Prof. Matthew Crump (School of Chemistry, University of Bristol)
Prof. Chris Willis (School of Chemistry, University of Bristol)
Prof. Christiane Berger-Schaffitzel (School of Biochemistry, University of Bristol)
Dr. Paul Race (School of Biochemistry, University of Bristol)
Start date September 2020
A PhD project is available for commencement in September 2020 as one of a number that are in competition for funding from the South West Biosciences Doctoral Training Partnership (BBSRC SWBio DTP). The SWBio DTP projects are designed to provide outstanding interdisciplinary training in a range of topics in Agriculture & Food Security and world-class Bioscience, underpinned by training in mathematics and complexity science. Each project will be supervised by an interdisciplinary team of academic staff and will follow a structured training 4-year PhD model. This program offers a tailored PhD experience with research rotations, lectures courses and a PIPS placement where you have the opportunity to work in an area you are interested in at a relevant organisation of your chosing. You will be part of a cohort of 20+ fellow students and the complete package makes an excellent training experience.
Project Background. Polyketide biosynthetic pathways generate vast numbers of diverse compounds that represent one of the largest collections of chemical structures with biological activities and high commercial value, many of which are already exploited across a spectrum of applications. How are they formed? Well, Henry Ford may be credited with inventing the car assembly line in the early 1900s, but he was beaten to it by microbial biosynthetic pathways (and by many millions of years!). Polyketides are generated by type I modular polyketide synthases, sophisticated biosynthetic mega-enzymes, like the assembly of enzymes shown opposite, which may be rationally manipulated to deliver functionally optimised products. At their extreme, these pathways involve 50-100 proteins with tight control over the order in which they act, their interactions and their interdependencies. How all of this is controlled, however, remains elusive and our laboratory strives to understand these principles.
This project aims to advance our understanding of these assemblies as applied to kalimantacin, an anti-MRSA antibiotic. The focus of the project will be to manipulate a very specific part of this pathway which exquisitely controls how kalimantacin is modified by branching of the carbon skeleton. These beta-branches are formed from methyl or exo-methylene groups that are appended in several different ways along kalimantacin (shown in red, green and blue) by a single dedicated cassette of enzymes. Synthetically this would be challenging but this clever molecular trick is extremely important as the branches are critical for the anti-bacterial potency of kalimantacin. We now have preliminary data (see references) on how the branching might be controlled or how the system is programmed to make each branch. In this PhD project key components of the systems (ECH or Enoyl CoA hydratase domains) will be engineered to explore if we can reverse the order of beta-branch incorporation and hence apply production line engineering approaches to delivering new chemical entities. In addition, the trimeric quaternary structure of ECH domains is incompatible with current models for polyketide synthases so a second part of the project will be to study how these modules assemble and you will learn to apply state of the art Cryo-EM techniques to this challenge.
Crucially, this synthetic biology project will draw on techniques encompassing structural biology, NMR, Cryo-EM, collaboration with synthetic chemists, microbiology and molecular modelling/design offering a wide array of avenues for the student to explore.
Closing date for applications is 02/12/2019.
For informal enquiries please contact [email protected]
or [email protected]
The studentship will provide funding for a stipend (currently £15,009 pa for 2019-20), research costs and UK/EU tuition fees at Research Council UK rates for 4 years for full-time students, pro-rata for part-time students. The SWBio DTP is a BBSRC-funded PhD training programme in the biosciences, delivered by a consortium comprising the Universities of Bristol (lead), Bath, Cardiff, Exeter, Rothamsted Research and associate partners. More information on this scheme can be found View Website. Appointment is by competitive interview and the closing date for online applications at the above SWBio website is Monday 2nd December.
Keywords Biosynthesis Antibiotics Kalimantacin Synthetic Biology
Key reference Control of β-Branching in Kalimantacin Biosynthesis: Application of 13C NMR to Polyketide Programming - Walker PD et al., ACIE, 2019, 58, 12446-12450