A Head-to-Head Comparison of Eneamide and Epoxyamide Inhibitors of Glucosamine-6-Phosphate Synthase from the Dapdiamide Biosynthetic Pathway

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• 作者：Marie A. Hollenhorst ; Ioanna Ntai ; Bernard Badet ; Neil L. Kelleher ; Christopher T. Walsh
• 刊名：Biochemistry
• 出版年：2011
• 出版时间：May 17, 2011
• 年：2011
• 卷：50
• 期：19
• 页码：3859-3861
• 全文大小：673K
• 年卷期：v.50,no.19(May 17, 2011)
• ISSN：1520-4995

文摘

The dapdiamides make up a family of antibiotics that have been presumed to be cleaved in the target cell to enzyme-inhibitory N-acyl-2,3-diaminopropionate (DAP) warheads containing two alternative electrophilic moieties. Our prior biosynthetic studies revealed that an eneamide warhead is made first and converted to an epoxyamide via a three-enzyme branch pathway. Here we provide a rationale for this logic. We report that the R,R-epoxyamide warhead is a more efficient covalent inactivator of glucosamine-6-phosphate synthase by 1 order of magnitude versus the eneamide, and this difference correlates with a >10-fold difference in antibiotic activity for the corresponding acyl-DAP dipeptides.