(BBSRC DTP) Probing the chemistry of the prenylated flavin cofactor: Synthesis, mechanistic probes, and biocatalysis

This cross-disciplinary project fuses chemical synthesis and mechanism, structural biology, computational (bio)chemistry and cutting-edge biotechnology in a highly innovative approach to the development of new biocatalytic processes of interest to industry and addresses the BBSRC’s strategic research priority, Bioenergy and Industrial Biotechnology. In the project, synthetic analogues of prenylated-flavin cofactor will be assembled and used to explore, understand and improve important biocatalytic transformations involving prenylated-flavin-dependent enzymes. The project will help team members maintain their positions at the forefront of their fields (BBSRC’s goal of maintaining the UK’s position as a global leader in the area of World-class Underpinning Bioscience). Finally, by driving a new collaboration between a synthetic chemist, a structural biologist and a biological computational chemist, the project aligns with exploiting new ways of working in the BBSRC strategic plan.

The portfolio of chemical reactions mediated by enzymes is greatly enhanced by cofactors: e.g. small organic molecules that are bound by the protein to constitute the active holo-enzyme. The Leys team has recently discovered a new prenylated-flavin cofactor that is an integral part of the widespread ubiD/ubiX enzyme system and exhibits striking chemical properties. This project will answer many outstanding questions regarding the chemistry of prenylated-flavin and use the improved understanding of enzyme mechanism to develop better biocatalysts (and chemocatalysts). The prenylated-flavin cofactor has the potential to play a major role in future synthetic science as the diverse UbiD (de)carboxylase enzyme family has a pivotal role in bacterial ubiquinone biosynthesis and microbial biodegradation of aryl and alkenyl compounds. The new cofactor significantly extends flavin chemistry by allowing access to new flavin-derived radical species by single-electron transfer (SET) oxidation. Crucially, it is believed that a particular reactive intermediate, called an ‘azomethine ylide’, is ultimately formed by SET oxidation. It is this key reactive intermediate that appears to instigate the important decarboxylation processes mediated by these enzymes by undergoing ring-forming or ‘cycloaddition’ reactions. This is believed to be the first example of a cycloaddition reaction of this kind being employed by an enzyme.

If enzyme systems using prenylated-flavin are to achieve their full potential for the sustainable production of key commodity chemicals, an improved mechanistic understanding of the chemical role played by the cofactor is needed. Using synthetic analogues of prenylated-flavin, and the cycloadducts that are thought to be so crucial, we will explore the role of prenylated-flavin and the role of the enzyme environment in the mechanism of important biocatalytic processes. Armed with improved mechanistic understanding, we will engineer synthetic prenylated-flavin cofactors for use in new and improved enzymes for the transformation of important chemical feedstocks.

The project is ideally suited to a synthetic chemist with an interest in biology. A multidisciplinary supervisory team of internationally-leading scientists will deliver a unique training programme. The project will embrace synthetic organic chemistry, electron transfer, chemocatalysis (Procter), synthetic biology and biocatalysis (Leys), and computational (bio)chemistry (Hay).

Contact for further information:
[Email Address Removed]
Procter Group Research: http://proctergroupresearch.com
Leys Group Research: http://www.manchester.ac.uk/research/David.leys/
Hay Group Research: https://www.research.manchester.ac.uk/portal/sam.hay.html

Entry Requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.