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

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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.