A head-to-head comparison of eneamide and epoxyamide inhibitors of glucosamine-6-phosphate synthase from the dapdiamide biosynthetic pathway

Marie A. Hollenhorst, Ioanna Ntai, Bernard Badet, Neil L. Kelleher, Christopher T. Walsh

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3859-3861
Number of pages3
JournalBiochemistry
Volume50
Issue number19
DOIs
StatePublished - May 17 2011

ASJC Scopus subject areas

  • Biochemistry

Fingerprint

Dive into the research topics of 'A head-to-head comparison of eneamide and epoxyamide inhibitors of glucosamine-6-phosphate synthase from the dapdiamide biosynthetic pathway'. Together they form a unique fingerprint.

Cite this