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 (eg cholesterol-lowering, statins with a global market value of $25 billion). 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. Polyketides are generated by polyketide synthases, many of which are giant assemblies of multi-modular polypeptides harbouring multiple sequential catalytic domains. The evolution of the natural product via simple carbon building blocks can progress in a systematic, in-cis, pathway dictated by the linear arrangement of enzymes in the covalently linked modules but critically can recruit free-standing in-trans partners at critical junctures to perform additional chemistry. Many questions remain about how these synthases control the in-cis and in-trans balance and and is a cornerstone of future synthetic biology and bio-engineering efforts of these pathways towards high-value ‘non-natural’ products.
This project’s main aim is to advance our understanding of these enzyme cascades as applied to a number of biologically active antibiotic and anti-cancer natural products. The focus of the project will be to explore how groups of enzymes in different pathways work together to exquisitely control incorporation of, for example, C-C bond branches to the main scaffold of the natural product, incorporate heteroatoms, eg sulfur or curtail key processing to retain different chemistry. Synthetically these transformations would be challenging, but Nature achieves this cleanly and efficiently.
To unpick the complex function of this mutli-enzyme cascade, we have designed a new tool that combines NMR and chemical synthesis. This allows us to essentially introduce a micro-antenna (a carbon-13 label) within a molecule and NMR lets us look at or “tune into” this signal. Hence the fate of a particular molecule can be followed in reconstructed enzymes assemblies in close to real time. The aim of the PhD is to investigate the structure and function of these enzyme cascades with applications to other new areas of biocatalysis.
Crucially, with this synthetic biology project you will learn techniques encompassing structural biology, NMR, X-ray crystallography, microbiology and molecular modelling/design as well as work with synthetic chemists, offering a wide array of avenues to explore.
Potential applicants (UK residents or EU citizens with settled status) should have a strong 4- year degree in Chemistry or Biochemistry. To apply to Bristol Chemistry, please follow the link here. For further information, please email the academic supervisor Professor Matthew Crump [Email Address Removed] or [Email Address Removed]
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