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Site‐Specific Modification of the Anticancer and Antituberculosis Polyether Salinomycin by Biosynthetic Engineering
Author(s) -
Luhavaya Hanna,
Williams Simon R.,
Hong Hui,
Gonzaga de Oliveira Luciana,
Leadlay Peter F.
Publication year - 2014
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201402300
Subject(s) - salinomycin , stereochemistry , chemistry , ionophore , biochemistry , combinatorial chemistry , membrane , antibiotics
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 new analogues, in both of which the C18C19 cis double bond is replaced by a hydroxy 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 new salinomycin analogues for use in mechanism‐of‐action studies.