Acetyl coenzyme A-acyl carrier protein

Selected entries from Methods in Enzymology [vol, page(s)] Assay, 1, 611 3, 935-938 63, 33 separation by HPLC, 72, 45 extraction from tissues, 13, 439 formation of, 1, 486, 518, 585 5, 466 free energy of hydrolysis, 1, 694 substrate for the following enzymes [acetyl-coenzyme A acyl carrier protein transacylase, 14, 50 acetyl-coenzyme A carboxylase, 14, 3, 9 acetyl-coenzyme A synthetase, 13, 375 N-acetyltransferase, 17B, 805 aminoacetone... 

Shimakata, T. and Stumpf, P.K. (1983) The purification and function of acetyl coenzyme A acyl carrier protein transacylase. J. Biol. them. 258, 3592-3598. 

T. Shimakata and P. K. Stumpf, The purification cuid function of acetyl coenzyme A acyl carrier protein tremsacylase, 3. Biol. Chem. 258 3592 (1983). 

We can descnbe the major elements of fatty acid biosynthesis by considering the for mation of butanoic acid from two molecules of acetyl coenzyme A The machinery responsible for accomplishing this conversion is a complex of enzymes known as fatty acid synthetase Certain portions of this complex referred to as acyl carrier protein (ACP), bear a side chain that is structurally similar to coenzyme A An important early step m fatty acid biosynthesis is the transfer of the acetyl group from a molecule of acetyl coenzyme A to the sulfhydryl group of acyl carrier protein... 

All polyketides use the same general mechanism for chain elongation. Acetyl coenzyme A provides acetate (C2) units, which are condensed by a ketosynthase (KS). This in turn catalyzes condensation of the growing chain onto an acyl carrier protein (ACP), as generalized in Fig. 1.4. Enzymes such as ketoreductase (KR), enoyl reductase (ER), and dehydratase (DH) establish the oxidation state of caibon during translation, imparting structural diversity. Successive translation of each module leads to a chain of the required length that is eventually passed to thioeste-rase (TE), which releases the chain as a free acid or lactone. 

The fatty acid synthase protein is known to contain an acyl carrier protein (ACP) binding site, and also an active-site cysteine residue in the P-ketoacyl synthase domain. Acetyl and malonyl gronps are successively transferred from coenzyme A esters and attached to the thiol groups of Cys and ACP. 

Each subunit of the enzyme binds acetyl residues as thioesters at two different SH groups at one peripheral cysteine residue (CysSH) and one central 4-phosphopante-theine group (Pan-SH). Pan-SH, which is very similar to coenzyme A (see p. 12), is covalently bound to a protein segment of the synthase known as the acyl-carrier protein (ACP). This part functions like a long arm that passes the substrate from one reaction center to the next. The two subunits of fatty acid synthase cooperate in this process the enzyme is therefore only capable of functioning as a dimer. 

This enzyme [EC 2.3.1.38], also referred to as acetyl-CoA [acyl-carrier protein] 5-acetyltransferase, transfers an acetyl group from one acetyl-CoA to an acyl-carrier-protein (ACP) to form free coenzyme A and the acetyl-[acyl-carrier-protein]. See also Fatty Add Synthase... 

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).

The sex pheromone is interesting from a biosynthetic perspective (see Fig. 4.3) because it is closely connected with primary metabohsm. That is, the monomer 4 is an intermediate in fatty acid biosynthesis. Condensation of acetyl-ACP (8 ACP, acyl carrier protein) with malonyl-CoA (9 CoA, coenzyme A) yields acetoacyl-ACP (10). Enantioselective reduction with NADPH leads to (R)-3-hydroxybutyryl-ACP (11). Two units of this precursor could then be condensed to form the pheromone 5, which then degrades to 4 and 6 as described above. Alternatively, 4 can also be formed by direct hydrolysis of intermediate 11. 

The introduction to Section 26.8 pointed out that mevalonic acid is the biosynthetic precursor of isopentenyl pyrophosphate. The early steps in the biosynthesis of mevalonate from three molecules of acetic acid are analogous to those in fatty acid biosynthesis (Section 26.3) except that they do not involve acyl carrier protein. Thus, the reaction of acetyl coenzyme A with malonyl coenzyme A yields a molecule of acetoacetyl coenzyme A. 

The sulfur of acyl carrier protein acts as a nucleophile and attacks the acetyl group of acetyl coenzyme A. 

Fatty acid synthesis starts with acetyl-CoA, and the chain grows from the tail end so that carbon 1 and the alpha-carbon of the complete fatty acid are added last. The first reaction is the transfer of the acetyl group to a pantothenate group of acyl carrier protein (ACP), a region of the large mammalian FAS protein. (The acyl carrier protein is a small, independent peptide in bacterial FAS, hence the name.) The pantothenate group of ACP is the same as is found on Coenzyme A, so the transfer requires no energy input ... 

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). 

Figure 1. General condensation reaction in polyketide biosynthesis. The starter units are attached to thiol groups of the ketosynthase (KS), and extender units to thiol groups of either acyl carrier protein or acetyl coenzyme A (X).

The reaction catalyzed by acetyl CoA carboxylase is the rate-limiting step in fatty acid biosynthesis. The malonyl group is transferred from coenzyme A to acyl carrier protein similarly, the acetyl group is transferred from coenzyme A to acyl carrier... 

To carry out these processes, the fatty acid synthase required a set of catalytic activities that are responsible for the respective step of a set of the cycle reactions. Acyltransferase (AT) transfers both the acetyl starter unit and malonyl chain-extender units from the respective coenzyme A esters to the appropriate thiol group of the synthase. P-Ketoacyl synthase and acyl carrier protein are responsible for chain elongation. P-Ketoreductase, dehydratase, and enoyl reductase are for... 

Though the reactions in fatty acid biosynthesis resemble the reversal of the analogous reactions in oxidation, fatty acid synthesis is distinct from fatty acid oxidation (Figure 18.23). For example, acyl groups are carried by acyl carrier protein in fatty acid synthesis, instead of coenzyme A. Furthermore, reducing equivalents come from NADPH and energy is provided by ATP. Overall, the biosynthesis of palmitate from 8 acetyl-CoAs requires 7 ATPs and 14 NADPHs. 

Biochemical function in human metabolism. Activation of metabolites by coenzyme A while a thioester as a high-energy compound is generated. Examples acetyl CoA, succinyl-CoA, acyl-CoA-derivates. The acyl-carrier protein is a component of the fatty acid-synthetase complex. Both coenzymes transfer acyl groups. 

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