Luhavaya Hanna, Williams Simon R, Hong Hui, Gonzaga de Oliveira Luciana, Leadlay Peter F
Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA (UK).
Chembiochem. 2014 Sep 22;15(14):2081-5. doi: 10.1002/cbic.201402300. Epub 2014 Aug 22.
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.
复杂的双螺环缩醛聚醚离子载体沙利霉素已被确定为一种针对癌症干细胞的独特选择性药物,并且在潜伏性结核病动物模型中也具有显著疗效。这些重要活性的基础尚不清楚。我们在此表明,删除salE基因会消除沙利霉素的产生,并产生两种新的类似物,在这两种类似物中,C18C19顺式双键被立体定向位于C19的羟基取代,但双螺环缩醛的构型彼此不同。这些结果确定SalE为一种新型脱水酶,并证明生物合成工程可用于重新引导氧化环化反应级联,以产生用于作用机制研究的新沙利霉素类似物。