Fatty acid synthase complex, structure

Pantothenic acid is a precursor for the synthesis of coenzyme A (CoA, CoASH) and forms part of the swinging sulfhydryl arm of the fatty acid synthase complex (Chapter 19). Its structure is shown in Figure 38-20. 

All the reactions in the synthetic process are catalyzed by a multienzyme complex, fatty acid synthase. Although the details of enzyme structure differ in prokaryotes such as Escherichia coli and in eukaryotes, the four-step process of fatty acid synthesis is the same in all organisms. We first describe the process as it occurs in A1, coli, then consider differences in enzyme structure in other organisms. 

FIGURE 21-7 Structure of fatty acid synthases. The fatty acid synthase of bacteria and plants is a complex of at least seven different polypeptides. In yeast, all seven activities reside in only two polypeptides the vertebrate enzyme is a single large polypeptide. 

Animal FASs are functional dimers [76]. While /3-ketoacyl synthase requires dimer formation for activity [77], catalysis of the remaining FAS reactions is carried out by the monomeric enzyme. This behavior is reminiscent of yeast fatty acid synthase, where the -ketoacyl synthase and ACP from different subunits also contribute to the same active site. Electron microscopy and small angle scattering experiments have further defined the structure of the functional complex [34,78]. The overall shape of the molecule, as visualized by electron microscopy, is two side by side cylinders with dimensions of 160x146 x 73 A [34]. 

Although the PKSs of plants have received little attention relative to those of microbial origin, the fatty acid synthases (FASs) of a wide range of plant, animal and microbial sources have been subjected to intensive study and shown to differ in their molecular structure and complexity. Thus type 1 FASs produced by animals, fimgi and yeasts are high molecular weight multienzyme complexes, in which the individual active sites may be covalently linked components of a single polypeptide chain. In the type II FASs of... 

Despite their enormous structural diversity, polyketide metabolites are related by their common derivation from highly functionalised carbon chains whose assemblies are controlled by multifunctional enzyme complexes, the polyketide synthases (PKSs) which, like the closely related fatty acid synthases, catalyse repetitious sequences of decarboxylative condensation reactions between simple acyl thioesters and malonate, as shown in Fig. 3 [7]. Each condensation is followed by a cycle of modifying reactions ketoreduction, dehydration and enoyl reduction. In contrast to fatty acid biosynthesis where the full cycle of essentially reductive modifications normally follow each condensation reduction, the PKSs can use this sequence in a highly selective and controlled manner to assemble polyketide intermediates with an enormous number of permutations of functionality along the chain. As shown in Fig. 3, the reduction sequence can be largely or entirely omitted to produce the classical polyketide intermediate which bears a carbonyl on every alternate carbon and which normally cyclises to aromatic polyketide metabolites. On the other hand, the reductive sequence can be used fully or partially after each condensation to produce highly functionalised intermediates such as the Reduced polyketide in Fig. 3. Basic questions to be answered are (i) what is the actual polyketide intermediate... 

Enzymes. The enzymes that catalyze fatty acid synthesis are significantly different in structure than those in /3-oxidation. In eukaryotes, most of these enzymes are components of a multienzyme complex referred to as fatty acid synthase. 

Malonyl-CoA is then used for fatty acid synthesis. This process requires Fatty Acid Synthase (FAS) (Chirala and Wakil, 2004) that uses acetyl-CoA as a primer, malonyl-CoA as a two-carbon donor, and NADPH as a reducing equivalent (Fig. 1.1). The predominant fatty acid produced by FAS is palmitic acid (Cl 6 0). The structure of FAS has been extensively studied (Asturias et al., 2005 Maier et ah, 2006). FAS is a multifunctional complex consisting of two identical monomers. However, only the dimeric form is active (Chirala et al.,... 

Chang, S.I., Hammes, G.G. 1990. Structure and mechanism of action of a multifunctional enzyme complex fatty acid synthase. Acc. Chem. Res. 23 363-369. 

Fig. 3 Quaternary structures of the (a) fatty acid beta-oxidation complex of E. coli (From [12], (b) porcine fatty acid synthase (From [14]), and (c) active sites of the Arabidopsis shikimate pathway enzymes, DHQ left) and SDH (right) (From [17])...

---