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BioMetals

, Volume 25, Issue 1, pp 95–102 | Cite as

Inhibition of fumarase by bismuth(III): implications for the tricarboxylic acid cycle as a potential target of bismuth drugs in Helicobacter pylori

  • Zhuo Chen
  • Qinglu Zhou
  • Ruiguang Ge
Article

Abstract

Helicobacter pylori causes various gastric diseases, such as gastritis, peptic ulcerations and gastric cancer. Triple therapy combining bismuth compounds with two antibiotics is the cornerstone of the treatment of H. pylori infections. Up to now, the molecular mechanisms by which bismuth inhibits the growth of H. pylori are far from clear. In the bacterial tricarboxylic acid (TCA) cycle, fumarase catalyses the reversible hydration of fumarate to malic acid. Our previous proteomic work indicated that fumarase was capable of bismuth-binding. The interactions as well as the inhibitory effects of bismuth to fumarase have been characterized in this study. The titration of bismuth showed that each fumarase monomer binds one mol equiv of Bi3+, with negligible secondary structural change. Bismuth-binding results in a near stoichiometric inactivation of the enzyme, leading to an apparent non-competitive mechanism as reflected by the Lineweaver–Burk plots. Our collective data indicate that the TCA cycle is a potential molecular target of bismuth drugs in H. pylori.

Keywords

Helicobacter pylori Fumarase Bismuth Tricarboxylic acid cycle 

Abbreviations

DTNB

5,5′-Dithiobis(2-nitrobenzoic acid)

FRD

Fumarate reductase

H. pylori

Helicobacter pylori

FPLC

Fast protein liquid chromatography

MS

Mass spectrometer

PBS

Phosphate-buffered saline

SDH

Succinate dehydrogenase

SDS–PAGE

Sodium dodecyl sulfate–polyacrylamide gel electrophoresis

TCA

Tricarboxylic acid

Notes

Acknowledgments

The authors thank the anonymous reviewer for insightful comments. This work was supported by National Natural Science Foundation of China (20801061), Guangdong Natural Science Foundation (8451027501001233) and the Fundamental Research Funds for the Central Universities (10lgpy19).

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Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  1. 1.The Laboratory of Integrative Biosciences, College of Life SciencesSun Yat-Sen UniversityGuangzhouChina

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