently linked together thus, all the components are on a single polypeptide chain, which functions in the presence of another identical polypeptide chain. Each cycle of fatty acid synthesis employs the acyl carrier protein and six enzymes acetyl transferase, malonyl transferase, p-ketoacyl synthase, p-ketoacyl reductase, dehydratase, and enoyl reductase. When the final fatty acid length is reached (usually C16), thioesterase hydrolyzes the fatty acid off of the synthase complex. 

The first step in de novo fatty acid synthesis is the production of malonyl-CoA from acetyl-CoA and bicarbonate. This committed step is catalyzed by acetyl-CoA carboxylase present in the cytoplasm of liver cells and adipocytes. After replacement of the CoA residue in acetyl-CoA by ACP (acyl carrier protein), malonyl-ACP is used to convert acetyl-ACP to butyryl-ACP by the fatty acid synthase complex. In this multistep reaction, NADPH is used as donor of hydrogen atoms and CO2 is produced. Butyryl-ACP is subsequently elongated to hexanoyl-ACP by a similar process in which malonyl-ACP serves as donor of two carbon atoms required for lengthening of the growing acyl chain. This process is repeated until palmitic acid... 

Glucose 6-phosphate dehydrogenase 6-Phosphogluconate dehydrogenase Pyruvate dehydrogenase Acetyl-CoA carboxylase Malic enzyme ATP-cItrate lyase Fatty acid synthase complex Stearoyl-CoA dehydrogenase Acyl-CoA-glycerol transferases... 

ACP is a protein that carries acyl moieties in fatty acid biosynthesis. It contains a phosphpantetheine moiety as found in coenzyme A (Figure 18.26). ACP may have a role acting as a swinging arm that carries the acyl moiety through the multiple activities of the fatty acid synthase complex. 

Fatty acid biosynthesis from acetyl-CoA to palmitate involves an enzyme complex called fatty acid synthase, which appears to operate by a swinging arm mechanism involving the growing fatty acyl group linked to acyl carrier protein (Figure 18.29). Each of the individual enyzmatic activities below is a part of the fatty acid synthase complex. 

Fig. 33.12. Phosphopantetheinyl residue of the fatty acid synthase complex. The portion derived from the vitamin, pantothenic acid, is indicated. Phosphopantetheine is covalently linked to a serine residue of the acyl carrier protein (ACP) segment of the enzyme. The sulfhydryl group reacts with malonyl CoA to form a thioester.

Fig. 33.15. Synthesis of palmitate on the fatty acid synthase complex. Initially, acetyl CoA adds to the synthase. It provides the to-methyl group of palmitate. Malonyl CoA provides the 2-carbon units that are added to the growing fatty acyl chain. The addition and reduction steps are repeated until palmitate is produced. 1. Transfer of the malonyl group to the phosphopantetheinyl residue. 2. Condensation of the malonyl and fatty acyl groups. 3. Reduction of the P-ketoacyl group. 4. Dehydration. 5. Reduction of the double bond. P = a phosphopantetheinyl group attached to the fatty acid synthase complex Cys-SH = a cysteinyl residue.

Acetyl CoA is converted to malonyl CoA, which provides the 2-carbon units for elongation of the growing fatty acyl chain on the fatty acid synthase complex. Acetyl CoA carboxylase, the enzyme that catalyzes the conversion of acetyl CoA to malonyl CoA, is controlled by three of the major mechanisms that regulate enzyme activity (Fig. 36.5). It is activated by citrate, which causes the enzyme to... 

Malonyl CoA, the product of the acetyl CoA carboxylase reaction, provides the carbons for the synthesis of palmitate on the fatty acid synthase complex. Malonyl CoA also inhibits carnitine palmitoyltransferase I (CPTI, also known as carnitine acyltransferase 1), the enzyme that prepares long-chain fatty acyl CoA for transport into mitochondria (Fig. 36.6). In the fed state, when acetyl CoA carboxylase is active and malonyl CoA levels are elevated, newly synthesized fatty acids are converted to triacylglycerols for storage, rather than being transported into mitochondria for oxidation and ketone body formation. 

