Toggle Main Menu Toggle Search

Open Access padlockePrints

The Newcastle University research output collection, currently available on ePrints, will shortly be moving to a new open repository platform, Figshare. To prepare for the data migration we have paused adding new content to ePrints, and will resume once the new repository is launched. During this time you will continue to have access to ePrints (but no new content will appear). We will share updates here when available.

Self-Immolation of a Bacterial Dehydratase Enzyme by its Epoxide Product

Lookup NU author(s): Paul ThompsonORCiD, Professor Alastair Hawkins

Downloads

Full text for this publication is not currently held within this repository. Alternative links are provided below where available.

Abstract

© 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.

Publication metadata

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

Altmetrics

Altmetrics provided by Altmetric

Share