Development of cyclopropane synthase enzymes as biocatalysts for cyclopropanation reactions
Project ID: 2228cd1368 (You will need this ID for your application)
Research Theme: Manufacturing The Future
UCL Lead department: Chemistry
Lead Supervisor: Daniele Castagnolo
Project Summary:
Cyclopropane synthase (CS) enzymes are broadly distributed in many bacteria, playing a crucial role in the synthesis of the bacterial cell wall. CS enzymes catalyse the formation of 3-members cyclopropane rings from unsaturated lipids using S-adenosyl-L-methionine (SAM) as cofactor for the construction of new C-C bonds. However, despite their wide distribution in nature, CS enzymes have never been used as biocatalysts in chemical biology and chemistry. The identification of enzymes able to catalyse such challenging organic reactions under mild conditions are highly appealing for chemical and pharmaceutical industry. This project will develop new CS biocatalysts to be used in the manufacturing of cyclopropane derivatives. The PhD project offers a unique combination of training and skills ranging from molecular biology, synthetic and analytical chemistry and computational molecular modelling to generate novel biocatalysts for the manufacturing of chemicals and drugs of industrial relevance. The project will train a high skilled researcher through a multidisciplinary approach. The project will be carried out in the new Manufacturing Futures Lab (MFL) at UCL, a multidisciplinary hub for research in sustainability. The project will be supervised by Dr Castagnolo and will also count on ongoing collaborations with researchers at MFL, GSK and King’s College. The PhD student will be trained on gene cloning, protein expression and purification, biocatalytic screening, LC-MS/GC-MS analytic techniques. The student will work on the identification of CS enzymes from natural sources and on the development of biocatalytic reactions. Variants of the CS biocatalysts will be generated by rational mutagenesis and directed evolution to evaluate their enzymatic activity on a wider panel of substrates. Computational studies will be carried out to identify the key amino acids involved in the biocatalytic reactions. The new CS biocatalysts will be used for the manufacturing of a selected range of cyclopropane APIs and chemicals.