Collaborative Research: Metabolite-responsive regulators for polyketide pathway engineering

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1159398/1159759 Cirino/TangPolyketides are an important class of bioactive natural products. The complexity of these compounds demands that their synthesis be conducted by dedicated enzymes with exquisite catalytic properties. Directed evolution of natural product pathway enzymes is limited by the lack of general high-throughput screens for the complex target compounds, as well as the genetic intractability of most organisms expressing these pathways. The proposed research addresses this technology gap through the engineering of synthetic genetic networks that can respond to a desired polyketide compound. Many bacterial regulatory proteins naturally control gene expression in response to a specific "effector" molecule. We will screen mutant libraries of regulatory proteins to isolate variants that activate expression of a reporter gene in response to polyketide compounds of interest. Then, using E. coli outfitted with the synthetic regulatory circuit, the aromatic polyketide biosynthetic pathway will be engineered towards enhanced production of bioactive metabolites and biosynthesis of new, "unnatural" compounds.This project is cofunded by the Biotehchnology, Biochemical and Biomass Engineering Program, Chemical, Bioengineerng, Environmental and Transport Systems Division, Engineering Directorate, and the Chemistry of Life Processes Program in the Chemistry Division of MPS.