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(BBSRC DTP) In silico enzymology: A mechanistic study of prenylated flavin-dependent enzymes

  • Full or part time
  • Application Deadline
    Friday, January 31, 2020
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Many enzymes make use of cofactors to aid in catalysis, as they offer alternative reactivities to the canonical amino acids found in the enzyme active site. One such cofactor is the recently discovered prenylated flavin (prFMN), which is used in the UbiD family of enzymes to catalyse reversible decarboxylation of a range of substrates (1,2); many of which are of interest to the bioenergy and biotechnology industries. This project will use a range of computational chemistry approaches, including density functional theory (DFT) modelling and molecular dynamics (MD) simulations, to study the mechanism of prFMN-dependent enzymes (3). Of particular interest is the reversible 1,3-dipolar cycloaddition thought to be crucial to catalysis, and the reversible (de)carboxylation that occurs readily under atmospheric COR2R. In order to benchmark these calculations, the project will also include an experimental component, comprising enzyme kinetic measurements made using steady state and rapid-mixing methods and kinetic isotope effect (KIE) measurements made using NMR. An element of both computational and experimental method development will be required and it is envisaged an iterative compute-test cycle will be used to validate proposed mechanism. Once the mechanism of wild-type enzyme(s) are established, the approach will be expanded to identify related enzymes with new substrate profiles and/or to improve the catalytic performance of established enzymes and to expand their substrate scope. The synthesis of prFMN by UbiX enzymes will also be investigated to explore the potential of the biosynthesis of new prFMN-like cofactors, which may expand the reactivity of prFMN-dependent enzymes.

The PhD student will be based in Department of Chemistry and the 28TManchester Institute of Biotechnology28T (MIB) and will be co-supervised by Dr Sam Hay (computational chemistry and KIE measurements) and Professor David Leys (enzymology and structural biology), with additional technical support and supervision from Senior Experimental Officer Dr Matthew Cliff (NMR spectroscopy). The project is interdisciplinary, giving the student the opportunity to gain broad experience in modern experimental biophysics, enzymology, biocatalysis and NMR spectroscopy alongside biochemically-relevant computational chemistry and data analysis.

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.

Funding Notes

This project is to be funded under the BBSRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the BBSRC DTP website View Website

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.


1. UbiX is a flavin prenyltransferase required for bacterial ubiquinone biosynthesis (2015). White et al., Hay and Leys. Nature, 522, 502-
2. New cofactor supports α,β-unsaturated acid decarboxylation via 1,3-dipolar cycloaddition (2015). Payne et al, Hay and Leys. Nature, 522, 497-
3. Atomic description of an enzyme reaction dependent on reversible 1,3-dipolar cycloaddition. Bailey et al, Hay and Leys. Nature Chemistry, in press; DOI: 10.1038/s41557-019-0324-8

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