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Bolz, C.* ; Bach, N.C.* ; Meyer, H.* ; Müller, G.* ; Dawidowski, M. ; Popowicz, G.M. ; Sieber, S.A.* ; Skerra, A.* ; Gerhard, M.*

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

Biol. Chem. 398, 341-357 (2017)
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Open Access Green as soon as Postprint is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Enzyme Kinetics ; Inhibitor ; Mass Spectrometry (ms) ; Protein Structure ; Small Molecule; Glutamyl-transpeptidase; Crystal-structure; Cancer-cells; Active-site; Acivicin; Binding; Antagonists; Mechanism; Receptor; Acid
ISSN (print) / ISBN 1431-6730
e-ISSN 1437-4315
Quellenangaben Volume: 398, Issue: 3, Pages: 341-357 Article Number: , Supplement: ,
Publisher de Gruyter
Publishing Place Berlin
Reviewing status Peer reviewed