Fatty acid synthase enzyme systems

The Fatty Acid Synthase Enzyme Systems The FAS enzyme systems are central for the biosynthesis of saturated fatty acids [1] and share many similarities with the polyketide synthases (PKSs) involved in the biosynthesis of many polyketides [6] see Section 2.1 for details. Common precursors, functional gronps, and reactions are involved in each biosynthetic step. Saturated fatty acids, such as palmitic acid (1, Scheme 3.2), represent a rather small and structurally simple class of natural products produced by the FAS enzyme systems. The FAS enzyme system in animals is a large multifunctional protein with seven individnal... 

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. 

The synthesis of long-chain fatty acids (lipogenesis) is carried out by two enzyme systems acetyl-CoA carboxylase and fatty acid synthase. 

Particularly important to the pathways of modular synthases is the incorporation of novel precursors, including nonproteinogenic amino acids in NRP systems [17] and unique CoA thioesters in PK and fatty acid synthases [18]. These building blocks expand the primary metabolism and offer practically unlimited variability applied to natural products. Noteworthy within this context is the contiguous placement of biosynthetic genes for novel precursors within the biosynthetic gene cluster in prokaryotes. Such placement has allowed relatively facile elucidation of biosynthetic pathways and rapid discovery of novel enzyme mechanisms to create such unique building blocks. These new pathways offer a continued expansion of the enzymatic toolbox available for chemical catalysis. 

Several architectural paradigms are known for polyketide and fatty acid synthases. While the bacterial enzymes are composed of several monofunctional polypeptides which are used during each cycle of chain elongation, fatty acid and polyketide synthases in higher organisms are multifunctional proteins with an individual set of active sites dedicated to each cycle of condensation and ketoreduction. Peptide synthetases also exhibit a one-to-one correspondence between the enzyme sequence and the structure of the product. Together, these systems represent a unique mechanism for the synthesis of biopolymers in which the template and the catalyst are the same molecule. 

Elongation by the fatty acid synthase complex stops on formation ofpalmitate ( 55). Further elongation and the insertion of double bonds are carried out by other enzyme systems. 

The enzyme system that catalyzes the synthesis of saturated long-chain fatty acids from acetyl CoA, malonyl CoA, and NADPH is called the fatty acid synthase. The constituent enzymes of bacterial fatty acid synthases are dissociated when the cells are broken apart. The availability of these isolated enzymes has facilitated the elucidation of the steps in fatty acid synthesis (Table 22.2). In fact, the reactions leading to fatty acid synthesis in higher organisms are very much like those of bacteria. 

Isoniazid interferes with mycolic acid synthesis by inhibiting an enoyl reductase (InhA) which forms part of the fatty acid synthase system in mycobacteria. Mycolic acids are produced by a diversion of the normal fatty acid synthetic pathway in which short-chain (16 carbon) and long-chain (24 carbon) fatty acids are produced by addition of 7 or 11 malonate extension units from malonyl coenzyme A to acetyl coenzyme A. InhA inserts a double bond into the extending fatty acid chain at the 24 carbon stage. The long-chain fatty acids are further extended and condensed to produce the 60-90 carbon (3-hydroxymycolic acids which are important components of the mycobacterial cell wall. Isoniazid is converted inside the mycobacteria to a free radical species by a catalase peroxidase enzyme, KatG. The active free radicals then attack and inhibit the enoyl reductase, InhA, by covalent attachment to the active site. 

Nature produces obviously not only interesting /1-lactams as in the antibiotics, but also structurally correspon ding jS-lactones. The high reactivity of the oxetanone system is crucial to the irreversible enzyme inhibition The oxetanone acylates a serine residue (Ser-152) in the active centre of the pancreas-lipase and thereby blocks its function (Fig. 5.110). [256] Some derivatives, e.g. tetrahydrolipstatin, also inhibit the thioesterase domain of the human fatty acid synthase. [257]... 

Within the free space of the cytoplasm reside all those intracellular enzymes which are not located in organelles. For example, the enzymes of the glycolytic pathway, the fatty acid synthase complex, the protein synthesizing system and all other enzymes involved in the metabolism of the yeast cell. Additionally, metabolic intermediates and storage compounds such as trehalose and starch reside in the cytoplasm. 

Methylsalicylate synthase (D 3.3.1), for instance, shares most of the enzyme activities of the fatty acid synthase system (D 3.2), a complex of two polyfunctional enzymes of primary metabolism, and specific antibodies show it to be a very similar protein (Packter 1973). Hence it is likely that 6-methylsalicylate synthase evolved from fatty acid synthase. 

Figure 3.2 Enzyme systems associated with the de novo synthesis of fatty acids in the plastid. (a) Acetyl-CoA carboxylase (EC 6.4.1.2) (b) [acyl-carrier protein] (ACP) acetyl-transferase (EC 2.3.1.38) (c) [ACP] malonyltransferase (EC 2.3.1.39) (dl) 3-oxoacyl-[ACP] synthase I (d2) 3-oxoacyl-[ACP] synthase II (EC 2.3.1.41) (d3) 3-oxoacyl-[ACP] synthase III (e) 3-oxoacyl-[ACP] reductase (EC 1.1.1.100) (f) 3-hydroxyacyl-[ACP] dehydratase (g) enoyl-[ACP] reductase (EC 1.3.1.9/10) (d)-(g) constitutes fatty acid synthase...

Fatty acid synthase. Fatty acid biosynthesis in plants occurs primarily in the plastids and is dependent upon the existence of the fatty acid synthase (or synthetase) II complex (FAS) (Harwood, 1988 Stumpf, 1989). This complex, unlike the system present in animals, is discontinuous (Shimakata and Stumpf, 1982a). Thus it has been possible to isolate and study the associated enzyme activities independently. Purification of each activity to homogeneity can then allow amino acid sequence analysis, cloning and elucidation of the gene, and subsequent application in the genetic engineering of plants. 

In animal cells and yeasts, multienzyme complexes localised in cytosol, referred to as type I fatty acid synthase (FAS I), carry out the bulk of the de novo fatty acid synthesis. In animals, it occurs primarily in the liver, adipose tissue, central nervous system and lactating mammary gland. FAS I contains seven distinct catalytic centres and is arranged around a central acyl carrier protein (ACP) containing bound pantothenic acid (see Section 5.9.1). In prokaryotes and plants, distinct soluble enzymes localised in mitochondria and plastids, referred to as type II fatty acid synthase (FAS II), carry out the reactions. 

Table 1. Effect of TLM on the individual enzymes of the fatty acid synthase system in E. coli... 

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