Saturated Oxygen Heterocycles: A Fusion of Synthesis and Biosynthesis

饱和氧杂环是许多具有生物活性的天然产物的共同结构特征，也是重要的药物骨架。该项目将使用有机合成、分子建模、光谱学和生物测定相结合的方法，以了解环氧化物水解酶的机制，该酶催化环氧醇的分子内环化，生成氧杂环（四氢吡喃和四氢呋喃）。长期目标是为关键杂环支架的清洁高效生产提供生物催化剂。该项目将从环氧化物水解酶MupZ开始开始，MupZ催化莫匹罗星四氢吡喃核心的形成，这对抗生素活性至关重要。然后，研究将扩展到其他生物合成途径/酶。在每种情况下，将设计和合成底物库，并用于SAR研究。与生物化学领域的同事合作，通过分子建模，使用诱变实验来改善酶的底物范围和催化活性。生物催化剂的价值将在生物活性化合物的全合成中得到体现。将研究进一步开发用于合成氮杂环的生物催化剂的机会。

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.