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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Sies, Helmut / Thomas, Douglas D. / Turk, Boris / Wittinghofer, Alfred


IMPACT FACTOR 2017: 3.022

CiteScore 2017: 2.81

SCImago Journal Rank (SJR) 2017: 1.562
Source Normalized Impact per Paper (SNIP) 2017: 0.705

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1437-4315
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Volume 398, Issue 3

Issues

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

Christian Bolz
  • Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Trogerstrasse 30, D-81675 München, Germany
  • ImevaX GmbH, Grillparzerstraße 18, D-81675 München, Germany
  • Other articles by this author:
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/ Nina C. Bach
  • Center for Integrated Protein Science (CIPSM), Department of Chemistry, Technische Universität München, Lichtenbergstraße 4, D-85748 Garching, Germany
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/ Hannelore Meyer
  • Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Trogerstrasse 30, D-81675 München, Germany
  • German Center for Infection Research (DZIF), Trogerstrasse 30, D-81675 Munich, Germany
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/ Gerhard Müller / Maciej Dawidowski
  • Institute of Structural Biology, Helmholtz Zentrum München, Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany
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/ Grzegorz Popowicz
  • Institute of Structural Biology, Helmholtz Zentrum München, Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany
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/ Stephan A. Sieber
  • Center for Integrated Protein Science (CIPSM), Department of Chemistry, Technische Universität München, Lichtenbergstraße 4, D-85748 Garching, Germany
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/ Arne Skerra
  • Munich Center for Integrated Protein Science (CIPS-M) and Lehrstuhl für Biologische Chemie, Technische Universität München, D-85354 Freising (Weihenstephan), Germany
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/ Markus Gerhard
  • Corresponding author
  • Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Trogerstrasse 30, D-81675 München, Germany
  • ImevaX GmbH, Grillparzerstraße 18, D-81675 München, Germany
  • German Center for Infection Research (DZIF), Trogerstrasse 30, D-81675 Munich, Germany
  • Email
  • Other articles by this author:
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Published Online: 2016-09-15 | DOI: https://doi.org/10.1515/hsz-2016-0198

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.

Keywords: enzyme kinetics; inhibitor; mass spectrometry (MS); protein structure; small molecule

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About the article

Received: 2016-05-05

Accepted: 2016-08-24

Published Online: 2016-09-15

Published in Print: 2017-03-01


Citation Information: Biological Chemistry, Volume 398, Issue 3, Pages 341–357, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/hsz-2016-0198.

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