Discovery, Characterisation and Engineering of New Ligase Enzymes for More Sustainable Amide Bond Synthesis.

生物基制药和先进材料的新途径对于未来的可持续社会至关重要。该项目旨在发现，培养和工程化新型连接酶，可以偶联羧酸和胺，使酰胺的生产更加高效和环境可持续。许多领先的药物（重磅药物）都具有酰胺功能。然而，用于酰胺合成的传统化学方法缺乏选择性，需要使用保护基团和有毒试剂以及有害溶剂，所有这些都以显著的成本出现。在这个项目中，我们将开发更可持续的酶促方法，在温和的条件下，在水中，利用更良性的酶和可再生的原料，提供关键的含酰胺的医药产品和中间体。与Prozomix Ltd合作，我们的目标是：（i）开发新的生物信息学方法，用于挖掘基因组和宏基因组，以发现新的酰胺连接酶;（ii）建立高通量克隆、表达和筛选酰胺连接酶的方法;（iii）表征新酶，包括获得选定连接酶的高分辨率X射线晶体结构;（iv）研究新酶的结构。（iv）进一步设计和扩大连接酶的底物范围，增加可以使用新酶产生的药物支架的尺寸和复杂性。培训将提供生物化学，生物化学，酶学，结构生物学（X射线晶体学），定向进化和合成生物学教授贾森米克尔菲尔德和大卫莱斯的监督下。该项目还将涉及与Prozomix科学家的密切互动，并将包括在Prozomix的实习期，学生可以在领先的生物技术实验室获得额外的培训和技能。鼓励化学或生物科学学位课程的学生申请，他们希望在化学-生物学界面进行前沿研究。

New biobased routes to pharmaceuticals and advanced materials are essential for a future sustainable society. This project aims to discover, characterise and engineer novel ligase enzymes that can couple carboxylic acids and amines, enabling more efficient and environmentally sustainable production of amides. Many of the leading pharmaceuticals (blockbuster drugs) possess amide functionality. However, the traditional chemical methods for amide synthesis lack selectivity, require the use of protecting groups and toxic reagents, as well as deleterious solvents, all of which come at significant cost. In this project, we will develop more sustainable enzymatic methods to deliver key amide containing pharmaceutical products and intermediates under mild conditions, in water, utilising more benign enzymes and renewable feedstocks. In collaboration with Prozomix Ltd, we aim to: (i) Develop new bioinformatics approaches for mining genomes and metagenomes to discover new amide ligase enzymes; (ii) Establish methods for high throughput cloning, expression and screening of amide ligases; (iii) Characterise the new enzymes, including obtaining high resolution X-ray crystal structures of selected ligases; (iv) Further engineer and expand the substrate scope of ligase enzymes, increasing the size and complexity of pharmaceutical scaffolds that can be generated using the novel enzymes. Training will be provided in biological chemistry, biochemistry, enzymology, structural biology (X-ray crystallography), directed evolution and synthetic biology under the supervision of Professors Jason Micklefield and David Leys. The project will also involve close interactions with scientists from Prozomix and will include a placement period at Prozomix where the student can obtain additional training and skills in leading biotechnology labs. Students from Chemistry or Biological Sciences degree programmes, who possess a desire to do cutting edge research at the Chemistry-Biology interface are encouraged to apply.