Mapping Protein-Protein Interactions in Modular Polyketide Synthases by Carbene Footprinting

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Bioactive natural products from plants and microorganisms have indispensable applications in both medicine and agriculture. They are often employed to treat life-threating conditions, including bacterial, fungal and viral infections and cancer. Moreover, these valuable molecules are also used as herbicides, insecticides and fungicides that are essential for the protection of food crops. Many of these compounds are assembled by giant enzymatic 'assembly lines', much like a car production line, with the compound being constructed in a logical stepwise manner. During production, each component of the assembly line must engage in productive communication with other enzymes in the assembly line. These interactions are critical to ensuring that the overall process is efficient and maintains product fidelity. In this project, I aim to use a combination of established and recently-developed techniques to develop a better understanding of the interactions driving these biosynthetic processes. My focus will concern the enzymes involved in production of a potent antiviral compound called quartomicin, which targets the viral reverse transcriptase and is part of a larger family of compounds called tetronates. This particular system provides the opportunity to study an array of interactions important for producing tetronate-containing natural products. This will broaden our understanding of the role played by protein-protein interactions in natural product assembly and allow us to establish the common principles underlying the way in which they recognise their interaction partners. The results of this research will reveal common principles that can be harnessed to produce more efficient enzymes for biocatalysis, and by extension novel derivatives of bioactive polyketides.Overall, this project will significantly deepen our understanding of the roles played by protein-protein interactions during natural product assembly and will establish a rational basis for exploiting such interactions to construct engineered assembly lines capable of producing novel natural product analogues.