title: Aurintricarboxylic acid structure modifications lead to reduction of inhibitory properties against virulence factor YopH and higher cytotoxicity.
abstract: Yersinia sp. bacteria owe their viability and pathogenic virulence to the YopH factor, which is a highly active bacterial protein tyrosine phosphatase. Inhibition of YopH phosphatase results in the lack of Yersinia sp. pathogenicity. We have previously described that aurintricarboxylic acid inhibits the activity of YopH at nanomolar concentrations and represents a unique mechanism of YopH inactivation due to a redox process. This work is a continuation of our previous studies. Here we show that modifications of the structure of aurintricarboxylic acid reduce the ability to inactivate YopH and lead to higher cytotoxicity. In the present paper we examine the inhibitory properties of aurintricarboxylic acid analogues, such as eriochrome cyanine R (ECR) and pararosaniline. Computational docking studies we report here indicate that ATA analogues are not precluded to bind in the YopH active site and in all obtained binding conformations ECR and pararosaniline bind to YopH active site. The free binding energy calculations show that ECR has a stronger binding affinity to YopH than pararosaniline, which was confirmed by experimental YopH enzymatic activity studies. We found that ATA analogues can reversibly reduce the enzymatic activity of YopH, but possess weaker inhibitory properties than ATA. The ATA analogues induced inactivation of YopH is probably due to oxidative mechanism, as pretreatment with catalase prevents from inhibition. We also found that ATA analogues significantly decrease the viability of macrophage cells, especially pararosaniline, while ATA reveals only slight effect on cell viability.
authors: Department of Medical Chemistry, Medical University of Gdansk, Gdańsk, Poland. alicjakuban@gumed.edu.pl.
authors: Alicja
authors: A
authors: Kuban-Jankowska
authors: Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Canada.|Department of Physics, University of Alberta, Edmonton, Canada.
authors: Kamlesh K
authors: KK
authors: Sahu
authors: Department of Medical Chemistry, Medical University of Gdansk, Gdańsk, Poland.
authors: Magdalena
authors: M
authors: Gorska
authors: Department of Analytical Chemistry, University of Gdansk, Gdańsk, Poland.
authors: Pawel
authors: P
authors: Niedzialkowski
authors: Department of Physics, University of Alberta, Edmonton, Canada.
authors: Jack A
authors: JA
authors: Tuszynski
authors: Department of Analytical Chemistry, University of Gdansk, Gdańsk, Poland.
authors: Tadeusz
authors: T
authors: Ossowski
authors: Department of Medical Chemistry, Medical University of Gdansk, Gdańsk, Poland.
authors: Michal
authors: M
authors: Wozniak
mesh_terms: D000818:Animals; D001312:Aurintricarboxylic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D001425:Bacterial Outer Membrane Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D001557:Benzenesulfonates / Q000737:chemistry* / Q000494:pharmacology; D020134:Catalytic Domain / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D051379:Mice; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011485:Protein Binding; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D012394:Rosaniline Dyes / Q000737:chemistry* / Q000494:pharmacology; D014052:Toluidines / Q000737:chemistry* / Q000494:pharmacology; D015007:Yersinia / Q000187:drug effects* / Q000201:enzymology
chemical_list: D001425:Bacterial Outer Membrane Proteins; D001557:Benzenesulfonates; D012394:Rosaniline Dyes; D014052:Toluidines; C005409:pararosaniline; C010332:solochrome cyanine R; D001312:Aurintricarboxylic Acid; D017027:Protein Tyrosine Phosphatases; C067571:yopH protein, Yersinia
keywords: Aurintricarboxylic acid (ATA); Eriochrome cyanine R; Pararosaniline; Protein tyrosine phosphatases (PTPs); YopH