Combinatorial biosynthesis of polyketides

Staunton, J. and Wilkinson, B. (2001) Combinatorial biosynthesis of polyketides and nonribosomal peptides. Current Opinion in Chemical Biology, 5, 159. 

By the methods presented for the combinatorial biosynthesis of polyketides, a multitude of modified and artificial polyketide substances should be available. New antibiotics, potentially with fewer side effects and consequently broader applicability, are desperately needed in the light of increasing resistance of bacteria towards established medications. 

N. A. Schnarr C. Khosla, Combinatorial Biosynthesis of Polyketides and Nonribosomal Peptides. In Chemical Biology, S. L. Schreiber, T. M. Kapoor, G. Wess, Eds. Wiley-VCH Verlag GmbH Co. KGaA Weinheim, 2007 Vol. 2, pp 519-536. 

For the past few decades, efforts toward combinatorial biosynthesis of polyketides and nonribosomal peptides have primarily focused on determining enzyme reactivity and specificity in truncated synthases [7-12]. Given the enormous size of the intact systems, obtaining information about individual steps would prove challenging. Despite this, several successful attempts at producing full-length products have been realized. This section will highlight some of these accomplishments for each class of molecule described above. 

Staunton J, Wilkinson B (2001). Combinatorial biosynthesis of polyketides and non-ribosomal peptides. Curr. Opin. Chem. Biol. 5 159-164. 

Weissman, K.J. and Leadlay, P.F. (2005) Combinatorial biosynthesis of reduced polyketides. Nature Reviews Microbiology, 3, 925. 

J Staunton. Combinatorial biosynthesis of erythromycin and complex polyketides. Curr Opin Chem Biol 2 339-345, 1998. 

CJ Tsoi, C Khosla. Combinatorial biosynthesis of unnatural natural products the polyketide example. Chem Biol 2 355-362, 1995. 

Weissman KJ, Leadlay PE (2005) Combinatorial Biosynthesis of Reduced Polyketides. Nat Rev Microbiol 3 925... 

The power of combinatorial biosynthesis has been best demonstrated through the engineered biosynthesis of polyketides." Polyketides consist of a structurally diverse family of natural products and are mostly biosynthesized by soil-bome actinomyces as secondary metabolites. Fungi and plants have also been sources of polyketides. 

Uncovering the biochemical principles governing these mechanisms is therefore important for the rational biosynthesis of lovastatin and other fungal polyketides. It will also allow the enzymatic components of iterative PKSs to be used as tools in the combinatorial biosynthesis of entirely new polyketide scaffolds. 

Weissman KJ, Leadlay PF. Combinatorial biosynthesis of reduced polyketides. Nat. Rev. Microbiol. 2005 3 925-936. 

The three types of PKSs described here, the enediyne PKS, the C-0 bondforming PKS, and the AT-less PKS, are only representive examples that reside outside the archetypical PKS paradigms. Continued exploration on the mechanism of polyketide biosynthesis will undoubtly uncover more unusual PKSs. These novel PKSs, in combination with the archetypical ones, will ultimately enhance the toolbox available to facilitate combinatorial biosynthesis and production of iinnatural natural products. The full realisition of the potential embodied by combinatorial biosynthesis of PKSs for natural product structural diversity, however, depends critically on the fundamental characterization of PKS structure, mechanism, and catalysis. 

The structures of KS/CLF, KR and ARO/CYC have provided strong clues to the molecular features that result in the observed chain length, ketoreduction and cyclization specificities during polyketide biosynthesis. Based on structural information, the polyketide chain length has been altered by mutations of the CLF residues at the KS/CLF dimer interface. In the future, it should be possible to mutate residues of KS/CLF, KR and ARO/CYC to change the specificity of ketoreduction and cyclization. Therefore, the crystal structures of PKS domains will serve as the blueprints to guide the combinatorial efforts of polyketide biosynthesis. 

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