Natural products combinatorial biosynthesis

Natural Product Combinatorial Biosynthesis Promises and Realities... 

Examples of Combinatorial Biosynthesis of Pharmaceutical Natural Products... 

Since the first description was only two decades ago, combinatorial biosynthesis has advanced from a limited set of proof-of-principle experiments into a more mature scientific discipline. To reach the maximal potential of natural product structural diversity, the combination of this approach with other established and emerging technologies will ultimately provide access to a rich variety of unnatural natural products with improved properties or new biological activities for future drug discovery and development. 

Galm, U. and Shen, B. (2006) Expression of biosynthetic gene clusters in heterologous hosts for natural product production and combinatorial biosynthesis. Expert Opinion on Drug Discovery, 1, 409. 

Thomas, M.G., Bixby, K.A. and Shen, B. (2005) Combinatorial biosynthesis of anticancer natural products, in Anticancer Agents from Natural Products (eds G.M. Cragg, D.G.I. Kingston and D.J. Newman), CRC Press, Boca Raton, FL, pp. 519-551. 

In this chapter, we will introduce an exciting class of natural product biosynthetic enzymes, the modular synthases, as well as their associated enzyme partners. We will discuss the use of metabolic engineering as a tool for small-molecule discovery and development, both through directed fermentation and combinatorial biosynthesis. In addition, we will review six classes of partner enzymes involved in the modification of polyketide (PK) and nonribosomal peptide (NRP) natural products. We believe that these enzymatic transformations hold great opportunities for synthetic chemists and will serve as the foundation for a new trend in both discovery and process chemistry. 

The biosynthesis of many hydroxylated natural products proceeds through regio- and enantioselective modification of polyketides, which are assembled through chain elongation via acetate or propionate units [2]. The enzymes responsible for the chain elongation and subsequent reduction, elimination, aromatiza-tion, and further modifications are classified as polyketide synthases [3]. These multifunctional enzymes have been used for whole-cell biotransformation toward unnatural metabolites that are within the scope of combinatorial biosynthesis... 

A major advantage of the natural products approach to drug discovery is that it is capable of providing complex molecules that would not be accessible by other routes. Compounds such as paclitaxel (Taxol, 8) or rapamycin (10) would never be prepared by standard "medicinal chemistry" approaches to drug discovery, even including the newer methods of combinatorial chemistry. Likewise, the new approach of combinatorial biosynthesis, although an important one, is unlikely in the near future to yield new compounds of the complexity of paclitaxel and camptothecin. 

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

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