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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Inhibition of schistosoma mansoni thioredoxin-glutathione reductase by Auranofin. Structural and kinetic aspects
Journal of Biological Chemistry, Volume 284, No. 42, Year 2009
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Description
Schistosomiasis is a parasitic disease affecting over 200 million people currently treated with one drug, praziquantel. A possible drug target is the seleno-protein thioredoxin-glutathione reductase (TGR), a key enzyme in the pathway of the parasite for detoxification of reactive oxygen species. The enzyme is a unique fusion of a glutaredoxin domain with a thioredoxin reductase domain, which contains a selenocysteine (Sec) as the penultimate amino acid. Auranofin (AF), a gold-containing compound already in clinical use as an anti-arthritic drug, has been shown to inhibit TGR and to substantially reduce worm burden in mice. Using x-ray crystallography we solved (at 2.5 Å resolution) the structure of wild type TGR incubated with AF. The electron density maps show that the actual inhibitor is gold, released from AF. Gold is bound at three different sites not directly involving the C-terminal Sec residue; however, because the C terminus in the electron density maps is disordered, we cannot exclude the possibility that gold may also bind to Sec. To investigate the possible role of Sec in the inactivation kinetics, we tested the effect of AF on a model enzyme of the same superfamily, i.e. the naturally Sec-lacking glutathione reductase, and on truncated TGR. We demonstrate that the role of selenium in the onset of inhibition by AF is catalytic and can be mimicked by an external source of selenium (benzeneselenol). Therefore, we propose that Sec mediates the transfer of gold from its ligands in AF to the redox-active Cys couples of TGR. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.
Authors & Co-Authors
Angelucci, Francesco
Italy, Rome
Sapienza Università Di Roma
Sayed, Ahmed Abdel Aziz
United States, Chicago
Illinois State University
Egypt, Cairo
College of Science
Williams, David Lee
United States, Chicago
Illinois State University
United States, Chicago
Rush University Medical Center
Boumis, Giovanna
Italy, Rome
Sapienza Università Di Roma
Brunori, Maurizio
Italy, Rome
Sapienza Università Di Roma
Dimastrogiovanni, Daniela
Italy, Rome
Sapienza Università Di Roma
Miele, Adriana Erica
Italy, Rome
Sapienza Università Di Roma
Pauly, Frida
Italy, Rome
Sapienza Università Di Roma
Bellelli, Andrea
Italy, Rome
Sapienza Università Di Roma
Statistics
Citations: 166
Authors: 9
Affiliations: 4
Identifiers
Doi:
10.1074/jbc.M109.020701
ISSN:
00219258
e-ISSN:
1083351X
Research Areas
Infectious Diseases