Sequence variation in CYP51A from the Y strain of Trypanosoma cruzi alters its sensitivity to inhibition

Autores
Cherkesova, Tatiana S.; Hargrove, Tatiana Y.; Vanrell, Maria Cristina; Ges, Igor; Usanov, Sergey A.; Romano, Patricia Silvia; Lepesheva, Galina I.
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
CYP51 (sterol 14α-demethylase) is an efficient target for clinical and agricultural antifungals and an emerging target for treatment of Chagas disease, the infection that is caused by multiple strains of a protozoan pathogen Trypanosoma cruzi. Here, we analyze CYP51A from the Y strain T. cruzi. In this protein, proline 355, a residue highly conserved across the CYP51 family, is replaced with serine. The purified enzyme retains its catalytic activity, yet has been found less susceptible to inhibition. These biochemical data are consistent with cellular experiments, both in insect and human stages of the pathogen. Comparative structural analysis of CYP51 complexes with VNI and two derivatives suggests that broad-spectrum CYP51 inhibitors are likely to be preferable as antichagasic drug candidates.
Fil: Cherkesova, Tatiana S.. National Academy of Sciences of Belarus. Institute of Bioorganic Chemistry; Bielorrusia
Fil: Hargrove, Tatiana Y.. Vanderbilt University; Estados Unidos
Fil: Vanrell, Maria Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina
Fil: Ges, Igor. Vanderbilt University; Estados Unidos
Fil: Usanov, Sergey A.. National Academy of Sciences of Belarus. Institute of Bioorganic Chemistry; Bielorrusia
Fil: Romano, Patricia Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina
Fil: Lepesheva, Galina I.. Vanderbilt University; Estados Unidos
Materia
Sterol 14a-demethylase
CYP51 sequence variation
Drug resistance
Structure-based drug design
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/32043
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/32043
network_acronym_str CONICETDig
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network_name_str CONICET Digital (CONICET)
spelling Sequence variation in CYP51A from the Y strain of Trypanosoma cruzi alters its sensitivity to inhibitionCherkesova, Tatiana S.Hargrove, Tatiana Y.Vanrell, Maria CristinaGes, IgorUsanov, Sergey A.Romano, Patricia SilviaLepesheva, Galina I.Sterol 14a-demethylaseCYP51 sequence variationDrug resistanceStructure-based drug designhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1CYP51 (sterol 14α-demethylase) is an efficient target for clinical and agricultural antifungals and an emerging target for treatment of Chagas disease, the infection that is caused by multiple strains of a protozoan pathogen Trypanosoma cruzi. Here, we analyze CYP51A from the Y strain T. cruzi. In this protein, proline 355, a residue highly conserved across the CYP51 family, is replaced with serine. The purified enzyme retains its catalytic activity, yet has been found less susceptible to inhibition. These biochemical data are consistent with cellular experiments, both in insect and human stages of the pathogen. Comparative structural analysis of CYP51 complexes with VNI and two derivatives suggests that broad-spectrum CYP51 inhibitors are likely to be preferable as antichagasic drug candidates.Fil: Cherkesova, Tatiana S.. National Academy of Sciences of Belarus. Institute of Bioorganic Chemistry; BielorrusiaFil: Hargrove, Tatiana Y.. Vanderbilt University; Estados UnidosFil: Vanrell, Maria Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Ges, Igor. Vanderbilt University; Estados UnidosFil: Usanov, Sergey A.. National Academy of Sciences of Belarus. Institute of Bioorganic Chemistry; BielorrusiaFil: Romano, Patricia Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Lepesheva, Galina I.. Vanderbilt University; Estados UnidosElsevier Science2014-11info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/32043Lepesheva, Galina I.; Romano, Patricia Silvia; Usanov, Sergey A.; Ges, Igor; Vanrell, Maria Cristina; Hargrove, Tatiana Y.; et al.; Sequence variation in CYP51A from the Y strain of Trypanosoma cruzi alters its sensitivity to inhibition; Elsevier Science; FEBS Letters; 588; 21; 11-2014; 3878-38850014-5793CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4252588/info:eu-repo/semantics/altIdentifier/doi/10.1016/j.febslet.2014.08.030info:eu-repo/semantics/altIdentifier/url/http://onlinelibrary.wiley.com/doi/10.1016/j.febslet.2014.08.030/abstractinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:03:17Zoai:ri.conicet.gov.ar:11336/32043instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:03:17.864CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Sequence variation in CYP51A from the Y strain of Trypanosoma cruzi alters its sensitivity to inhibition
title Sequence variation in CYP51A from the Y strain of Trypanosoma cruzi alters its sensitivity to inhibition
spellingShingle Sequence variation in CYP51A from the Y strain of Trypanosoma cruzi alters its sensitivity to inhibition
Cherkesova, Tatiana S.
