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Lookup NU author(s): Paul Thompson, Professor Alastair Hawkins
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© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. Disabling the bacterial capacity to cause infection is an innovative approach that has attracted significant attention to fight against superbugs. A relevant target for anti-virulence drug discovery is the type I dehydroquinase (DHQ1) enzyme. It was shown that the 2-hydroxyethylammonium derivative 3 has in vitro activity since it causes the covalent modification of the catalytic lysine residue of DHQ1. As this compound does not bear reactive electrophilic centers, how the chemical modification occurs is intriguing. We report here an integrated approach, which involves biochemical studies, X-ray crystallography and computational studies on the reaction path using combined quantum mechanics/molecular mechanics Umbrella Sampling Molecular Dynamics, that evidences that DHQ1 catalyzes its self-immolation by transforming the unreactive 2-hydroxyethylammonium group in 3 into an epoxide that triggers the lysine covalent modification. This finding might open opportunities for the design of lysine-targeted irreversible inhibitors bearing a 2-hydroxyethylammonium moiety as an epoxide proform, which to our knowledge has not been reported previously.
Author(s): Lence E, Maneiro M, Sanz-Gaitero M, van Raaij MJ, Thompson P, Hawkins AR, Gonzalez-Bello C
Publication type: Article
Publication status: Published
Journal: Chemistry - A European Journal
Year: 2020
Volume: 26
Issue: 36
Pages: 8035-8044
Print publication date: 26/06/2020
Online publication date: 07/04/2020
Acceptance date: 07/04/2020
ISSN (print): 0947-6539
ISSN (electronic): 1521-3765
Publisher: Wiley-VCH Verlag
URL: https://doi.org/10.1002/chem.202000759
DOI: 10.1002/chem.202000759
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