Polyketide natural products such as the antibiotic erythromycin A, the immunosuppressant rapamycin, or the anticancer compound geldanamycin, are synthesised on giant multienzyme assemblies whose size rivals or exceeds that of the ribosome. We aim to understand the structure of these polyketide synthases (PKSs) and the mechanism of polyketide chain assembly and the further enzymatic tailoring of the products using a wide range of genetic, enzymological and protein engineering approaches. We are also exploring the creation of hybrid multienzymes capable of producing novel analogues of important polyketide drugs.
Our current projects include: (1) detailed mechanistic analysis of ketosynthase, ketoreductase, acyltransferase and dehydratase enzymes from PKSs, their protein engineering and directed evolution; (2) design and assembly of novel PKSs in order to produce rare anticancer polyketides of marine origin; and (3) detailed functional analysis of a large number of novel PKS clusters to deepen our understanding of the potential of these systems for synthetic biology. As an example, we are collaborating with the group of Stewart Cole (Institut Pasteur, Paris) to analyse the remarkable polyketide synthases that produce mycolactone, a highly toxic polyketide implicated in the emerging disease known as Buruli ulcer, which may lead to more effective therapies. We are also interested in novel ways of identifying the intracellular protein targets of such polyketide drugs and toxins.
Lab members: Reda Deglau, Shilo Dickens, Freddie Dudbridge, Anna Efimova, Hui Hong, Fanglu Huang, Chompoonik Kanchanabanca, Carolina Lascelles, John Lester, Reidun Lillestol, Hanna Luhavaya, Annabel Murphy, Anna Reva, Markiyan Samborskyy, Nataliya Scott, Qiulin Wu, Marie Yurkovich, Yongjun Zhou
- Oliynyk, M., Samborskyy, M., Lester, J.B., Mironenko, T., Scott, N., Dickens, S., Haydock, S.F. and Leadlay, P.F. (2007). Complete genome sequence of the erythromycin-producing bacterium Saccharopolyspora erythraea NRRL23338. Nature Biotech. 24, 447-453.
- Hong, H., Demangel, C., Pidot, S.J., Leadlay, P.F. and Stinear, T. (2008) Mycolactones: immunosuppressive and cytotoxic polyketides produced by aquatic mycobacteria. Nat. Prod. Rep. 3, 447-454.
- Demydchuk, Y., Sun, Y., Hong, H., Staunton, J., Spencer, J.B. and Leadlay, P.F. (2008) Analysis of the tetronomycin gene cluster: insights into the biosynthesis of a polyether tetronate antibiotic. ChemBioChem. 9, 1136-1145.