Polyketides biosynthetic diversity

The second largest class of compounds reported from macroalgae is the polyketides, which comprise approximately a quarter of known algal compounds (Blunt et al. 2007). Polyketides are polymers of acetate (C2) and occasionally propionate (C3) and are very similar to fatty acids in their biosynthetic origin. Polyketides can be found in plants, animals, bacteria, and fungi. With a range of activities as broad as their structures, the polyketides are a diverse family of natural products classified based upon the polyketide synthases (PKSs) responsible for their biosynthesis, primarily type I and type II. 

Polyketides constitute a large class of natural products grouped together on purely biosynthetic grounds. Their diverse structures can be explained as being derived from poly-P-keto chains, formed by coupling of acetic acid (C2) units via condensation reactions,... 

The biosynthetic studies undertaken to date on microbial marine natural products well illustrate the diversity of metabolic pathways encountered in cultured marine bacteria. Examples include brominated alkaloids such as pentabromopseudiline (Structure 2.1),19 polyketide or mixed polyketide metabolites such as oncorhyncholide (Structure 2.2),20 aplasmomycin (Structure 2.3),21 and andrimid (Structure 2.4),22 or the cyclic depsipeptide salinamide A (Structure 2.5).23 As researchers continue to define more specific culture media and a wider range of marine bacteria from diverse habitats are successfully placed into culture, the true biosynthetic potential of these prolific and adaptable microorganisms can be explored. 

Because these genes are often arranged in clusters, this has allowed a combinatorial biosynthetic approach for the construction of diverse libraries of polyketides and nonribosomal peptides.388387 The use of E. coli as a production host whereby precursor supply and selected pathway enzymes are modified has resulted in respectable titers of targeted compounds as well as novel derivatives.388393... 

Polyketides (PKs) are a typical example of a large and diverse class of NPs that derive from several related biosynthetic pathways. Their stmctures contain repeating units iteratively assembled into a range of diverse chemical structures (Fig. 10.43). PKs can be taken as an example of the application of combinatorial biosynthesis as both the... 

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. 

Many important therapeutics, in use in clinics today, are biosynthesized by the nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) paradigm. For example, many of the antibiotics (penicillin, cephalosporin, vancomycin, erythromycin, etc.), immunosuppressors (cyclosporine, rapamycin), antiviral agents (luzopeptin A), antitumor agents (bleomycin), and toxins (thaxtomin) are NRPS and PKS derived.20-22 Figure 1 displays a small selection of natural products that are NRPS and PKS derived and illustrates the diversity of molecular structures generated by these biosynthetic paradigms. 

Owing to the fact that the primary source of antibacterial agents for biomedical applications are secondary metabolites and chemical derivates of actinomycetes, fungi, and certain soil bacteria such as myxobacteria, most of the recent advances in molecular engineering have been made in relation to polyketide and peptide antibiotics (e.g., erythromycin and vancomycin)24 Recent literature on this topic suggests a greater mechanistic diversity in biosynthetic potential of bacterial natural products that was believed previously. 

Natural products represent a diversity of chemical compounds with varied biological activities. Natural products are an important source of novel pharmaceuticals as well as agricultural pesticides (1,2). Natural products are derived from a number of pathways that create basic scaffolds that are further modified by various tailoring enzymes to create the wide diversity of structures that exist in nature. Polyketide synthases are responsible for the synthesis of an array of natural products including antibiotics such as erythromycin in bacteria (3) and mycotoxins such as aflatoxin in fungi (4). Furthermore, in plants they are part of the biosynthetic machinery of flavonoids, phytoalexins, and phenolic lipi (5,6). 

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