Saturated Oxygen Heterocycles: A Fusion of Synthesis and Biosynthesis

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Saturated oxygen heterocycles are common structural features of many biologically active natural products as well as important scaffolds for pharmaceuticals. This project will use a combination of organic synthesis, molecular modelling, spectroscopy and bioassays to gain an understanding of the mechanisms of epoxide hydrolases which catalyse the intramolecular cyclisation of epoxy-alcohols to generate oxygen heterocycles (tetrahydropyrans and tetrahydrofurans). The longer- term goal is to provide biocatalysts for the clean and efficient production of key heterocyclic scaffolds. The program will begin with the epoxide hydrolase MupZ which catalyses formation of the tetrahydropyran core of mupirocin, essential for antibiotic activity. Investigations will then be extended to other biosynthetic pathways/enzymes. In each case, a substrate library will be designed and synthesised and used in SAR studies. In collaboration with colleagues in biochemistry, the substrate scope and catalytic activity of the enzymes will be improved using mutagenesis experiments, informed by molecular modelling. The value of the biocatalysts will be showcased in the total synthesis of bioactive compounds. Opportunities for further exploitation of the biocatalysts for the synthesis of nitrogen heterocycles will be investigated.