Coupling and rearrangement reactions in the biosynthesis of bis-heterocyclic natural products

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There is an urgent need for new antibiotic and anticancer agents. One important route to generate new drug molecules is to engineer biosynthetic pathways to existing molecules to create derivatives with improved pharmacological properties. Bacteria are a rich source for such drug molecules and biosynthetic pathways. The clustering of biosynthetic genes in their genomes enables a variety of studies: facile identification of new gene clusters, heterologous expression of entire pathways, and rapid engineering to generate new biosynthetic derivatives. This grant is focused on the biosynthetic pathways to bis-heterocyclic molecules, a group of compounds containing two dimerized, heterocyclic monomers in their structures. Little is known about the mechanisms that lead to the production of such molecules. The objective of this program is to characterize the biosynthetic pathways and key biosynthetic enzymes to two important bis-heterocyclic molecules. My hypothesis is that these two molecules are derived from enzymatic coupling and rearrangement reactions that fuse and contort well-studied heterocyclic monomers into unusual, dimerized molecular skeletons. This hypothesis will be tested by identifying the gene cluster responsible for the production of each molecule and carrying out genetic experiments to test the roles of individual biosynthetic genes. Further, we will biochemically and structurally characterize key enzymes in each pathway. Our proposed biosynthetic studies are significant because they will provide the necessary data and materials to enable studies to generate libraries of structurally related derivatives of these drug molecules. The proposed research is innovative because it focuses on the enzymatic basis for the dimerization and rearrangement of heterocyclic monomers to give bis-heterocyclic natural products and will provide new knowledge about how nature constructs this class of molecules.