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(BBSRC DTP CASE) Discovery and Engineering of Expanded Halogenases for Late Stage Enzymatic Functionalisation

Project Description

The project aims to discover and engineer novel enzymes (biocatalysts) that can affect regioselective halogenation of complex molecules enabling more efficient and environmentally sustainable production of pharmaceuticals which are urgently required to combat disease. Many of the leading pharmaceuticals (blockbuster drugs), possess halogen substituents. However, the traditional chemical halogenation methods that are used to introduce halogens lack selectivity and use toxic reagents as well as deleterious solvents, all of which come at significant cost. In this project we will develop more sustainable enzymatic methods to deliver key halogenated pharmaceutical products and intermediates under mild conditions, in water, utilising more benign reagents and renewable feedstocks [1-5]. In collaboration with Prozomix Ltd, we aim to: (i) Develop new bioinformatics approaches for mining genomes and metagenomes for new halogenase enzymes; (ii) Establish methods for high throughput cloning, expression and screening for halogenases; (iii) Further engineer and expand the substrate scope of halogenase enzymes, increasing the size and complexity of pharmaceutical scaffolds that can be subjected to efficient late-stage regioselective halogenation. Training will be provided in biological chemistry, biochemistry, enzymology, directed evolution and synthetic biology under the supervision of Prof. Jason Micklefield. The project will also involve close interactions with scientists from Prozomix and will include a placement period at Prozomix where the student can obtain additional training and skills in leading biotechnology labs. Students from Chemistry or Biological Sciences degree programmes, who possess a desire to do cutting edge research at the Chemistry-Biology interface are encouraged to apply.


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] Integrated Catalysis Opens New Arylation Pathways via Regiodivergent Enzymatic C-H Activation. J. Latham, H. H. Sharif, J.-M. Henry, B. R. K. Menon, S. A. Shepherd, M. F. Greaney, J. Micklefield Nature Commun. 2016, 7, 11873 (http://dx.doi.org/10.1038/NCOMMS11873);
[2] RadH: AVersatile Halogenase for Integration into Synthetic Pathways. B Menon, E. Brandenburger, H. H. Sharif, U. Klemstein, S. A. Shepherd, M. F. Greaney, J. Micklefield Angew. Chem. Int. Ed. 2017 (http://dx.doi.org/10.1002/anie.201706342);
[3] An Engineered Tryptophan Synthetase Opens New Enzymatic Pathways to -Methyltryptophan and Derivatives. D. Francis, M. Winn, J. Latham, M. F. Greaney, J. Micklefield ChemBioChem 2017, 18, 382-386 (http://dx.doi.org/10.1002/cbic.201600471);
[4] Extending the biocatalytic scope of regiocomplementary flavin-dependent halogenase enzymes. S. A. Shepherd, C. Karthikeyan, J. Latham, A.-W. Struck, M. L. Thompson, B. Menon, C. Levy, D. Leys and J. Micklefield Chemical Science 2015, 6, 3454-3460 (http://dx.doi.org/10.1039/C5SC00913H);
[5] Development of Halogenase Enzymes for Use in Synthesis. J. Latham, E. Brandenburger, S. A. Shepherd, B. R. K. Menon and J.Micklefield Chem. Rev. 2018, 118, 232-269 (http://dx.doi.org/10.1021/acs.chemrev.7b00032).

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