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，也是重要的药物支架材料。这个项目将结合有机合成、分子模拟、光谱学和生物分析来了解环氧化物水解酶催化环氧醇分子内环化生成氧杂环(四氢吡喃和四氢呋喃)的机理。更长期的目标是为清洁高效地生产关键的杂环支架提供生物催化剂。该计划将从Mupirocin的环氧化物水解酶MupZ开始，该酶催化形成对抗生素活性至关重要的四氢吡喃核心。然后，研究将扩展到其他生物合成途径/酶。在每一种情况下，都将设计和合成一个底物库，并将其用于合成孔径雷达研究。在与生物化学同事的合作下，将通过分子建模的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展示。将研究进一步开发生物催化剂合成氮杂环的机会。

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.