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Unravelling the mechanism of glutamyl-tRNA reductase, a target for broad-spectrum antibiotic development

  • Full or part time
  • Application Deadline
    Sunday, December 01, 2019
  • Competition Funded PhD Project (Students Worldwide)
    Competition Funded PhD Project (Students Worldwide)

Project Description

Antimicrobial resistance is on the rise. This global threat is predicted to claim more lives than cancer by 2050 if not properly addressed. We urgently need novel drugs that affect new molecular targets. Broad-spectrum antibiotics are indispensable in cases of acute bacterial infections, especially in cases where a diagnosis regarding the bacterial species is missing. The bacterial enzyme glutamyl-tRNA reductase (GluTR) is a validated target for antimicrobial discovery: GluTR is absolutely essential for survival and growth of most pathogenic bacteria, but has no homologues in humans, which bodes well for the design of specific GluTR inhibitors that will steer clear of human proteins.
GluTR is the first enzyme in the biosynthesis of 5-aminolevulinic acid, the common precursor in the synthesis of tetrapyrroles, including heme. The enzyme catalyses the NADPH-dependent reduction of glutamyl-tRNA to glutamate 1-semialdehyde, also generating NADP+ and free tRNA in the process.
In this project, the student will dissect the mechanism of this reaction, including solving the crystal structure of the enzyme with substrates and/or products, uncovering the nature of reaction intermediates, identifying rate-limiting steps, and elucidating the role of key residues in catalysis. The results will inform the rational design of potent and specific GluTR inhibitors to be further developed as antibiotics.
A student in this project will acquire training in gene cloning, site-directed mutagenesis and heterologous gene expression, protein purification and crystallography, enzyme kinetics in steady-state and pre-steady-state, and several biophysical methods such as circular dichroism, isothermal titration calorimetry, differential scanning fluorescence, and mass spectrometry. These are highly sought-after skills in both academic and industrial settings.
Furthermore, the student will be part of a vibrant and highly collaborative interdisciplinary department, the Biomedical Sciences Research Complex (BSRC), where scientists from Biology, Chemistry, Medicine, and Physics work on challenging problems related to health and disease. The student will have access to the award-winning GradSkills courses at the University of St Andrews, will have training in scientific writing through the preparation of reports and manuscripts for publication, public speaking through presentation of their work in the da Silva lab group meetings and BSRC Friday talks, and will be part of an enthusiastic cohort PhD students in the BSRC. In the da Silva lab, they will join a diverse and enthusiastic group of biochemists and chemists working on various aspects of enzymology and inhibitor design.
The successful candidate will have a 1st-class honours BSc and/or an MSc in Biochemistry, Chemistry, or a closely related field, some research experience, and enthusiasm for elucidating enzyme mechanisms for drug development. Interested candidates should fill out the application form and submit their cover letter, CV, and degree transcripts. Candidates should contact Dr da Silva to discuss their application and the project before applying.

Funding Notes

Eligibility requirements: Upper second-class degree in Biology or a related area.
Funding: Fees and stipend is provided for 3.5 years.

References

Nogaj et al. (2005) Physical and Kinetic Interactions between Glutamyl-tRNA Reductase and Glutamate-1-semialdehyde Aminotransferase of Chlamydomonas reinhardtii. J Biol Chem 208, 24301–24307.

Moser et al. (2001) V-shaped structure of glytamyl-tRNA reductase, the first enzyme of tRNA-dependent tetrapyrrole biosynthesis. EMBO J 20, 6583-6590.

Harding et al. (2018) Uncovering the mechanisms of Acinetobacter baumannii virulence. Nature Rev 16, 91-102.

How good is research at University of St Andrews in Biological Sciences?

FTE Category A staff submitted: 50.45

Research output data provided by the Research Excellence Framework (REF)

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