Elucidating and Engineering Legonmycin Biosynthesis

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Many drugs that we rely on for the treatment of cancer, and infections are either natural products or are derived from natural products. As such natural products remain a major source of lead compounds for the development of new drugs. However, natural products are often complex in terms of their structure making it difficult for synthetic chemists to access them. In contrast bacteria possess an amazing inventory of complex chemistry that organic chemists can only dream of. We will study two bacterial enzymes that have the capability to convert linear peptides into heterobicyclic molecules under mild reactive conditions. These heterobicyclic rings are critical components of many biologically important and industrially relevant molecules. We will advance our initial mechanistic work by using substrates with different stereogenic centres and through site direct mutagenesis of the active site. Substrate tolerance is a key feature for a successful industrial biocatalyst and we will synthesize peptide thioesters equipped with different chemical handles and probe the substrate flexibility of the target enzymes. By working out the catalytic capabilities of the two enzymes we will gain the ability to develop their industrial biotechnological potential and be able to access new biologically active scaffolds.