About the Project
The human enzyme 2′-deoxynucleoside 5′-phosphate N-hydrolase 1 (DNPH1) catalyses the N-ribosidic bond hydrolysis of the noncanonical nucleotide 5-hydroxymethyl-2′-deoxyuridine 5′-monophosphate, producing 5-hydroxymethyluracil and 2-deoxyribose 5-phosphate. This reaction proceeds by a double-displacement mechanism whereby Glu104 nucleophilically attacks 5-hydroxymethyl-2′-deoxyuridine 5′-monophosphate to form a covalent 5-phospho-2-deoxyribosylated enzyme intermediate, which is subsequently…
hydrolysed. DNPH1 is a nucleotide-sanitizing enzyme that degrades non-canonical a nucleotide to prevent its incorporation into DNA. Specific and potent inhibitors of DNPH1 are useful tools to interrogate the role of DNPH1 catalysis in health and disease.
This project design and synthesize potent and selective inhibitors of DNPH1 and elucidate their inhibition mechanism. The PhD student leading this project will gain theoretical and practical expertise in structure- and mechanism-based inhibitor design, organic synthesis, small molecule spectroscopic characterisation, enzyme structure and kinetics, and dissection of enzyme inhibition mechanism. The successful candidate will have a 1st-class degree in Chemistry with a focus on Medicinal Chemistry. Hands-on experience in organic synthesis and chemical biology is preferred.
The successful candidate will join two collaborative research groups in the Biomedical Sciences Research Complex (BSRC) at the University of St Andrews, the da Silva lab from the School of Biology and the Florence lab from the School of Chemistry. The BSRC is a highly collaborative research centre that brings together scientists from Biology, Chemistry, Physics and Medicine. The ethos of the BSRC is to break down barriers among disciplines and conduct world-class research relevant to health and disease. The BSRC offers state-of-the-art infrastructure for Structural Biology, Enzymology and Molecular Biophysics. The laboratories house incubators and FPLCs; spectrophotometers, stopped-flow spectrofluorimeter, quench-flow and plate readers; microcalorimeters and CD spectrophotometer; computer clusters and university-wide software licenses; NMR, HPLC and MS spectrometers, including native mass spec; a wide array of microscopies for single-molecule biophysics; a fully robotised suite for crystallisation and access to Diamond Light Source and ESRF; fume hoods and all necessary infrastructure for organic synthesis and characterisation of compounds.
HOW TO APPLY
Application instructions can be found on the EASTBIO website- How to Apply | EastBio Doctoral Training Partnership | Biology
- Download and complete the Equality, Diversity and Inclusion survey.
- Download and complete the EASTBIO Application Form.
- Please complete an application on our online portal: How to apply - Study at St Andrews - University of St Andrews
- Select the course ‘PhD with internship’
- Your online application must include the following documents:
- Completed EASTBIO application form
- Academic Qualifications
- English Language Qualification (if applicable)
- 2 References: this must be completed on the EASTBIO Reference Form, also found on the EASTBIO website.
Please download the EASTBIO reference form and send it to your referees. They can either upload it directly to the portal using the automated email they will receive, or they can email it to Rachel at pgrecbiology@st-andrews.ac.uk
CONTACT
Queries on the project can be directed to the project supervisor.
Queries on the application process can be directed to Rachel Horn at pgrecbiology@st-andrews.ac.uk
UKRI eligibility guidance: Terms and Conditions: View Website International/EU: View Website
Funding Notes
This 4 year PhD project is part of a competition funded by EASTBIO BBSRC Doctoral Training Partnership.
This opportunity is open to UK and International students and provides funding to cover stipend at UKRI standard rate and UK level tuition fees. The University of St Andrews will cover the Home-International fee difference.
References
References:
- The energy landscape of N-ribosidic bond cleavage catalysed by 2'-deoxynucleoside 5'-phosphate N-hydrolase 1. Carberry, Das, Harrison, Hirschi, da Silva Biochemical Journal 482 (2025) 1897-1918.
- Human 2'-deoxynucleoside 5'-phosphate N-hydrolase 1: the catalytic roles of Tyr24 and Asp80. Carberry, Devi, Harrison, da Silva ChemBioChem 25 (2024) e202400047.
- Human 2'-deoxynucleoside 5'-phosphate N-hydrolase 1: mechanism of 2'-deoxyuridine 5'-monophosphate hydrolysis. Devi, Carberry, Zickuhr, Dickson, Harrison, da Silva Biochemistry 62 (2023) 2658-2668.