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(BBSRC DTP CASE) Characterisation of drug metabolites using mass spectrometry and associated technologies


Department of Chemistry

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Prof J Waltho , Prof A Munro No more applications being accepted Competition Funded PhD Project (Students Worldwide)
Manchester United Kingdom Biochemistry Bioinformatics Biophysics Microbiology Molecular Biology Pharmacology Structural Biology

About the Project

The cytochromes P450 are a diverse group of enzymes that contain a haem prosthetic group. The P450s become activated when they are reduced by their partner enzymes, the cytochrome P450 reductases, also known as CPR enzymes for convenience. To activate the P450 enzyme, a substrate must bind in the active site cavity of the particular P450, and then the CPR transfers electron derived (typically) from NADPH to the haem prosthetic group. This occurs in two stages by transferring 2 successive electrons from the CPR. This results in the electrons being transported to the heme iron through a canonical pathway, resulting in the formation of a highly reactive iron-oxo species (known as compound I, or Cpd I) that attacks the substrate and facilitates the transfer of an oxygen atom onto the substrate – usually resulting in its hydroxylation, but often creating other types of outcome (e.g. epoxidation, decarboxylation, dehalogenation, sulfoxidation etc) that give rise to a range of different oxidised molecules and to the expulsion of a water molecule. The P450 proteins are typically triagonal in shape, but their active sites can be very different in their shape and space available for the binding of their substrates. Many of the substrates bound in the P450 active sites are mobile and this can give rise to oxidative reactions on different parts of the substrate molecule. Due to the “flexibility” of many of the P450 enzymes, larger substrates can also penetrate into the relevant P450 active site cavity. In our ongoing work, we are exploring the oxidative transformations of a series of pharmaceutical and related drug compounds. Using mass spectrometry and other approaches we have established that such xenobiotics (and related molecules) and other drug compounds can be oxidatively transformed to produce novel derivatives of the parent compounds – a number of which are the same (or similar) to human drug metabolites. The overall outcomes of our project will involve the characterisation of a series of drug molecules through their oxidative transformation in their host P450 cavities. Ultimately, we intend to produce a series of drug metabolites and to explore their catalytic and other properties. Through using a series of P450 enzymes we expect to identify a number of new metabolites and to use fermentation methods in order to scale up the quantities of the various metabolites for their further analysis.

https://www.research.manchester.ac.uk/portal/j.waltho.html
https://www.research.manchester.ac.uk/portal/en/researchers/andrew-munro(8eb33a03-e35b-451d-b248-789d0f6c35b2)/contact.html

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 Primary 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 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

This is a CASE studentship in partnership with Cypex Ltd. 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 scholarships 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.


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