Oncotarget

Research Papers: Pathology:

Redox process is crucial for inhibitory properties of aurintricarboxylic acid against activity of YopH: virulence factor of Yersinia pestis

Kuban-Jankowska Alicja _, Sahu Kamlesh K, Niedzialkowski Pawel, Gorska Magdalena, Tuszynski Jack A, Ossowski Tadeusz and Wozniak Michal

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Oncotarget. 2015; 6:18364-18373. https://doi.org/10.18632/oncotarget.4625

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Abstract

Alicja Kuban-Jankowska1, Kamlesh K Sahu2,3,*, Pawel Niedzialkowski4,*, Magdalena Gorska1, Jack A Tuszynski2,3, Tadeusz Ossowski4, Michal Wozniak1

1Department of Medical Chemistry, Medical University of Gdansk, Gdansk, Poland

2Department of Physics, University of Alberta, Edmonton, Canada

3Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Canada

4Department of Analytical Chemistry, Faculty of Chemistry, University of Gdansk, Gdansk, Poland

*These authors have contributed equally to this work

Correspondence to:

Kuban-Jankowska Alicja, e-mail: alicjakuban@gumed.edu.pl

Keywords: Pathology Section, ATA (aurintricarboxylic acid), YopH, protein tyrosine phosphatase inhibitor, virulence factor inhibition, oxygen reduction/oxidation

Received: May 25, 2015     Accepted: July 09, 2015     Published: July 22, 2015

ABSTRACT

YopH is a bacterial protein tyrosine phosphatase, which is essential for the viability and pathogenic virulence of the plague-causing Yersinia sp. bacteria. Inactivation of YopH activity would lead to the loss of bacterial pathogenicity. We have studied the inhibitory properties of aurintricarboxylic acid (ATA) against YopH phosphatase and found that at nanomolar concentrations ATA reversibly decreases the activity of YopH. Computational docking studies indicated that in all binding poses ATA binds in the YopH active site. Molecular dynamics simulations showed that in the predicted binding pose, ATA binds to the essential Cys403 and Arg409 residues in the active site and has a stronger binding affinity than the natural substrate (pTyr). The cyclic voltammetry experiments suggest that ATA reacts remarkably strongly with molecular oxygen. Additionally, the electrochemical reduction of ATA in the presence of a negative potential from −2.0 to 2.5 V generates a current signal, which is observed for hydrogen peroxide. Here we showed that ATA indicates a unique mechanism of YopH inactivation due to a redox process. We proposed that the potent inhibitory properties of ATA are a result of its strong binding in the YopH active site and in situ generation of hydrogen peroxide near catalytic cysteine residue.


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