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(BBSRC DTP) Design and Evolution of Enzymes with Non-Canonical Catalytic Mechanisms


Project Description

The ability to rationally design an enzyme for any desired transformation would have major impacts across the pharmaceutical and wider chemical sectors, leading to more efficient and sustainable synthetic routes to high value chemicals. The combination of computational enzyme design and directed evolution is currently the most attractive strategy to achieve this ambition. However, the limited range of functional groups presented by the genetic code (i.e. 20 amino acids) restricts the range of catalytic mechanisms which can be installed into designed active sites, thus severely limiting the repertoire of chemical transformations accessible.

Advanced protein engineering technologies available in our laboratory now allow us to install non-canonical ‘chemically inspired’ amino acids into enzyme active sites, thus greatly expanding upon the limited range of functionality accessible with Nature’s genetically encoded residues. We have recently combined this genetic code expansion technology with computational enzyme design and laboratory evolution to create the first enzyme that operates via a non-canonical organocatalytic mechanism (Nature 2019, 570, 219). In this PhD studentship, we will now expand ambitiously upon this early success, to demonstrate that the integration of non-canonical amino acids into computational design and directed evolution workflows can lead to the creation of enzymes with novel catalytic mechanisms and new activities. The design of new functional amino acids will be inspired by small molecule organocatalysts which are able to promote a plethora of valuable transformations not observed in Nature. Our approach merges the complementary disciplines of organocatalysis and biocatalysis, combining the mechanistic and functional versatility of small molecule systems with the enormous rate accelerations and reaction selectivities achievable within evolvable protein scaffolds.
This is a highly interdisciplinary project at the cutting edge of enzyme design and engineering research, and will provide the student with expertise in advanced protein engineering methods, directed evolution, organic synthesis and structural biology, skills that are highly relevant to a future career in the pharmaceutical and wider chemical industry.

https://www.research.manchester.ac.uk/portal/anthony.green.html
https://www.research.manchester.ac.uk/portal/michael.greaney.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

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.

References

1. Burke, A. J., Lovelock, S. L., Frese, A. Crawshaw, R., Ortmayer, M., Dunstan, M. Levy, C. Green, A. P.* Design and evolution of an enzyme with a non-canonical organocatalytic mechanism. Nature 2019, 570, 219.
2. Ortmayer, M. Fisher, K., Basran, J., Wolde-Michael, E. M., Heyes, D. J., Levy, C. Lovelock, S. L. Raven, E. L., Hay, S., Rigby, S. E. J., Green, A. P.* Rewiring the ‘Push-Pull’ Catalytic Machinery of a Haem Enzyme using an Expanded Genetic Code. under review in J. Am. Chem. Soc.
3. Pott, M. Hayashi, T., Mori, T. Mittl, P. R. E., Green, A. P.,* Hilvert, D.* A Non-Canonical Proximal Heme Ligand Affords an Efficient Peroxidase in a Globin fold. J. Am. Chem. Soc. 2018, 140, 1535.
4. Hayashi, T., Hilvert, D., Green, A. P.* Engineered Metalloenzymes with Non-Canonical Coordination Environments. Chem. Eur. J. 2018, 24, 11821.
5. Bailey, S. S., Payne, K. A. P., Saaret, A. Marshall, A. A., Gostimskaya, I. Kosov, I., Fisher, K., Hay, S., Leys, D. Enzymatic control of cycloadduct conformation ensures reversible 1,3-dipolar cycloaddition in a prFMN-dependent decarboxylase. Nature Chemistry, in press; DOI: 10.1038/s41557-019-0324-8

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