Covalent inhibitors of LgtC: a blueprint for the discovery of non-substrate-like inhibitors for bacterial glycosyltransferases

Yong Xu, Ruth Smith, Mirella Vivoli, Masaki Ema, Niina Goos, Sebastian Gehrke, Nicholas J. Harmer, Gerd K. Wagner

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Non-substrate-like inhibitors of glycosyltransferases are sought after as chemical tools and potential lead compounds for medicinal chemistry, chemical biology and drug discovery. Here, we describe the discovery of a novel small molecular inhibitor chemotype for LgtC, a retaining α-1,4-galactosyltransferase involved in bacterial lipooligosaccharide biosynthesis. The new inhibitors, which are structurally unrelated to both the donor and acceptor of LgtC, have low micromolar inhibitory activity, comparable to the best substrate-based inhibitors. We provide experimental evidence that these inhibitors react covalently with LgtC. Results from detailed enzymological experiments with wild-type and mutant LgtC suggest the non-catalytic active site residue Cys246 as a likely target residue for these inhibitors. Analysis of available sequence and structural data reveals that non-catalytic cysteines are a common motif in the active site of many bacterial glycosyltransferases. Our results can therefore serve as a blueprint for the rational design of non-substrate-like, covalent inhibitors against a broad range of other bacterial glycosyltransferases.
Original languageEnglish
Pages (from-to)3182–3194
JournalBioorganic & Medicinal Chemistry
Issue number12
Early online date11 Apr 2017
Publication statusPublished - 15 Jun 2017


  • covalent inhibitor
  • enzyme
  • glycosyltransferase
  • chemical tool
  • virulence factor

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