Inhibition of Schistosoma mansoni Thioredoxin-glutathione Reductase by Auranofin

@article{Angelucci2009InhibitionOS,
  title={Inhibition of Schistosoma mansoni Thioredoxin-glutathione Reductase by Auranofin},
  author={Francesco Angelucci and Ahmed A. Sayed and David L. Williams and Giovanna Boumis and Maurizio Brunori and Daniela Dimastrogiovanni and Adriana Erica Miele and Frida Pauly and Andrea Bellelli},
  journal={The Journal of Biological Chemistry},
  year={2009},
  volume={284},
  pages={28977 - 28985}
}
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… 
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This study dissects the catalytic cycle of Schistosoma mansoni TGR by structural and functional analysis of the U597C mutant and proposes the putative functionally relevant conformational change of the C terminus after the transfer of reducing equivalents from NADPH to the redox sites of the enzyme.

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Variants of SmTGR were generated and it was suggested that reducing equivalents from NADPH can indeed reach the Cys-28/Cys-31 disulfide in the Grx domain to facilitate reductions effected by this cysteine pair, and selenocysteine is important but is not the sole determinant for the broad substrate tolerance of the enzyme.

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The structural study revealed that TGR functions are achieved not only through a mobile Sec-containing redox center but also by rotation of the Grx domain and distinct binding sites for thioredoxin and the glutaredoxin domain.

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The high‐resolution crystal structure of Schistosoma mansoni Thioredoxin (SmTrx) is described, believing its crystal structure may provide clues for the formation of granulomas and the pathogenesis of the chronic disease.

Characterization of lead compounds targeting the selenoprotein thioredoxin glutathione reductase for treatment of schistosomiasis.

This effort has identified several active compound series that may serve as the basis for the development of new schistosomicidal compounds.

Targeting thioredoxin glutathione reductase as a potential antischistosomal drug target.

Cheminformatics Models for Inhibitors of Schistosoma mansoni Thioredoxin Glutathione Reductase

It is shown that a combined approach of machine learning and other cheminformatics approaches such as substructure comparison and molecular docking is efficient to prioritise molecules from large molecular datasets.

Thioredoxin Glutathione Reductase as a Novel Drug Target: Evidence from Schistosoma japonicum

This study confirms that a multifunctional enzyme SjTGR selenoprotein, instead of separate TrxR and GR enzymes, exists in S. japonicum and indicates that TGR may be a potential target for development of novel agents against schistosomes.

New drug target in protozoan parasites: the role of thioredoxin reductase

Evidence suggests that auranofin has the potential to become a broad spectrum alternative therapeutic agent for diseases with a large global burden of amebiasis.

X-ray structures of thioredoxin and thioredoxin reductase from Entamoeba histolytica and prevailing hypothesis of the mechanism of Auranofin action.

...

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