Sterol 14a-demethylase
CYP51 sequence variation
Drug resistance
Structure-based drug design
title_short Sequence variation in CYP51A from the Y strain of Trypanosoma cruzi alters its sensitivity to inhibition
title_full Sequence variation in CYP51A from the Y strain of Trypanosoma cruzi alters its sensitivity to inhibition
title_fullStr Sequence variation in CYP51A from the Y strain of Trypanosoma cruzi alters its sensitivity to inhibition
title_full_unstemmed Sequence variation in CYP51A from the Y strain of Trypanosoma cruzi alters its sensitivity to inhibition
title_sort Sequence variation in CYP51A from the Y strain of Trypanosoma cruzi alters its sensitivity to inhibition
dc.creator.none.fl_str_mv Cherkesova, Tatiana S.
Hargrove, Tatiana Y.
Vanrell, Maria Cristina
Ges, Igor
Usanov, Sergey A.
Romano, Patricia Silvia
Lepesheva, Galina I.
author Cherkesova, Tatiana S.
author_facet Cherkesova, Tatiana S.
Hargrove, Tatiana Y.
Vanrell, Maria Cristina
Ges, Igor
Usanov, Sergey A.
Romano, Patricia Silvia
Lepesheva, Galina I.
author_role author
author2 Hargrove, Tatiana Y.
Vanrell, Maria Cristina
Ges, Igor
Usanov, Sergey A.
Romano, Patricia Silvia
Lepesheva, Galina I.
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv Sterol 14a-demethylase
CYP51 sequence variation
Drug resistance
Structure-based drug design
topic Sterol 14a-demethylase
CYP51 sequence variation
Drug resistance
Structure-based drug design
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv CYP51 (sterol 14α-demethylase) is an efficient target for clinical and agricultural antifungals and an emerging target for treatment of Chagas disease, the infection that is caused by multiple strains of a protozoan pathogen Trypanosoma cruzi. Here, we analyze CYP51A from the Y strain T. cruzi. In this protein, proline 355, a residue highly conserved across the CYP51 family, is replaced with serine. The purified enzyme retains its catalytic activity, yet has been found less susceptible to inhibition. These biochemical data are consistent with cellular experiments, both in insect and human stages of the pathogen. Comparative structural analysis of CYP51 complexes with VNI and two derivatives suggests that broad-spectrum CYP51 inhibitors are likely to be preferable as antichagasic drug candidates.
Fil: Cherkesova, Tatiana S.. National Academy of Sciences of Belarus. Institute of Bioorganic Chemistry; Bielorrusia
Fil: Hargrove, Tatiana Y.. Vanderbilt University; Estados Unidos
Fil: Vanrell, Maria Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina
Fil: Ges, Igor. Vanderbilt University; Estados Unidos
Fil: Usanov, Sergey A.. National Academy of Sciences of Belarus. Institute of Bioorganic Chemistry; Bielorrusia
Fil: Romano, Patricia Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina
Fil: Lepesheva, Galina I.. Vanderbilt University; Estados Unidos
description CYP51 (sterol 14α-demethylase) is an efficient target for clinical and agricultural antifungals and an emerging target for treatment of Chagas disease, the infection that is caused by multiple strains of a protozoan pathogen Trypanosoma cruzi. Here, we analyze CYP51A from the Y strain T. cruzi. In this protein, proline 355, a residue highly conserved across the CYP51 family, is replaced with serine. The purified enzyme retains its catalytic activity, yet has been found less susceptible to inhibition. These biochemical data are consistent with cellular experiments, both in insect and human stages of the pathogen. Comparative structural analysis of CYP51 complexes with VNI and two derivatives suggests that broad-spectrum CYP51 inhibitors are likely to be preferable as antichagasic drug candidates.
publishDate 2014
dc.date.none.fl_str_mv 2014-11
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/32043
Lepesheva, Galina I.; Romano, Patricia Silvia; Usanov, Sergey A.; Ges, Igor; Vanrell, Maria Cristina; Hargrove, Tatiana Y.; et al.; Sequence variation in CYP51A from the Y strain of Trypanosoma cruzi alters its sensitivity to inhibition; Elsevier Science; FEBS Letters; 588; 21; 11-2014; 3878-3885
0014-5793
CONICET Digital
CONICET
url http://hdl.handle.net/11336/32043
identifier_str_mv Lepesheva, Galina I.; Romano, Patricia Silvia; Usanov, Sergey A.; Ges, Igor; Vanrell, Maria Cristina; Hargrove, Tatiana Y.; et al.; Sequence variation in CYP51A from the Y strain of Trypanosoma cruzi alters its sensitivity to inhibition; Elsevier Science; FEBS Letters; 588; 21; 11-2014; 3878-3885
0014-5793
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4252588/
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.febslet.2014.08.030
info:eu-repo/semantics/altIdentifier/url/http://onlinelibrary.wiley.com/doi/10.1016/j.febslet.2014.08.030/abstract
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier Science
publisher.none.fl_str_mv Elsevier Science
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.070432

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