AGP is a molecule that earmarks acyl groups for fatty-acid synthesis. It can be managed separately from acyl-GoA groups. Also, the AGP attaches to the acyl groups like a swinging arm that tethers it to the fatty-acid synthase complex. 

AGP carrier of acyl groups in the biosynthesis of fatty acids. This protein (9000 Daltons) is central to the fatty acid synthase complex and binds covalently to the acyl intermediates. The acyl derivative is often represented as acyl-ACP. See also acyl coenzyme A. 

The malonyl group is transferred onto an acyl carrier protein, and then reacts with the growing fatty acid chain, bound to the central acyl carrier protein of the fatty acid synthase complex. The carbon dioxide that was added to form malonyl CoA is lost in this reaction. For the first cycle of reactions, the central acyl carrier protein carries an acetyl group, and the product of reaction with malonyl CoA is acetoacetyl-ACP in subsequent reaction cycles, it is the growing fatty acid chain that occupies the central ACP, and the product of reaction with malonyl CoA is a ketoacyl-ACP. 

In bacteria and plants, the individual enzymes of the fatty acid synthase system are separate, and the acyl radicals are found in combination with a protein called the acyl carrier protein (ACP). However, in yeast, mammals, and birds, the synthase system is a multienzyme polypeptide complex that incorporates ACP, which takes over the role of CoA. It contains the vitamin pantothenic acid in the form of 4 -phosphopan-tetheine (Figure 45-18). The use of one multienzyme functional unit has the advantages of achieving the effect of compartmentalization of the process within the cell without the erection of permeability barriers, and synthesis of all enzymes in the complex is coordinated since it is encoded by a single gene. 

Figure 21-2. Fatty acid synthase multienzyme complex. The complex is a dimer of two identical polypeptide monomers, 1 and 2, each consisting of seven enzyme activities and the acyl carrier protein (ACP). (Cys— SH, cysteine thiol.) The— SH of the 4 -phosphopantetheine of one monomer is in close proximity to the— SH of the cysteine residue of the ketoacyl synthase of the other monomer, suggesting a "head-to-tail" arrangement of the two monomers. Though each monomer contains all the partial activities of the reaction sequence, the actual functional unit consists of one-half of one monomer interacting with the complementary half of the other. Thus, two acyl chains are produced simultaneously. The sequence of the enzymes in each monomer is based on Wakil.

Fatty add synthase is a large multienzyme complex in the cytoplasm that is rapidly induced in the liver after a meal by high carbohydrate and the concomitant rise in insulin levels. It contains an acyl carrier protein (AGP) that requires the vitamin pantothenic add. Althoi malonyl CoA is the substrate used by fetty acid synthase, only the carbons from the acetyl CoA portion are actually incorporated into the fatty acid produced. Therefore, the fetty add is derived entirely from acetyl CoA. 

The elongation of the fatty acid by fatty acid synthase concludes at Cie, and the product, palmitate (16 0), is released. Unsaturated fatty acids and long-chain fatty acids can arise from palmitate in subsequent reactions. Fats are finally synthesized from activated fatty acids (acyl CoA) and glycerol 3-phosphate (see p. 170). To supply peripheral tissues, fats are packed by the hepatocytes into lipoprotein complexes of the VLDL type and released into the blood in this form (see p. 278). 

Figure 8-2. Pathway for synthesis of palmitate by the fatty acid synthase (FAS) complex. Schematic representation of a single cycle adding two carbons to the growing acyl chain. Formation of the initial acetyl thioester with a cysteine residue of the enzyme preceded the first step shown. Acyl carrier protein (ACP) is a component of the FAS complex that carries the malonate covalently attached to a sulfhydryl group on its phosphopantatheine coenzyme (-SH in the scheme).

Pantothenic acid (8.48), a hydroxyamide, occurs mainly in liver, yeast, vegetables, and milk, but also in just about every other food source, as its name implies [pantos (Greek) = everywhere]. It is part of coenzyme A, the acyl-transporting enzyme of the Krebs cycle and lipid syntheses, as well as a constituent of the acyl carrier protein in the fatty-acid synthase enzyme complex. 

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