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Biosynthetic Lego: Building antibiotic assembly lines from first principles


School of Biochemistry

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Dr P Race Applications accepted all year round Self-Funded PhD Students Only

About the Project

Nature has evolved many elegant strategies for the construction of complex bioactive natural products. The most sophisticated of these involves the action of giant assembly line like megaenzymes, which fuse and tailor simple carboxylic acid building blocks into a vast array of elaborate carbon scaffolds. Many of the products of these systems are the basis for, or inspiration behind, our most important clinically used antibiotics, e.g. erythromycin.

This project will build on ongoing work in the Race laboratory in attempting to assemble from first principles a series of ‘designer’ biosynthetic assembly lines with the capacity to produce novel antibiotic compounds for clinical use. The project will combine molecular biology, protein biochemistry, synthetic biology, biomolecular engineering and analytical chemistry, and will involve significant collaboration with chemists and biologists in Bristol and thought the UK and Europe.

References

1) Lees NR, Han L-C, Byrne MJ, Davies JA, Parnell AE, Moreland PEJ, Stach JEM, van der Kamp MW, Willis CL, Race PR (2019) An Esterase-like Lyase Catalyzes Acetate Elimination in Spirotetronate/Spirotetramate Biosynthesis. Angew Chem Int Ed. 58(8): 2305-2309.

2) Maschio L, Parnell AE, Stach JE, Willis CL, Schaffitzel C, Race PR (2019) Cloning, Expression and Purification of Intact Polyketide Synthase Modules. Methods in Enzymol. 617: 63-82.

3) Wang L, Parnell AE, Williams C, Bakar N, Challand MR, van der Kamp MW, Simpson TJ, Race PR, Crump MP, Willis CL. (2018) A Rieske oxygenase/epoxide hydrolase cascade creates oxygen heterocycles in antibiotic biosynthesis. Nature Catalysis. 1: 968-976.
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