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Characterisation of bacterial cyclopropane fatty acid synthase (CFAS) enzymes towards novel biocatalysts for sustainable synthesis

Omar, Iman Ibrahim; (2024) Characterisation of bacterial cyclopropane fatty acid synthase (CFAS) enzymes towards novel biocatalysts for sustainable synthesis. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Cyclopropane rings are the 10th most frequently found ring system in small molecule drugs such as antibiotics, anti-virals and anti-diabetics. This moiety is an important structural motif present in many pharmaceutical compounds and widely used as a reactive building block in the synthesis of chemicals. Existing synthetic methods for cyclopropanation are highly challenging organic reactions that generally require the use of scarce transition metals and highly reactive and explosive species. They are also limited in terms of substrate scope. Whilst cyclopropanation remains a challenging reaction for the scientific community, in nature cyclopropane fatty acid synthases (CFAS), catalyse the cyclopropanation of unsaturated phospholipids in bacteria and plants using the co-factor S-adenosylmethionine (SAM) under mild conditions. Developing CFAS enzymes, into a biocatalyst for cyclopropane ring formation is highly appealing to industry as using an enzymatic approach will allow this otherwise challenging reaction to take place without the need for toxic co- substrates and under mild reaction conditions. This greener approach to chemistry is also appealing as the world moves towards more sustainable chemical processes. Despite their wide distribution in nature, CFAS remain elusive enzymes, and little is known about their substrate specificity, selectivity, and catalytic mechanism. Here we identify a range of bacterial CFAS enzymes and characterise their activity against a range of natural and unnatural substrates. The impact of liposomes as substrates and the effect of their supramolecular structures on CFAS catalysis is investigated. Mutagenesis and in-silico experiments highlight the role of key amino acids involved in the catalytic cyclopropanation and the first, crucial biological insight into the structural features which determine substrate preference in ecCFAS. We show the potential of CFAS biocatalysed cyclopropanation as an alternative to existing methods.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Characterisation of bacterial cyclopropane fatty acid synthase (CFAS) enzymes towards novel biocatalysts for sustainable synthesis
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2024. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
URI: https://discovery.ucl.ac.uk/id/eprint/10187671
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