Zhang Lab
School of Science, Westlake University

2. Assembly Line Biosynthesis and Bioengineering
    Assembly line enzymes are the most sophisticated biosynthetic machinery that produce numerous structural varieties. Among these products, polyketides and nonribosomal peptides are the leading class of natural products in antibiotics discovery and development. The biosynthesis of polyketides, for example in macrolide antibiotics erythromycin, is catalyzed by a set of multimodular polyketide synthase (PKS) megaenzymes in a sequential manner. This assembly line biosynthesis has been a target for rational bioengineering since their discovery in 1990s, though we are still far from flexible reprogramming of these assembly line enzymes. Interestingly, the exponentially accumulating sequences of biosynthetic genes now offers opportunity to understand the evolution of multimodular PKSs and NRPSs in nature. Our group aims to understand the evolution of polyketide and nonribosomal peptide biosynthesis and apply it for evolution-guided engineering to realize plug-and-play reprogramming of assembly line biosynthesis.    
1. Evolution-guided Nature Product Discovery
   Hundreds of thousands of natural products, or specialized metabolites, have been recorded nowadays. However, recent (meta)genomic analysis suggested the existence of vast amount of “microbial dark matter” that remain unexplored but potentially encode enzymes for new natural products. We are interested in the distribution and diversity of natural products. To better characterize these “dark matters”, we take interdisciplinary approach integrating bioinformatics, metabolomics, and traditional natural product chemistry for the discovery of new natural products. Our group is working on global analysis of the entire natural products world, and at the same time pursuing big-data and evolution driven targeted discovery of clinically important class of molecules.

Natural products have been the major source of antibiotics. As we enter the era of antibiotic resistance crisis, there is a keen need for discovery of new antibiotics. How much do new drugs remain to be discovered from nature?  How can we create new “unnatural” natural products? Our lab applies evolutionary perspective to understand the diversity of natural products and their biosynthesis, and aims to accelerate natural product evolution by synthetic biology.

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