Cargando…
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...
Autores principales: | , , , , , , , |
---|---|
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 |
_version_ | 1782222184720105472 |
---|---|
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. |
format | Online Article Text |
id | pubmed-3266496 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Springer Vienna |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT ilariandrea agoldcontainingdrugagainstparasiticpolyaminemetabolismthexraystructureoftrypanothionereductasefromleishmaniainfantumincomplexwithauranofinrevealsadualmechanismofenzymeinhibition AT baioccopaola agoldcontainingdrugagainstparasiticpolyaminemetabolismthexraystructureoftrypanothionereductasefromleishmaniainfantumincomplexwithauranofinrevealsadualmechanismofenzymeinhibition AT messoriluigi agoldcontainingdrugagainstparasiticpolyaminemetabolismthexraystructureoftrypanothionereductasefromleishmaniainfantumincomplexwithauranofinrevealsadualmechanismofenzymeinhibition AT fiorilloannarita agoldcontainingdrugagainstparasiticpolyaminemetabolismthexraystructureoftrypanothionereductasefromleishmaniainfantumincomplexwithauranofinrevealsadualmechanismofenzymeinhibition AT boffialberto agoldcontainingdrugagainstparasiticpolyaminemetabolismthexraystructureoftrypanothionereductasefromleishmaniainfantumincomplexwithauranofinrevealsadualmechanismofenzymeinhibition AT gramicciamarina agoldcontainingdrugagainstparasiticpolyaminemetabolismthexraystructureoftrypanothionereductasefromleishmaniainfantumincomplexwithauranofinrevealsadualmechanismofenzymeinhibition AT dimucciotrentina agoldcontainingdrugagainstparasiticpolyaminemetabolismthexraystructureoftrypanothionereductasefromleishmaniainfantumincomplexwithauranofinrevealsadualmechanismofenzymeinhibition AT colottigianni agoldcontainingdrugagainstparasiticpolyaminemetabolismthexraystructureoftrypanothionereductasefromleishmaniainfantumincomplexwithauranofinrevealsadualmechanismofenzymeinhibition AT ilariandrea goldcontainingdrugagainstparasiticpolyaminemetabolismthexraystructureoftrypanothionereductasefromleishmaniainfantumincomplexwithauranofinrevealsadualmechanismofenzymeinhibition AT baioccopaola goldcontainingdrugagainstparasiticpolyaminemetabolismthexraystructureoftrypanothionereductasefromleishmaniainfantumincomplexwithauranofinrevealsadualmechanismofenzymeinhibition AT messoriluigi goldcontainingdrugagainstparasiticpolyaminemetabolismthexraystructureoftrypanothionereductasefromleishmaniainfantumincomplexwithauranofinrevealsadualmechanismofenzymeinhibition AT fiorilloannarita goldcontainingdrugagainstparasiticpolyaminemetabolismthexraystructureoftrypanothionereductasefromleishmaniainfantumincomplexwithauranofinrevealsadualmechanismofenzymeinhibition AT boffialberto goldcontainingdrugagainstparasiticpolyaminemetabolismthexraystructureoftrypanothionereductasefromleishmaniainfantumincomplexwithauranofinrevealsadualmechanismofenzymeinhibition AT gramicciamarina goldcontainingdrugagainstparasiticpolyaminemetabolismthexraystructureoftrypanothionereductasefromleishmaniainfantumincomplexwithauranofinrevealsadualmechanismofenzymeinhibition AT dimucciotrentina goldcontainingdrugagainstparasiticpolyaminemetabolismthexraystructureoftrypanothionereductasefromleishmaniainfantumincomplexwithauranofinrevealsadualmechanismofenzymeinhibition AT colottigianni goldcontainingdrugagainstparasiticpolyaminemetabolismthexraystructureoftrypanothionereductasefromleishmaniainfantumincomplexwithauranofinrevealsadualmechanismofenzymeinhibition |