Acyl carrier protein fatty acid synthetase

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. 

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... 

NADP+ [EC 1.3.1.10] to produce 2,3-dehydroacyl-[acyl-carrier-protein] and NADH or NADPH. See also Fatty Acid Synthetase... 

This enzyme, officially known as 3-hydroxypalmitoyl-[acyl-carrier protein] dehydratase [EC 4.2.1.61], is the fatty-acid synthase component that catalyzes the conversion of (3 i )-3-hydroxypalmitoyl-[acyl-carrier protein] to form 2-hexadecenoyl-[acyl-carrier protein] and water. This enzyme displays specificity toward 3-hydroxyacyl-[acyl-carrier protein] derivatives (with chain lengths from Ci2 to Cie), with highest activity on the palmitoyl derivative. See also Fatty Acid Synthetase... 

This enzyme [EC 2.3.1.41], also known as 3-oxoacyl-[acyl-carrier protein] synthase, catalyzes the reaction of an acyl-[acyl-carrier protein] with malonyl-[acyl-carrier protein] to produce a 3-oxoacyl-[acyl-carrier protein], carbon dioxide, and the [acyl-carrier protein]. See also Fatty Acid Synthetase... 

The rate limiting step in fatty acid synthesis is catalyzed by acetyl-CoA carboxylase to produce malonyl-CoA at the expense of one ATP.31 Malonate and acetate are transferred from CoA to acyl carrier protein in the cytosolic fatty acid synthetase complex, where chain extension leads to the production of palmitate. Palmitate can then be transferred back to CoA, and the chain can be extended two carbons at a time through the action of a fatty acid elongase system located in the endoplasmic reticulum. The >-hydroxylation that produces the >-hydroxyacids of the acylceramides is thought to be mediated by a cytochrome p450 just when the fatty acid is long enough to span the endoplasmic reticular membrane. 

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 ... 

The pathway from acetate to palmitic acid (actually a palmitic acid-acyl carrier protein complex) involves at least nine enzymes acetyl CoA synthetase, acetyl CoA carboxylase, and the seven enzyme fatty acid synthetase complex. We chose first to test the effect of these compounds on acetyl CoA carboxylase (ACCase) activity. There were several reasons to select ACCase as the... 

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. 

It is assumed that the coenzyme A ester (CoA-ester) of the R(-)-enantiomer acts as a substrate for the fatty acid deshydrogenase, thus eliminating the chiral center. The next step may, or may not, take place, depending whether or not the CoA-ester must be transferred to an acyl-carrier protein or another site in the fatty acid synthetase system, so that a stereoselective reduction by an enoykeductase can take place. Thus the nature of X is unknown. Similar epimerization reactions were also described for some other arylpropionic acids such as benoxaprofen, carprofen, and isopropyl-indanyl-propionic acid. ° It was demonstrated that the configural inversion does not take place in the liver, and that the responsible enzyme, R-(-)-aryIpro-... 

Both acyl carrier protein (ACP) of fatty acid synthetase and coenzyme A (CoA)... 

The utility of this methodology is illustrated by the stereoselective synthesis of ( + )-cer-ulenin (759), an antifungal antibiotic first isolated from the culture filtrate of Cephalosporium caerulens. Its ability to inhibit lipid biosynthesis in Escherichia coli by irreversibly binding P-keto-acyl-carrier protein synthetase, the enzyme responsible for the chain lengthening reaction in fatty acid synthesis, has attracted interest in its mechanism of action. D-Tartaric acid... 

Fatty acid synthesis occurs by way of a rather complex series of reactions catalyzed by a multienzyme complex called the fatty acid synthetase system. This system is made up of six enzymes and an additional protein, acyl carrier protein (ACP), to which all intermediates are attached. 

In Escherichia coli an acyl-acyl carrier protein synthetase that uses acyl carrier protein instead of CoA for fatty acid activation has been described (Ray and Cronan, 1976). The hydrocarbon utilizing yeast, Candida lipolyti-ca fabricates two distinct long chain acyl-CoA synthetases one of them activates fatty acids exclusively for lipid synthesis, while the other one does so for p-oxidation (Numa, 1981). Comparisons of the mitochondrial and microsomal long chain acyl-CoA synthetases of rat liver have shown, however, that the two enzymes are very similar (Philipp and Parsons, 1979 Tanaka et al., 1979). 

Synthesis of long-chain fatty acids from acetyl-CoA and malonyl-CoA involves a number of sequential reactions (Fig. 11.1). Acyl groups are attached to the 4 -phosphopantetheine prosthetic group of acyl carrier protein (ACP) during modification by fatty acid synthetase. 

Figure 11.2 A comparative picture of the fatty acid synthetase (FAS) systems in yeast, animal, bacterial and plant cells. fi-KS, -ketoacyl AGP synthetase P-KR, A-ketoacyl AGP reductase DH, -OH acyl-AGP dehydrase ER, enoyl AGP reductase AT, acetyl transacylase MT, malonyl transacylase TE, thioesterase AGP, acyl carrier protein. See Shimakata and Stumpf (19S2a,b) and Wakil etal, (1983) for details.

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. 

There is increasing evidence that in plant tissues the synthesis of palmitic acid, the most abundant and important saturated fatty acid in higher plants, involves at/e novo system, so called because it utilizes acetyl-CoA, malonyl-CoA, acyl carrier protein (ACP), and a battery of soluble, nonassociated enzymes (palmitoyl-ACP synthetase) to form, as its terminal product, palmi-toyl-ACP. Palmitoyl-ACP is then elongated by another set of enzymes called... 

The 3-keto reductase step is equivalent to that found in fatty acid synthesis, although it occurs late (and only once) in this process. Indeed, thiol-bound acetoacetate proved inactive as a substrate for the aromatic complex, whereas it was reduced by fatty acid synthetase (Dimrothe/a/., 1972). Thus, the carbonyl group adjacent to the terminal methyl position is not susceptible to reduction by the aromatic synthetase, despite the apparent presence of a suitable reductase, possibly because it is held on the enzyme surface in an inappropriate enolic configuration (Packter, 1973). If so, it may not prove acceptable, since the 3-ketoacyl-acyl carrier protein (ACP) reductase from Escherichia coli only accepts keto substrates and does not react with or bind to the enol form of 3-ketoacyl derivatives (Schulz and Wakil, 1971). 

Sohby C. Regulation of fatty acid synthetase activity. J Biol Chem 1979 254 8561-8566. ElhusseinSA, MiemykJA, OhlroggeJB. Plant holo-(acyl carrier protein) synthase. Biixzhem J 1988 252 39-45. 

Fatty acid biosynthesis utilizes acetyl CoA. Radioactive acetate is the common experimental substitute, but in the developing seed sucrose from the mother plant is the initial source of substrate. Biosynthesis is a multi-step process (Fig. 3.14) which firstly involves the formation of malonyl CoA by carboxylation of acetyl CoA with carbon dioxide. This malonyl CoA is then accepted by acyl carrier protein (ACP) which is part of a multienzyme complex called the ACP fatty acid synthetase complex. The malonyl CoA is then condensed with... 

---