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Engineered oxidative enzymes as catalysts for the formation of quinone methides in integrated chemical synthesis

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  • Full or part time
    Dr Wong
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

In synthetic chemistry, there has been increasing prominence in the use of engineered enzymes to execute chemical transformations. These biocatalysts are attractive since they offer highly efficient synthesis in terms of yields and selectivity, together with an inherent environmental sustainability stemming from a minimal reliance on halogenated or metallic feedstocks.

In particular, there is currently great interest in the integration of biocatalytic reactions into larger multi-step synthetic schemes to enable the “telescoped” construction of molecules. This is an area that is of particular interest in chemical industries where there is a need for the rapid construction of complex molecules (e.g. pharmaceuticals, agrochemicals), yet research in this area is still in its infancy. For example, we have recently demonstrated the combination of two convergent biocatalytic reactions: a peroxidase-mediated oxidation of catechols to quinones, which is coupled with an aromatic amine that has undergone halogenase-catalysed bromination and/or chlorination – all in a single vessel.

Of current particular interest is the in situ generation of o-quinone methides (QM), which are versatile intermediates in chemical synthesis. This project will aim to further explore the biocatalytic generation of these QMs and develop the “one-pot” reaction sequences, through modifications of the reaction conditions as well as the mutagenic engineering of the enzymes. Indeed, the development of engineered peroxidase enzymes that are particularly suited for synthetic chemistry will be a major goal of this project. For example, the development of enzymes that have a high redox potential (to enable the oxidation of unreactive aromatic compounds), and that are resistant to extremes of pH and high concentrations of organic solvents.

The student will therefore work at the interface between organic chemistry (bioorganic chemistry) and biochemistry (enzymology). They will thus gain a wide range of expertise that are critical for the industrial biotechnology sector – the ability to rationally engineer new, high-value biocatalysts through fundamental insights in biomolecular structure and chemical reactivity.

Qualification
Applicants should have or expect a good I or II(i) honours degree in general area of bioorganic chemistry.

Contact for further Information
For more information and informal inquiries please contact Dr Lu Shin Wong: [email protected]

Funding Notes

Funding
Applications are invited from self-funded students. For UK/EU tuition fees are £8250 and International are £23,500 for 2017/18 academic year.

References

References:
[1] A. Pordea, Curr. Opin. Chem. Biol. 2015, 25, 124-132.
[2] H. Gröger, W. Hummel, Curr. Opin. Chem. Biol. 2014, 19, 171-179.
[3] J. Hosford, S. A. Shepherd, J. Micklefield, L. S. Wong, Chem. Eur. J. 2014, 20, 16759–16763.
[4] M. T. Reetz, Angew. Chem. Int. Ed. 2011, 50, 138-174.
[5] L. Casella, E. Monzani, S. Nicolis, in Biocatalysis Based on Heme Peroxidases (Eds.: M. Ayala, E. Torres), Springer, Heidelberg, 2010, pp. 111-154.

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