Fatty acid biosynthesis acyl carrier protein

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... 

Biosynthesis of coen2yme A (CoA) ia mammalian cells incorporates pantothenic acid. Coen2yme A, an acyl group carrier, is a cofactor for various en2ymatic reactions and serves as either a hydrogen donor or an acceptor. Pantothenic acid is also a stmctural component of acyl carrier protein (AGP). AGP is an essential component of the fatty acid synthetase complex, and is therefore requited for fatty acid synthesis. Free pantothenic acid is isolated from hver, and is a pale yeUow, viscous, and hygroscopic oil. 

The 4-phosphopantetheine group of CoA is also utilized (for essentially the same purposes) in acyl carrier proteins (ACPs) involved in fatty acid biosynthesis (see Chapter 25). In acyl carrier proteins, the 4-phosphopantetheine is covalently linked to a serine hydroxyl group. Pantothenic acid is an essential factor for the metabolism of fat, protein, and carbohydrates in the tricarboxylic acid cycle and other pathways. In view of its universal importance in metabolism, it is surprising that pantothenic acid deficiencies are not a more serious problem in humans, but this vitamin is abundant in almost all foods, so that deficiencies are rarely observed. 

AGP, acyl carrier protein Figure 4 Biosynthesis of fatty acids. 

An alternative route to mevalonic acid is also possible, which differs from the former one in that the formation of P-hydroxy-P-methylglutaryl residue occurs on the surface of an acyl carrier protein (like in fatty acid biosynthesis). The intermediary product in this route, P-hydroxy-p-methylglutaryl-S-ACP, is re-duced by another enzyme to mevalonic acid. 

Phosphopantetheine tethering is a posttranslational modification that takes place on the active site serine of carrier proteins - acyl carrier proteins (ACPs) and peptidyl carrier proteins (PCPs), also termed thiolation (T) domains - during the biosynthesis of fatty acids (FAs) (use ACPs) (Scheme 23), polyketides (PKs) (use ACPs) (Scheme 24), and nonribosomal peptides (NRPs) (use T domain) (Scheme 25). It is only after the covalent attachment of the 20-A Ppant arm, required for facile transfer of the various building block constituents of the molecules to be formed, that the carrier proteins can interact with the other components of the different multi-modular assembly lines (fatty acid synthases (FASs), polyketide synthases (PKSs), and nonribosomal peptide synthetases (NRPSs)) on which the compounds of interest are assembled. The structural organizations of FASs, PKSs, and NRPSs are analogous and can be divided into three broad classes the types I, II, and III systems. Even though the role of the carrier proteins is the same in all systems, their mode of action differs from one system to another. In the type I systems the carrier proteins usually only interact in cis with domains to which they are physically attached, with the exception of the PPTases and external type II thioesterase (TEII) domains that act in trans. In the type II systems the carrier proteins selectively interact... 

Scheme 23 Example of an acyl carrier protein (ACP in red) in a type I FAS. The palmitic acid is depicted as a representative fatty acid. During its biosynthesis, the ACP (red) interacts iteratively with each domain (DH, dehydrogenase ER, enoyl reductase KR, ketoreductase KS, ketosynthase TE, thioesterase) until the palmitic acid has reached its proper length.

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. 

Fatty acid chains are taken apart two carbon atoms at a time by (3 oxidation. Biosynthesis of fatty acids reverses this process by using the two-carbon acetyl unit of acetyl-CoA as a starting material. The coupling of ATP cleavage to this process by a carboxylation-decarboxylation sequence, the role of acyl carrier protein (Section H,4), and the use of NADPH as a reductant (Section I) have been discussed and are summarized in Fig. 17-12, which gives the complete sequence of... 

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. 

After malonyl-CoA synthesis, the remaining steps in fatty acid synthesis occur on fatty acid synthase, which exists as a multienzyme complex. In the initial reactions acetyl-CoA and malonyl-CoA are transferred onto the protein complex by acetyl-CoA transacylase and malonyl-CoA transacylase (step 1 and step 2 in fig. 18.12a). The acceptor for the acetyl and malonyl groups is acyl carrier protein (ACP). ACP also carries all of the intermediates during fatty acid biosynthesis. The prosthetic group that binds these intermediates is... 

Outline of the reactions for fatty acid biosynthesis. Fatty acids grow in steps of two-carbon units and take place on a multienzyme complex, (a) The initial reactions of fatty acid biosynthesis are shown. In the first reaction, acetyl-CoA reacts with ACP (acyl carrier protein) to form acetyl-ACP (step 1). ACP is shown with its SH group emphasized (see fig. 18.13) to remind readers that the acyl derivatives are linked to ACP via a thioester bond. Malonyl-CoA, derived from the carboxylation of acetyl-CoA (see fig. 18.9), reacts... 

Figure 1 Polyketide biosynthesis. Polyketide backbones are formed via condensations from acyl-CoA thioesters of carboxylic acids. The (3-ketone which results from each condensation can undergo a series of reductive steps analogous to fatty acid biosynthesis. However, either none or only some of the reductive activities may occur in a given cycle. This allows PKSs to generate diversity through selection of priming and extender units, variation of the reductive cycle, and stereoselectivity. (ACP, acyl carrier protein AT, acyl transferase KS, ketosynthase DH, dehydratase ER, enoylreductase KR, ketoreductase TE, thioesterase.) The structure depicted in the lower right-hand corner is representative of the possible structural variations that can arise during polyketide biosynthesis.

Heath, R.J., Rock, C.O. Roles of the FabA and FabZ beta-hydroxyacyl-acyl carrier protein dehydratases in Escherichia coli fatty acid biosynthesis. J Biol Chem 271 (1996) 27795-27801. 

Each of the enzymatic activities located in a single polypeptide chain of the mammalian fatty acid synthetase exists as a distinct protein in E. coli. The acyl-carrier protein (ACP) of E. coli has an Mr = 8,847 and contains 4-phosphopantotheine. The dehydratase has a molecular weight of 28,000 and catalyzes either trans 2-3 or cis 3-4 dehydration of the hydroxy acid intermediates in the biosynthesis of palmitic acid. When the chain length of the hydroxy fatty acid is C[ the synthesis of palmitoleic acid is achieved as follows ... 

Pantothenic acid has a central role in energy-yielding metabolism as the functional moiety of coenzyme A (CoA), in the biosynthesis of fatty acids as the prosthetic group of acyl carrier protein, and through its role in CoA in the mitochondrial elongation of fatty acids the biosynthesis of steroids, porphyrins, and acetylcholine and other acyl transfer reactions, including postsynthetic acylation of proteins. Perhaps 4% of all known enzymes utilize CoA derivatives. CoA is also bound by disulfide links to protein cysteine residues in sporulating bacteria, where it may be involved with heat resistance of the spores, and in mitochondrial proteins, where it seems to be involved in the assembly of active cytochrome c oxidase and ATP synthetase complexes. 

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