“Exploiting Microbial Genomes to Access New Enzymology and Valuable Chemicals”
Natural products-based drug discovery has achieved tremendous successes, but the high rate of rediscovery and limited chemical supply are two major challenges the field is facing. On the other hand, recent advances of DNA sequencing techniques illuminate extraordinarily rich potential of microbial strains for drug discovery and development, of which we have only tapped the surface. Over the past five years, my research laboratory has focused on the exploitation of microbial genomes to access new enzymology and to develop synthetic biology approaches to synthesize valuable substances. In this talk, I will share our recent studies in the discovery of new enzymology and the production of chemicals. Specifically, we characterized the catalytic features of ATP-grasp ligases in modifying multiple core peptides within a single substrate in the biosynthesis of one ribosomally synthesized and post-translationally modified peptide (RiPP) microviridin. Microviridins possess potent andselective inhibitory activity toward serine proteases, some of which are proven targets of FDA-approved drugs. Our work shows the distributive and unstrictly directional modifications of the enzymes, which fundamentally advances the understanding of modular RiPP biosynthesis. In addition, we have developed synthetic biology tools and approaches to produce natural products from microbial genomes. Our progresses are highlighted by the in vivo and in vitro synthesis of thaxtomin analogs. Thaxtomins, determining virulent factors of tens of plant pathogenic Streptomyces strains, have been approved as bioherbicide by EPA but not commercialized mainly due to the low productivity of native producers. We achieved their high-yield synthesis in nonnative hosts and produced hundreds of new analogues through in vitro biocombinatorial synthesis. Overall, our work suggests the promising potential of microbial genomes for basic and translational research.
~ Coffee/tea will be served prior to lecture~