Combinatorial biosynthesis future

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. 

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. 

Like conventional combinatorial biosynthesis, glycorandomization requires flexible glycosyltransferases. As recently pointed out in the case of novobiocin [79], a highly specific glycosyltransferase limits the library size. Despite such issues that need to be addressed in future work, glycorandomization is a promising approach to make use of the metabolic potential of procaryotic cells and should promote drug development in the future. 

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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