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

Xu, Yong, Smith, Ruth, Vivoli, Mirella, Ema, Masaki, Goos, Niina, Gehrke, Sebastian, Harmer, Nicholas J. and Wagner, Gerd K. (2017) Covalent inhibitors of LgtC: a blueprint for the discovery of non-substrate-like inhibitors for bacterial glycosyltransferases. Bioorganic & Medicinal Chemistry, 25 (12). 3182–3194. ISSN 0968-0896

[img]
Preview
PDF (Accepted manuscript) - Submitted Version
Available under License Creative Commons Attribution Non-commercial No Derivatives.

Download (1MB) | Preview

Abstract

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.

Item Type: Article
Uncontrolled Keywords: covalent inhibitor,enzyme,glycosyltransferase,chemical tool,virulence factor
Faculty \ School: Faculty of Science > School of Pharmacy
Related URLs:
Depositing User: Pure Connector
Date Deposited: 21 Apr 2017 05:10
Last Modified: 22 Apr 2020 03:40
URI: https://ueaeprints.uea.ac.uk/id/eprint/63271
DOI: 10.1016/j.bmc.2017.04.006

Actions (login required)

View Item View Item