About the Project
In this project, the aim is to develop ways to control how polyketide synthases, an important class of natural biocatalytic machinery, set the stereochemistry of their products, polyketides. This will be explored by modifying – or redesigning – a key enzyme in polyketide synthase systems called a ketoreductase. Ketoreductases control the stereochemistry of reductive steps in the formation of the polyketide. A key feature of these systems is that substrates are also tethered to an acyl-carrier protein (ACP), which presents the evolving polyketide chain to the ketoreductase (and other enzymes). Existing structural information on the interaction between the ACP and the ketoreductase involved in making the polyketide actinorhodin (a natural antibiotic) will guide the development of computational prediction protocols. This will be the bulk of the work, involving combined quantum mechanical / molecular mechanical (QM/MM) reaction simulations, molecular dynamics and protein-protein docking. The simulations will predict new ketoreductase variants that alter the stereochemical outcome. To test and improve these computational predictions, experimental characterisation of promising enzyme variants (product outcome, kinetics and structural biology) will be performed. Once successful, the atomic detail of selected new variants will be confirmed through structural biology techniques (NMR, X-ray crystallography).
This interdisciplinary project combines the expertise in computational simulation of enzymes in Bristol and the expertise from an internationally leading academic team with multidisciplinary expertise of polyketide systems and the relevant experimental techniques (enzymology, molecular biology, chemistry and structural biology). Combining simulation and experiment in this way is still developing, but will be increasingly important in the future. The strategies and protocols developed in this project will therefore be of general use in natural product research. The multidisciplinary environment ensures the student will acquire a range of skills that will arm them for a future career in academic or industrial bioscience (including pharmaceutical science). The student will be embedded in the vibrant research environment in Bristol, including the Bristol Computational Biochemistry group (www.bristol.ac.uk/bcompb) and the Bristol BioDesign institute, ensuring a wide range of interactions, seminars and courses.
Main supervisor: Dr Marc van der Kamp (Biochemistry, University of Bristol)
Second supervisor: Prof Matthew Crump (Chemistry, University of Bristol)
Additional supervisory team: Dr Paul Race, Prof Chris Willis
International collaborator: Prof Sheryl Tsai (University of California, Irvine)
Applicants must have obtained, or be about to obtain, a First or Upper Second Class UK first degree, or the equivalent qualifications gained outside the UK, in an appropriate area of science or technology.
Follow the ’Start a new application’ link on this page: http://www.bristol.ac.uk/study/postgraduate/apply/
Please ensure that you quote the supervisor’s name and project title in the ‘Your research interests’ section. The deadline for the receipt of applications is Monday 3 December 2018.
The determinants of activity and specificity in actinorhodin type II polyketide ketoreductase. Javidpour P, Bruegger J, Srithahan S, Korman TP, Crump MP, Crosby J, Burkart MD, Tsai SC. Chem. Biol. (2013) 20, p. 1225-1234
The fourth wave of biocatalysis is approaching. Bornscheuer, UT. Phil. Trans. R. Soc. A (2018) 376, 20170063
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