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A gold-containing drug against parasitic polyamine metabolism: the X-ray structure of trypanothione reductase from Leishmania infantum in complex with auranofin reveals a dual mechanism of enzyme inhibition

Auranofin is a gold(I)-containing drug in clinical use as an antiarthritic agent. Recent studies showed that auranofin manifests interesting antiparasitic actions very likely arising from inhibition of parasitic enzymes involved in the control of the redox metabolism. Trypanothione reductase is a ke...

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Autores principales: Ilari, Andrea, Baiocco, Paola, Messori, Luigi, Fiorillo, Annarita, Boffi, Alberto, Gramiccia, Marina, Di Muccio, Trentina, Colotti, Gianni
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Vienna 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3266496/
https://www.ncbi.nlm.nih.gov/pubmed/21833767
http://dx.doi.org/10.1007/s00726-011-0997-9
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author Ilari, Andrea
Baiocco, Paola
Messori, Luigi
Fiorillo, Annarita
Boffi, Alberto
Gramiccia, Marina
Di Muccio, Trentina
Colotti, Gianni
author_facet Ilari, Andrea
Baiocco, Paola
Messori, Luigi
Fiorillo, Annarita
Boffi, Alberto
Gramiccia, Marina
Di Muccio, Trentina
Colotti, Gianni
author_sort Ilari, Andrea
collection PubMed
description Auranofin is a gold(I)-containing drug in clinical use as an antiarthritic agent. Recent studies showed that auranofin manifests interesting antiparasitic actions very likely arising from inhibition of parasitic enzymes involved in the control of the redox metabolism. Trypanothione reductase is a key enzyme of Leishmania infantum polyamine-dependent redox metabolism, and a validated target for antileishmanial drugs. As trypanothione reductase contains a dithiol motif at its active site and gold(I) compounds are known to be highly thiophilic, we explored whether auranofin might behave as an effective enzyme inhibitor and as a potential antileishmanial agent. Notably, enzymatic assays revealed that auranofin causes indeed a pronounced enzyme inhibition. To gain a deeper insight into the molecular basis of enzyme inhibition, crystals of the auranofin-bound enzyme, in the presence of NADPH, were prepared, and the X-ray crystal structure of the auranofin–trypanothione reductase–NADPH complex was solved at 3.5 Å resolution. In spite of the rather low resolution, these data were of sufficient quality as to identify the presence of the gold center and of the thiosugar of auranofin, and to locate them within the overall protein structure. Gold binds to the two active site cysteine residues of TR, i.e. Cys52 and Cys57, while the thiosugar moiety of auranofin binds to the trypanothione binding site; thus auranofin appears to inhibit TR through a dual mechanism. Auranofin kills the promastigote stage of L. infantum at micromolar concentration; these findings will contribute to the design of new drugs against leishmaniasis.
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spelling pubmed-32664962012-02-03 A gold-containing drug against parasitic polyamine metabolism: the X-ray structure of trypanothione reductase from Leishmania infantum in complex with auranofin reveals a dual mechanism of enzyme inhibition Ilari, Andrea Baiocco, Paola Messori, Luigi Fiorillo, Annarita Boffi, Alberto Gramiccia, Marina Di Muccio, Trentina Colotti, Gianni Amino Acids Original Article Auranofin is a gold(I)-containing drug in clinical use as an antiarthritic agent. Recent studies showed that auranofin manifests interesting antiparasitic actions very likely arising from inhibition of parasitic enzymes involved in the control of the redox metabolism. Trypanothione reductase is a key enzyme of Leishmania infantum polyamine-dependent redox metabolism, and a validated target for antileishmanial drugs. As trypanothione reductase contains a dithiol motif at its active site and gold(I) compounds are known to be highly thiophilic, we explored whether auranofin might behave as an effective enzyme inhibitor and as a potential antileishmanial agent. Notably, enzymatic assays revealed that auranofin causes indeed a pronounced enzyme inhibition. To gain a deeper insight into the molecular basis of enzyme inhibition, crystals of the auranofin-bound enzyme, in the presence of NADPH, were prepared, and the X-ray crystal structure of the auranofin–trypanothione reductase–NADPH complex was solved at 3.5 Å resolution. In spite of the rather low resolution, these data were of sufficient quality as to identify the presence of the gold center and of the thiosugar of auranofin, and to locate them within the overall protein structure. Gold binds to the two active site cysteine residues of TR, i.e. Cys52 and Cys57, while the thiosugar moiety of auranofin binds to the trypanothione binding site; thus auranofin appears to inhibit TR through a dual mechanism. Auranofin kills the promastigote stage of L. infantum at micromolar concentration; these findings will contribute to the design of new drugs against leishmaniasis. Springer Vienna 2011-08-11 2012-02 /pmc/articles/PMC3266496/ /pubmed/21833767 http://dx.doi.org/10.1007/s00726-011-0997-9 Text en © Springer-Verlag 2011
spellingShingle Original Article
Ilari, Andrea
Baiocco, Paola
Messori, Luigi
Fiorillo, Annarita
Boffi, Alberto
Gramiccia, Marina
Di Muccio, Trentina
Colotti, Gianni
A gold-containing drug against parasitic polyamine metabolism: the X-ray structure of trypanothione reductase from Leishmania infantum in complex with auranofin reveals a dual mechanism of enzyme inhibition
title A gold-containing drug against parasitic polyamine metabolism: the X-ray structure of trypanothione reductase from Leishmania infantum in complex with auranofin reveals a dual mechanism of enzyme inhibition
title_full A gold-containing drug against parasitic polyamine metabolism: the X-ray structure of trypanothione reductase from Leishmania infantum in complex with auranofin reveals a dual mechanism of enzyme inhibition
title_fullStr A gold-containing drug against parasitic polyamine metabolism: the X-ray structure of trypanothione reductase from Leishmania infantum in complex with auranofin reveals a dual mechanism of enzyme inhibition
title_full_unstemmed A gold-containing drug against parasitic polyamine metabolism: the X-ray structure of trypanothione reductase from Leishmania infantum in complex with auranofin reveals a dual mechanism of enzyme inhibition
title_short A gold-containing drug against parasitic polyamine metabolism: the X-ray structure of trypanothione reductase from Leishmania infantum in complex with auranofin reveals a dual mechanism of enzyme inhibition
title_sort gold-containing drug against parasitic polyamine metabolism: the x-ray structure of trypanothione reductase from leishmania infantum in complex with auranofin reveals a dual mechanism of enzyme inhibition
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3266496/
https://www.ncbi.nlm.nih.gov/pubmed/21833767
http://dx.doi.org/10.1007/s00726-011-0997-9
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