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(BBSRC DTP) Organohalide pollutant detoxification using engineered reductive dehalogenases


Department of Chemistry

About the Project

The improper disposal of man-made compounds can lead to accumulation and toxic effects on the environment, and is most frequently seen with organohalide compounds (i.e. PCBs, dioxins, perchloroethene, flame-retardants etc). By virtue of the stability of the carbon-halogen bond, these molecules are persistent and frequently accumulate at contaminated anaerobic sites [1]. Certain bacteria are able to respire on organohalide compounds, relying on an unusual family of vitamin B12-containing enzymes, the reductive dehalogenases (RDases) [2]. The process of organohalide respiration presents an attractive bioremediation tool, although the substrate scope is limited and the reaction is often slow or incomplete. We will seek to gather further fundamental insights into what governs substrate scope and how to rationally repurpose these catalysts towards environmentally relevant pollutants. The RDases can be split into two classes: i) the canonical respiratory dehalogenases, which use a halogenated compound as a final electron acceptor during the process of organohalide respiration, and ii) the catabolic respiratory dehalogenases that occur in the catabolic pathways of non-organohalide respiring bacteria. The catabolic RDase enzymes tend to be oxygen-tolerant, suggesting these are the more desirable targets for future mechanistic studies and bioremediation applications [3-5]. A range of mechanisms have been proposed on the basis of the few substrate/ligand complex crystal structures available. Building upon our work with catabolic reductive dehalogenases [3-5], we will determine the molecular aspects that underpin substrate binding and explore the scope to rationally evolve this. We will establish both the mechanism of B12-mediated substrate reduction using X-ray crystallographic methods and NAD(P)H-mediated B12-reduction (using time-resolved spectroscopic approaches) to provide a complete mechanistic understanding of catalysis. We will use fundamental understanding gained in order to guide in vivo bioremediation of environmentally relevant organohalides. This will make use of rational laboratory-based evolution of RDases to create a toolbox of enzymes able to degrade organohalide pollutants.

The project will be carried out at the Manchester Institute of Biotechnology (MIB) at Manchester (under guidance of Prof. D. Leys, S. Hay and A. W. Munro), with a 12 month placement at our international partners at BioZone, University of Toronto, Canada (Prof. E. A. Edwards). The work at Manchester will focus on molecular enzymology and rational evolution of reductive dehalogenases, with the fundamental knowledge gained at MIB used to guide research into real-world applications at BioZone, using microbiology and chemical engineering approaches.
Informal enquires can be made to .

https://www.research.manchester.ac.uk/portal/david.leys.html
https://chem-eng.utoronto.ca/faculty-staff/faculty-members/elizabeth-a-edwards/

Entry Requirements:
Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

UK applicants interested in this project should make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. International applicants (including EU nationals) must ensure they meet the academic eligibility criteria (including English Language) as outlined before contacting potential supervisors to express an interest in their project. Eligibility can be checked via the University Country Specific information page (https://www.manchester.ac.uk/study/international/country-specific-information/).

If your country is not listed you must contact the Doctoral Academy Admissions Team providing a detailed CV (to include academic qualifications – stating degree classification(s) and dates awarded) and relevant transcripts.

Following the review of your qualifications and with support from potential supervisor(s), you will be informed whether you can submit a formal online application.

To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the BBSRC DTP website http://www.manchester.ac.uk/bbsrcdtpstudentships

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/

MIB

Funding Notes

Funding will cover UK tuition fees/stipend only. The University of Manchester aims to support the most outstanding applicants from outside the UK. We are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

References

1. Löffler, F. E.; Edwards, E. A. Curr. Opin. Biotechnol. 2006, 17, 274–284.
2. Leys, D.; Adrian, L.; Smidt, H. Philos. Trans. R. Soc. B Biol. Sci. 2013, 368, 8–10.
3. Payne, K. A. P.; Quezada, C. P.; Fisher, K.; Dunstan, M. S.; Collins, F. A.; Sjuts, H.; Levy, C.; Hay, S.; Rigby, S. E. J.; Leys, D. Nature. 2015, 517, 513–516.
4. Collins, F.; Fisher, K.; Payne, K.A.P.; Mondragon, S.G.; Rigby, S.E.J.; Leys. D. Biochemistry 2018 57, 3493-3502
5. Halliwell, T.; Leys D. Microorganisms 2020, 8, 1344

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