The Biosynthesis of Polyketides

This chapter covers the literature appearing between January 1979 and December 1981 and follows the format of the previous report. It has been a particularly active period with a welcome, increasing trend towards studies aimed at elucidating the 

A potentially more useful technique than the a-isotope 3, . 2. 

In this, H is placed 8 to the C nucleus in a doubly labelled precursor an isotope 

The stereochemical mechanism of enoyl reductase, the enzyme catalysing the final reduction in the cycle of condensation-reduction-dehydration-reduction that lengthens the fatty acid 

However with the reductase from both E. coli. 10 

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Cytochrome P450 enzymes have been the subject of a number of recent reviews in which their mechanism and scope of action are covered in much detail [1, 6, 10, 11]. The reader is referred to these articles for a more thorough account of the mechanism and reactivity of cytochrome P450 enzymes, while we present a few representative examples of cytochrome P450-catalyzed epoxidation below. The enzymes we chose are all involved in the biosynthesis of polyketide natural products. Polyketides are a large, structurally diverse family of compounds and have provided a wealth of therapeutically useful drugs and drug leads. 

The biosynthesis of polyketides (including chain initiation, elongation, and termination processes) is catalyzed by large multi-enzyme complexes called polyketide synthases (PKSs). The polyketides are synthesized from starter units such as acetyl-CoA, propionyl-CoA, and other acyl-CoA units. Extender units such as malonyl-CoA and methylmalonyl-CoA are repetitively added via a decarboxylative process to a growing carbon chain. Ultimately, the polyketide chain is released from the PKS by cleavage of the thioester, usually accompanied by chain cyclization [49]. 

The chemoenzymatic synthesis of dTDP-p-L-olivose and dTDP-a-L-olivose, donor substrates for the biosynthesis of polyketides and other drugs, has been described. Starting from 2-deoxy-D- ra/u o-hexose 6-phosphate, dTDP D-oliose was also synthesized.174... 

The biosynthesis of polyketides is analogous to the formation of long-chain fatty acids catalyzed by the enzyme fatty acid synthase (FAS). These FASs are multi-enzyme complexes that contain numerous enzyme activities. The complexes condense coenzyme A (CoA) thioesters (usually acetyl, propionyl, or malonyl) followed by a ketoreduction, dehydration, and enoylreduction of the [3-keto moiety of the elongated carbon chain to form specific fatty acid products. These subsequent enzyme activities may or may not be present in the biosynthesis of polyketides. 

For a review on polyether biosynthesis in dinoflagellates Rein KS, Snyder RV. The biosynthesis of polyketide metabolites by dinoflagellates. Adv. Appl. Microbiol. 2006 50 93-125. 

Biodiversity New Leads for the Pharmaceutical and Agrochemical Industries reviews and discusses aspects of modern natural products research. The central theme of many articles is the sustainable use of global biodiversity. Microbial, plant and marine products are presented as the sources of new drugs, including anti-fungal products, antibiotics, anti-cancer agents and animal health products. There is also coverage of the biosynthesis of polyketides and the chemical synthesis of natural products and their derivatives. 

Two chapters in section five describe different aspects of the biosynthesis of polyketides, which are numerically the most abimdant and structurally diverse class of natural products. The first chapter reports in vivo and in vitro studies aimed at enhancing our understanding of the basic pathways of polyketide assembly with a view to producing novel compounds. In the second chapter, a consistent difference in the modes of cyclisation of the fused ring polyketides of fungi and streptomycetes is described, which provides the basis for a new biosynthetic classification of these metabolites. 

In their simplest form, polyketides are natural compounds containing alternating carbonyl and methylene groups ( p-polyketones ). The biosynthesis of polyketides begins with the condensation of a starter unit (typically, acetyl-CoA or propionyl-CoA) with an extender unit (commonly malonyl-CoA or methylmalonyl-CoA, followed by decarboxylation of the extender unit (/, 2) (Fig. 1). Repetitive decarboxylative condensations result in lengthening of the polyketide carbon chain, and additional modifications such as ketoreduction, dehydratation, and enoylreduction may also occur (discussed below). 

