Site-specific modification of the anti-cancer and anti-tuberculosis polyether salinomycin by biosynthetic engineering
Gonzaga, de Oliveira Luciana
MetadataShow full item record
Luhavaya, H., Williams, S., Hong, H., Gonzaga, d. O. L., & Leadlay, P. (2014). Site-specific modification of the anti-cancer and anti-tuberculosis polyether salinomycin by biosynthetic engineering. ChemBioChem, 15 2081-2085. https://doi.org/10.1002/cbic.201402300
The complex bis-spiroacetal polyether ionophore salinomycin has been identified as a uniquely selective agent against cancer stem cells and is also strikingly effective in an animal model of latent tuberculosis. The basis for these important activities is unknown. We show here that deletion of the salE gene abolishes salinomycin production and yields two novel analogues, in both of which the C18-C19 cis double bond is replaced by a hydroxyl group stereospecifically located at C19, but which differ from each other in the configuration of the bis-spiroacetal. These results identify SalE as a novel dehydratase and demonstrate that biosynthetic engineering can be used to redirect the reaction cascade of oxidative cyclization to yield novel salinomycin analogues for use in mechanism-of-action studies.
biosynthesis, polyketides, ionophore, dehydratase, spiroacetal
This work was supported by the Biotechnology and Biological Sciences Research Council (BBSRC) and by Biotica Technology Ltd. through an Industrial Partnership Award BB/I002513/1 to P. F. Leadlay. H. Luhavaya acknowledges a studentship from the Cambridge Overseas Trust and S. R. Williams acknowledges a studentship from the Todd-Raphael Fund and Prof. Ian Paterson. L. Gonzaga de Oliveira was supported by the São Paulo Research Foundation (2011/17510-6). P. F. Leadlay is a Research Awardee of the Alexander von Humboldt Foundation.
External DOI: https://doi.org/10.1002/cbic.201402300
This record's URL: https://www.repository.cam.ac.uk/handle/1810/245424