Dr S De Visser, Prof Anthony Green, Prof Sam Hay
Applications accepted all year round
Competition Funded PhD Project (European/UK Students Only)
About the Project
Cheap and efficient synthesis of drug molecules remains a challenge and often leads to a large amount of by-products. Nature has developed a large range of enzymes for Natural Product Synthesis, but only few of them are able to incorporate an isonitrile group into a substrate. Interestingly, a recently discovered nonheme iron oxidase is able to do this as part of a biosynthesis pathway, but little is known on the substrate scope and conversion. Isonitrile containing products would be relevant to the chemical and pharmaceutical industry and no efficient mechanism exist to regio- and chemoselectively incorporate these groups in molecules; however, an enzymatic scaffold may help. Understanding the mechanism of isonitrile-synthesizing nonheme iron oxidases may open opportunities for the biosynthesis of drug molecules. In addition, the isonitrile-containing compound has been linked to tuberculosis bacteria and gaining insight into its mechanism may lead to viable therapies against this fatal disease. In this studentship we aim to explore the possibilities of isonitrile-containing compounds for drug synthesis. In particular, research will be focused on the nonheme iron oxidases using a unique multidisciplinary approach ranging from structural characterization, spectroscopy, kinetics and computational modelling. The work is likely to give valuable insight into how these enzymes are able to catalyse an energetically challenging reaction at room temperature and will open pathways for successful implementation in an Industrial setting. Bioengineering of isonitrile-synthesizing enzymes may lead to the development of novel structures for the biosynthesis of isonitrile containing molecules as drug targets and fine-chemicals and provide a new avenue for efficient drug synthesis in an approach that links Chemical Engineering, Chemistry and Biochemistry.
http://www.manchester.ac.uk/research/sam.devisser/research
https://www.research.manchester.ac.uk/portal/anthony.green.html
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.
Funding Notes
No direct funding is available, but Departmental and external funding will be sought. 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.
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.
References
1. N. C. Harris et al, “Isonitrile formation by a non-heme iron(II)-dependent oxidase/decarboxylase.” Angew. Chem. Int. Ed. 2018, 57, 9707–9710.
2. M. G. Quesne, T. Borowski, S. P. de Visser, “Quantum mechanics/molecular mechanics modelling of enzymatic processes: Caveats and breakthroughs.” Chem. Eur. J. 2016, 22, 2562–2581.
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