The Biosynthesis of Polyketides, Tetramic Acids, and Pyridones in Fungi... 

The biosynthetic pathways for more uncommon substrates such as 3-amino-5-hy-droxybenzoic acid are also encoded by genes that are clustered with the PKSs that utilize those substrates [98]. Thus, it would be possible to clone and express these genes alongside the PKS genes. Additionally, some of the enzymes responsible for the biosynthesis of polyketide star-... 

Acyl-CoA thioesterase enzymes (EC 3.1.2.-), although their catalytic activity simply entails the hydrolysis of CoA and ACP thioesters to release the fatty acids and other carboxylic acids bound to them (Equation (19)), have wide and varied physiological functions that includes the regulation of fatty acid metabolism and playing a central role in the biosynthesis of polyketide and nonribosomal peptide-based metabolites (especially the macrocyclic versions) and the degradation of aromatic compounds. These enzymes are thoroughly discussed in several recent reviews as well as the relevant chapters of this series that include fatty acids, polyketides, and nonribosomal peptide biosynthesis ° ° (see Chapters 1.05,1.02, and 5.19) therefore, only a brief overview of the structural and mechanistic diversity of acyl-CoA and acyl-ACP thioesterases is provided in this section. 

Besides MMCM and GM, two other coenzyme B -dependent carbon skeleton mutases are known. These are (1) methylene glutarate mutase (MGM) from the anaerobe Eubacterium (Clostridium) barkeri, which catalyzes the equilibration of 2-methylene-glutarate with (R)-3-methylitaconate as part of a degradative path of nicotinic acid [175,199] and (2) isobutyryl-CoA mutase (ICM), which is observed in species of gram-positive bacteria Strep-tomyces and catalyzes the reversible rearrangement of iso-butyryl-CoA and n-butyryl-CoA [177]. The isomerization of iso-butyryl-CoA and n-butyryl-CoA in ICM is relevant in the biosynthesis of polyketide antibiotics [177]. 

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... 

Figure 2.1 Predicted pattern in the biosynthesis of polyketide aflatoxin B1.

Simpson, T. J., The biosynthesis of polyketides, in Specialist Periodical Reports, Biosynthesis, Vol. 7 (R. B. Herbert and T. J. Simpson, eds.), 1-44, Royal Society of Chemistry, London,... 

Suppression by excess nutrients has been found in the biosynthesis of polyketides (D 3.3), of gibberellins (D 6.3), of certain antibiotics, e.g., streptomycin (D 1.3), neomycin C (D 1.3), actinomycins (D 8.4.1), chloramphenicol (D 8.2), bacitracin A (D 23), enniatin B (D 23), cephalosporins (D 23.3), and penicillins (D 23.3), of alkaloids, e.g., benzodiazepines (D 8.4.2), and ergolines (D 21.2) etc. Usually the suppression of secondary product formation is accompanied by the suppression of other characteristics of cell specialization (such as conidiospore formation in Peni-cillium cyclopium), indicating a general influence of nutrient supply on cell specialization. 

The synthesis of polyketides resembles the formation of fatty acids by fatty acid synthase in terms of the precursors used and the mode of their alignment (D 3.2). In contrast to the formation of fatty acids, however, the biosynthesis of polyketides proceeds without obligate reduction of intermediates. Most probably polyketo acids are formed, which are unstable and have not yet been detected in the free state. They seem to be attached to the core unit of the enzyme complex, stabilized by hydrogen bonding or by chelation of its semieno-lates with metal ions held by the enzymes. 

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... 

SCHEME 15.9 Key steps in the biosynthesis of polyketides. Elongation Elongation... 

In spite of the differences in structure between cyclic polyethers and the dinophysistoxins, these molecules are all regarded as polyketides, and it has now been established that the mechanisms of biosynthesis are completely different from those of the traditional polyketides. This fundamental originality of the biosynthesis of polyketides by dinoflagellates was clearly stimmed up in... 

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