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dc.contributor.authorLuhavaya, Hannaen
dc.contributor.authorWilliams, Simonen
dc.contributor.authorHong, Huien
dc.contributor.authorGonzaga, de Oliveira Lucianaen
dc.contributor.authorLeadlay, Peteren
dc.date.accessioned2014-07-09T11:30:09Z
dc.date.available2014-07-09T11:30:09Z
dc.date.issued2014-08-22en
dc.identifier.citation(2014) ChemBioChem 15: 2081-2085
dc.identifier.issn1439-4227
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/245424
dc.description.abstractThe 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.
dc.description.sponsorshipThis 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.
dc.languageEnglishen
dc.language.isoenen
dc.subjectbiosynthesisen
dc.subjectpolyketidesen
dc.subjectionophoreen
dc.subjectdehydrataseen
dc.subjectspiroacetalen
dc.titleSite-specific modification of the anti-cancer and anti-tuberculosis polyether salinomycin by biosynthetic engineeringen
dc.typeArticle
dc.description.versionThis is the author accepted manuscript and will be under embargo until the 22nd of August 2015. The final version has been published in ChemBioChem here: http://onlinelibrary.wiley.com/doi/10.1002/cbic.201402300/abstract.en
prism.endingPage2085
prism.publicationDate2014en
prism.publicationNameChemBioChemen
prism.startingPage2081
prism.volume15en
rioxxterms.versionofrecord10.1002/cbic.201402300en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2014-08-22en
dc.contributor.orcidLeadlay, Peter [0000-0002-3247-509X]
dc.identifier.eissn1439-7633
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idBBSRC (BB/I002413/1)
pubs.funder-project-idBBSRC (BB/D018943/1)
rioxxterms.freetoread.startdate2015-08-22


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