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Cyclopropane Synthase Enzymes as Biocatalysts for Green Cyclopropanation Reactions

Project description

Cyclopropane synthases as novel biocatalysts

Cyclopropane rings are present in many pharmaceutical compounds and serve as reactive building blocks in the synthesis of chemicals. The EU-funded CycloproBio project will explore cyclopropane synthase (CS) enzymes as a novel safe method for biocatalytic cyclopropanation. The study will characterise the catalytic properties of previously cloned cyclopropane fatty acid synthase (CFAS) from Escherichia coli and develop an appropriate activity assay to investigate its substrate specificity and physiochemical characteristics. Following that, new CS enzymes will be generated via mutagenesis of putative substrate-binding residues. The objective of the project is to use new data to develop cyclopropanation biocatalysts for the sustainable synthesis of chemicals and pharmaceuticals.

Objective

The cyclopropane ring is an important structural motif present in many pharmaceutical compounds and widely used as reactive building blocks in the synthesis of chemicals. Many synthetic strategies to access cyclopropanes have been developed to date, most of which typically require the use of potentially explosive diazo-carbene compounds as substrates. Even recently proposed enzymatic transformations, exploiting cytochromes P450 and myoglobin, require the use of stoichiometric carbene co-substrates, thus narrowing their industrial applications. The CycloproBio project aims to explore cyclopropane synthase (CS) enzymes as a potentially mild method for biocatalytic cyclopropanation. Cyclopropane synthases are SAM dependent transferase enzymes able to catalyse cyclopropanation of unsaturated phospholipids in bacterial membranes. Even if CS are common to most bacteria, many questions on factors affecting their substrate selectivity remain unanswered. Moreover, despite their potential, CS enzymes have not been explored yet as potential biocatalysts. This project will initially characterize the cyclopropane fatty acid synthase (CFAS) from E. coli which has been cloned, expressed and purified in preliminary work. The catalytic properties of the E. coli CFAS will be studied through the development of an appropriate activity assay, the investigation of its substrate specificity and the study of its physio-chemical properties. To broaden the study, genome mining for other CS enzymes from different bacterial species will be carried out to gain insight into the factors which affect the selectivity of these enzymes. Finally, new CS enzyme variants will be generated through rational mutagenesis of putative substrate binding residues. The data generated will provide fundamental information on the CS family. The primary aim of this project is to use this data to develop cyclopropanation biocatalysts for the sustainable synthesis of chemicals and pharmaceuticals.

Coordinator

UNIVERSITY COLLEGE LONDON
Net EU contribution
€ 224 933,76
Address
GOWER STREET
WC1E 6BT London
United Kingdom

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Region
London Inner London — West Camden and City of London
Activity type
Higher or Secondary Education Establishments
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Total cost
€ 224 933,76

Participants (1)