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Licensed Unlicensed Requires Authentication Published by De Gruyter September 15, 2016

Comparison of enzymatic properties and small molecule inhibition of γ–glutamyltranspeptidases from pathogenic and commensal bacteria

  • Christian Bolz , Nina C. Bach , Hannelore Meyer , Gerhard Müller , Maciej Dawidowski , Grzegorz Popowicz , Stephan A. Sieber , Arne Skerra and Markus Gerhard EMAIL logo
From the journal Biological Chemistry

Abstract

Helicobacter pylori infects the stomach of 50% of the population worldwide, thus causing chronic gastritis. Although this infection can be cured by antibiotic treatment, therapeutic options are increasingly limited due to the development of resistances. The γ-glutamyl-transpeptidase (gGT) of H. pylori (HpgGT) is a virulence factor important for colonization and contributes to bacterial immune evasion. Therefore, this enzyme is a potential target for developing new anti-infectives. As species specificity of such compounds is required in order to avoid off-target or adverse effects, comparative analysis of the gGTs from different organisms is a prerequisite for drug development. To allow detailed biochemical and enzymatic characterization, recombinant gGTs from five different bacteria as well as Homo sapiens were characterized and compared. Investigation of the enzymatic activity, the binding modes of known inhibitors to the catalytic center, and a high resolution X-ray structure of the HpgGT provided a starting point for the identification of new inhibitory substances targeting HpgGT. Inhibitors with Ki values in the nm to mm range were identified and their binding modes were analyzed by mass spectrometry. The results of this study provide a basis for the development of species-specific lead compounds with anti-infective potential by effectively inhibiting HpgGT.

Acknowledgments

We are grateful to Dr. Mirko Rossi for providing the HbgGT expression plasmid and Prof. Dr. Han for supplying the phosphono-esters AHPP-butyric acid, AMOP-butyric acid and DL-AP4-butyric acid. Bundesministerium für Bildung und Forschung, (Grant/Award Number: ‘16EX1022J’).

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Received: 2016-5-5
Accepted: 2016-8-24
Published Online: 2016-9-15
Published in Print: 2017-3-1

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