Modularity is a highly sought after feature in engineering design. A modular catalyst is a multi-component system whose parts can be predictably interchanged for functional flexibility and variety. Over the past two decades, much of the research in our laboratory has focused on understanding the modularity of a of multifunctional enzymes called polyketide synthases (PKSs). PKSs catalyze the biosynthesis of a broad range of complex natural products in microorganisms, including many well-known and emerging antibiotics. A better understanding of the fundamental principles governing their modular chemistry promises to create powerful opportunities for engineering new medicines, and may even open the door to radically new catalytic processes for functionally dense, chiral synthons.
Research interests in this laboratory lie at the interface between chemistry and biology. Assembly line enzymes such as polyketide synthases have extraordinary potential for the programmable biosynthesis of complex natural products. Our laboratory seeks to understand the mechanistic logic of assembly line polyketide synthases, and to harness these insights in order to engineer new antibiotics. The prototypical system of interest to us is the 6-deoxyerythronolide B synthase, which synthesizes the macrocyclic core of erythromycin. Other examples of antibiotic biosynthetic pathways under...
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