Combining organic synthesis and synthetic biology to explore and exploit polyketide biosynthesis Chris Willis University of Bristol, UK Polyketide-derived natural products isolated from microorganisms exhibit a range of important biological activities making them attractive leads for the development of therapeutics and agrochemicals. They are assembled in the host organism via sophisticated multiple enzyme architectures – polyketide synthases. Our overall aim is to fully understand how polyketides are produced to enable rational engineering of the complex biosynthetic machinery to deliver novel bioactive compounds cleanly and efficiently in scalable amounts. This lecture will focus on the combination of synthetic biology and organic synthesis to investigate polyketide biosynthesis thus enabling the generation of new bioactive targets and biocatalysts of potential widespread value. Examples will be taken from our recent work and will show case the value of a combined selective carbon-13 labelling/ NMR strategy to probe enzyme-catalysed transformations in situ. References 1. J. Byrne, N.R. Lees, L.-C Han, M. van der Kamp, A.J. Mulholland, J.E.M. Stach, C.L. Willis and P.R. Race, The catalytic mechanism of a natural Diels-Alderase revealed in molecular detail J. Am. Chem. Soc . 2016 , 138 , 6095. 2. L. Wang, A.E. Parnell, C. Williams, N.A. Baker, M.R. Challand, M. van der Kamp, T.J. Simpson, P. R. Race, M..P. Crump and C. L. Willis, A Rieske oxygenase/epoxide hydrolase-catalysed reaction cascade creates oxygen heterocycles in mupirocin biosynthesis Nature Catalysis , 2018 , 1 , 968. 3. N.R. Lees, L.C Han, M.J. Byrne, J.A. Davies, A.E. Parnell, P.E.J. Moreland, J.E.M. Stach, M.W. van der Kamp, C.L. Willis and P.R. Race, An esterase-like lyase catalyzes acetate elimination in spirotetronate/ spirotetramate biosynthesis Angew. Chem. Int. Ed. 2019 , 58 , 2305. 4. L. Wang, Z. Song, P.R. Race, J. Spencer, T.J. Simpson, M.P. Crump and C.L. Willis, Mixing and matching genes of marine and terrestrial origin in the biosynthesis of the mupirocin antibiotics, Chem Sci. , 2020 , 11 , 5221-5226.
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