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Toxins 2017, 9(1), 32; doi:10.3390/toxins9010032

Auranofin Inhibits the Enzyme Activity of Pasteurella multocida Toxin PMT in Human Cells and Protects Cells from Intoxication

1
Institute of Pharmacology and Toxicology, University of Ulm Medical Center, Albert-Einstein-Allee 11, Ulm 89081, Germany
2
Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, Freiburg 79104, Germany
3
Centre for Biological Signalling Studies (BIOSS), University of Freiburg, Freiburg 79104, Germany
*
Author to whom correspondence should be addressed.
Academic Editor: Katharina Kubatzky
Received: 16 November 2016 / Revised: 23 December 2016 / Accepted: 10 January 2017 / Published: 13 January 2017
(This article belongs to the Special Issue Pasteurella multocida and Its Virulence Factors)
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Abstract

The AB-type protein toxin from Pasteurella multocida (PMT) contains a functionally important disulfide bond within its catalytic domain, which must be cleaved in the host cell cytosol to render the catalytic domain of PMT into its active conformation. Here, we found that the reductive potential of the cytosol of target cells, and more specifically, the activity of the thioredoxin reductase (TrxR) is crucial for this process. This was demonstrated by the strong inhibitory effect of the pharmacological TrxR inhibitor auranofin, which inhibited the intoxication of target cells with PMT, as determined by analyzing the PMT-catalyzed deamidation of GTP-binding proteins (G-proteins) in the cytosol of cells. The amount of endogenous substrate levels modified by PMT in cells pretreated with auranofin was reduced compared to cells treated with PMT alone. Auranofin had no inhibitory effect on the activity of the catalytic domain of constitutively active PMT in vitro, demonstrating that auranofin did not directly inhibit PMT activity, but interferes with the mode of action of PMT in cells. In conclusion, the results show that TrxR is crucial for the mode of action of PMT in mammalian cells, and that the drug auranofin can serve as an efficient inhibitor, which might be a starting point for novel therapeutic options against toxin-associated diseases. View Full-Text
Keywords: Pasteurella multocida toxin (PMT); deamidation; G-protein; thioredoxin reductase (TrxR); auranofin Pasteurella multocida toxin (PMT); deamidation; G-protein; thioredoxin reductase (TrxR); auranofin
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MDPI and ACS Style

Carle, S.; Brink, T.; Orth, J.H.C.; Aktories, K.; Barth, H. Auranofin Inhibits the Enzyme Activity of Pasteurella multocida Toxin PMT in Human Cells and Protects Cells from Intoxication. Toxins 2017, 9, 32.

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