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Biocatalytic formation of amide bonds

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  • Full or part time
    Prof Grogan
    Prof Fairlamb
  • Application Deadline
    No more applications being accepted
  • Funded PhD Project (UK Students Only)
    Funded PhD Project (UK Students Only)

Project Description

The amide bond is one of the most frequently encountered in pharmaceutical chemistry, featuring in
drug molecules such as atorvastatin, lidocaine and captopril. Despite its simplicity, synthesis of the
amide bond presents challenges to industrial synthetic chemistry, as widely-used coupling methods
employ toxic reagents and represent poor atom economy. Enzyme-catalysed amide bond formations
might provide possible solutions to these issues, as they would be catalytic, selective and
environmentally benign, however, usable enzymatic methods for amide formation have largely been
restricted to hydrolase-based processes with narrow substrate specificity in either acid or amine
components. The characterization of non-ribosomal peptide synthase (NRPS) mediated biosynthetic
pathways is revealing novel amide bond forming enzymes (ABFEs) in which substrate specificity is
wider than for hydrolase-mediated reactions, and for which the prospects of application to the
synthesis of pharmaceutically relevant molecules are much more promising. In this project, funded
by GlaxoSmithKline and the BBSRC, we will explore the utility of novel ABFEs for the synthesis of
industrially relevant amides. We will employ techniques in molecular biology, gene expression and
FPLC-based protein purification for the isolation of ABFEs. We will also perform the synthesis of
substrates and products of interest for assays, using both traditional organic and biocatalytic
techniques. X-ray crystallography will be used to obtain structures of ABFEs in complex with
substrates, products and intermediates in order to shed light on substrate specificity and mechanism.
Finally, structure-informed enzyme engineering, using limited in vitro evolution methods, coupled to a
high-throughput screen, will be used to improve and alter the activity of ABFEs towards novel target
compounds of interest.
The project will be supervised in the laboratories of Professors Gideon
Grogan (molecular biology, enzymology, structural enzymology;
https://www.york.ac.uk/chemistry/staff/academic/d-g/ggrogan/) and Ian Fairlamb (catalysis, organic
synthesis; http://www.york.ac.uk/chemistry/staff/academic/d-g/ifairlamb/) and would suit applicants
with a degree in Chemistry, Biochemistry or a related subject, and who are interested in research at
the interface between biology and chemistry.

The Department of Chemistry holds an Athena SWAN Gold Award and is committed to supporting equality and diversity for all staff and students

Funding Notes

This studentship is fully funded by an Industrial CASE award from the BBSRC with GSK and covers: (i) a tax-free annual stipend at the standard Research Council rate (£14,057 for 2015-2016, typically increasing annually in line with inflation), (ii) research costs, and (iii) tuition fees at the UK/EU rate. The studentship is available to UK and EU students who meet the UK residency requirements. Students from EU countries who do not meet the residency requirements may still be eligible for a fees-only award. Further information about eligibility for Research Council UK funding can be found at the following website:http://www.bbsrc.ac.uk/web/FILES/Guidelines/studentship_eligibility.pdf

How good is research at University of York in Chemistry?

FTE Category A staff submitted: 47.06

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

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