Polyketides and fatty acid biosynthesis

The basic assembly cycle for both polyketide and fatty acid biosynthesis is shown in Fig. 1 in which a starter unit, normally acetate is transferred to the ketosynthase (KS) or condensing enzyme which catalyzes a decarboxylative condensation with... 

Figure 3. Relationship between polyketide and fatty acid biosynthesis. The simplest ( minimaV) PKSs possess ketosynthase activity and produce linear polyketide products. In contrast, FASs also catalyze successive ketoreduction-dehydration-enoyl reduction reactions following each condensation. Diverse PKSs may perform none, part, or all of this reductive sequence. KS, ketosynthase KR, ketoreductase DH, dehydratase ER, enoyl reductase.

Despite the structural diversity of polyketides, the building blocks of these compounds are simple acyl-CoAs, and the biosynthetic logic is closely associated with that of fatty acid synthases (FASs) [9, 10]. In both polyketide and fatty acid biosynthesis, the growing chain is covalently tethered to an acyl carrier protein (ACP) via a phosphopantetheine (PPant) moiety. The PPant chain, derived from CoA, is attached post-translationaUy to a conserved serine residue on the npo-ACP by a phosphopantetheinyl transferase (PPTase), yielding the mature to-ACP (Scheme 1.1) [11,12],... 

Polyketide and fatty acid biosyntheses begin with condensation of the coenzyme A thioester of a short-chain carboxylic acid starter unit such as acetate or propionate with the coenzyme A thioester of a dicarboxylic acid extender unit such as malonate or methyl malonate. The driving force for the condensation is provided by the decarboxylation of the extender unit. In the case of fetty acid synthesis, the resulting -carbonyl is completely reduced to a methylene however, during the synthesis of complex poly-ketides, the -carbonyl may be left untouched or variably reduced to alcohol, olefinic, or methylene functionalities depending on the position that the extender unit will occupy in the final product. This cycle is repeated, and the number of elongation cycles is a characteristic of the enzyme catalyst. In polyketide biosynthesis, the full-length polyketide chain cyclizes in a specific manner, and is tailored by the action of additional enzymes in the pathway. 

Macrolides are secondary metabolites of polyketide origin [146-151]. The apparent similarity between macrolide and fatty acid biosynthesis was... 

Redirecting reactions via conformational control In the final example of this chapter, we will show how understanding of enzyme stereoelectronics allows one to redirect reactivity of known substrate into a new direction. When the stractural constraints of enzyme active sites are removed, a new set of stereoelectronic constraints can be imposed on the same substrate to enforce a different reactivity. For example, the effect of stereoelectronic factors on the relative order of steps in the deprotonation/decarboxylation sequence were recently analyzed for an enzyme-catalyzed vs. Cu-catalyzed reactions of the similar substrates (Figure 11.66). The first process is involved in the biosynthesis of polyketides and fatty acids where enzymatic activation of... 

Discrete plant KRs have been identified that interact with CHS for the biosynthesis of 6 -deoxychalcone (20) (Fig. 3D) [133, 136-139]. Interestingly, the plant KR has no similarity with those that catalyze the reduction of the poly- -ketone intermediates in polyketide or fatty acid biosynthesis [49, 50, 81-84]. Instead it is similar to various aldo/keto-reductases, mostly from carbohydrate metabolism [139-141], and contains a leucine zipper motif known to be involved in protein-protein interaction [142]. Plant 0-methyltransferases are well known [143], but enzymes for C-methylation have not been described. The... 

As briefly explained in Sect. 1.2.1, the -270 residue TE domain catalyses either a hydrolysis or an intermolecular cyclisation reaction to terminate the biosynthesis of polyketides and fatty acids, releasing the final prodnct from the assembly line. The TE domain exhibits an a/fi-hydrolase fold and is dimeric in modular type I PKS systems. The mechanism of both hydrolytic cleavage and macrolactonisa-tion commences with the transfer of the polyketide chain from the final ACP onto the active site serine of the TE, forming an acyl-TE intermediate. The hydrolytic... 

Hopwood D.A. and Sherman, D.H., Molecular genetics of polyketides and its comparison with fatty acid biosynthesis, Anna. Rev. Genet., 24, 37, 1990. 

Microbial fatty acid biosynthesis and the evolution of the polyketides... 

Carreras CW, Pieper R, Khosla C (1997) The Chemistry and Biology of Fatty Acid, Polyketide, and Nonribosomal Peptide Biosynthesis. 188 85-126 Ceulemans A (1994) The Doublet States in Chromium (III) Complexes. A Shell-Theoretic View. 171 27-68... 

Many of the unusual compounds that indicate the exciting chemistry to be discovered in marine natural products are polyketides. Polyketides are a family of structurally complex natural products that include a number of important pharmaceuticals. They are produced primarily by microorganisms through a specialized metabolism that is a variation of fatty acid biosynthesis [430]. Polyketides fall into two structural classes aromatic and complex. Polyketides are formed by enzyme complexes... 

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.

As the polyketide chain is built up, any of the reductions or eliminations from fatty acid biosynthesis can occur at any stage. The simple metabolite 6-methyl salicylic acid (6-MSAJ is made in the microorganism Penicillium patulum, and it could come from the same intermediate as orsellinic acid with one reduction,... 

The Chemistry and Biology of Fatty Acid, Polyketide, and Nonribosomai Peptide Biosynthesis... 

Because they often function as virulence factors, the enzymes involved in siderophore biosynthesis are potential targets for developing antimicrobial strategies. The mechanisms of siderophore biosynthesis follow the same fundamental biosynthetic logic involving similar protein machinery, which we describe in greater detail in Chapter 5 for fatty acid biosynthesis. It is also used in the microbial biosynthesis of many important natural products polyketides and peptides (including many antibiotics). Essentially, as is illustrated in Fig. 4.20, for enterobactin, it involves... 

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