About the Project
Previously, we demonstrated how highly regioselective flavin-dependent halogenase (Fl-Hal) enzymes, that use benign inorganic halides, are an attractive alternative to traditional toxic and nonselective chemical halogenation methods. We also used active site mutagenesis to improve catalytic activity of Fl-Hal and we were able to switch the regioselectivity of these enzymes with various non-natural substrates. In addition, we succeeded in integrating Fl-Hal with chemocatalysts to open up new reaction pathways in vitro. We demonstrated, for the first time, the integration of Fl-Hal with transition metal-catalysed cross-coupling chemistry, in one-pot, to achieve regiodivergent arylation or alkenylation of aromatic scaffolds. In this project, we aim to integrate Fl-Hal with a range of other chemocatalysts providing unprecedented C−H activation reactions for C−C, C−N, C−F, C−CF3 bond formation. In addition, we will develop other integrated cascades, with multiple different enzymes and chemocatalysts combined in a single reaction vessel (reactor).
Applicants should hold, or expect to obtain, a degree (or equivalent) in Chemistry, Biochemistry or Biological Science and should possess a strong interest in biological chemistry/chemical biology. The successful candidate will gain training and skills in organic chemistry, chemocatalysis and also biocatalysis working in a highly stimulating multidisciplinary environment with a large team of chemical biologists in the Manchester Institute for Biotechnology (http://www.mib.ac.uk) and synthetic organic chemists in the School of Chemistry.
Contact for further Information
Professor Jason Micklefield FRSC
PA Sarah Jones: [email protected]
Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or the overseas equivalent) in Chemistry, Biochemistry, Bioscience or a related area/subject. Candidates with experience in Chemical biology (biological chemistry), with an interest in enzymes (biocatalysis) and/or synthesis (chemocatalysis) are encouraged to apply.
• 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)
• RadH: A Versatile Halogenase for Integration into Synthetic Pathways. B. R. K. Menon, E. Brandenburger, H. H. Sharif, U. Klemstein, S.A. Shepherd, M. F. Greaney, J. Micklefield Angew. Chem. Int. Ed. 2017, 56, 11841 –11845 (http://dx.doi.org/10.1002/anie.201706342)
• A Structure-Guided Switch in the Regioselectivity of a Tryptophan Halogenase. S. A. Shepherd, B. R. K. Menon, H. Fisk, A.-W. Struck, C. Levy, D. Leys, J. Micklefield ChemBioChem 2016, 17, 821-824 (http://dx.doi.org/10.1002/cbic.201600051)
• 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, M. Styles, C. Levy, D. Leys and J. Micklefield Chemical Science 2015, 6, 3454-3460 (http://dx.doi.org/10.1039/C5SC00913H)
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