Solanesyl diphosphate synthase, an enzyme of ubiquinone synthetic pathway, is required throughout the life cycle of Trypanosoma brucei

Autores
De Hua, Lai; Poropat, Estefanía; Pravia, Carlos; Landoni, Malena; Couto, Alicia Susana; Perez Rojo, Fernando G.; Fuchs, Alicia G.; Dubin, Marta; Elingold, Igal; Rodriguez, Juan Bautista; Marcela Ferella; Esteva, Mónica I.; Bontempi, Esteban J.; Lukes, Julius
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Ubiquinone 9 (UQ9), the expected product of the long-chain solanesyl diphosphate synthase of Trypanosoma brucei (TbSPPS), has a central role in reoxidation of reducing equivalents in the mitochondrion of T. brucei. The ablation of TbSPPS gene expression by RNA interference increased the generation of reactive oxygen species and reduced cell growth and oxygen consumption. The addition of glycerol to the culture medium exacerbated the phenotype by blocking its endogenous generation and excretion. The participation of TbSPPS in UQ synthesis was further confirmed by growth rescue using UQ with 10 isoprenyl subunits (UQ10). Furthermore, the survival of infected mice was prolonged upon the downregulation of TbSPPS and/or the addition of glycerol to drinking water. TbSPPS is inhibited by 1-[(n-oct-1-ylamino)ethyl] 1,1-bisphosphonic acid, and treatment with this compound was lethal for the cells. The findings that both UQ9 and ATP pools were severely depleted by the drug and that exogenous UQ10 was able to fully rescue growth of the inhibited parasites strongly suggest that TbSPPS and UQ synthesis are the main targets of the drug. These two strategies highlight the importance of TbSPPS for T. brucei, justifying further efforts to validate it as a new drug target
Fil: De Hua, Lai. Academy of Sciences of the Czech Republic; República Checa. University Of South Bohemia; República Checa
Fil: Poropat, Estefanía. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio E Instituto de Salud; Argentina
Fil: Pravia, Carlos. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud; Argentina
Fil: Landoni, Malena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Centro de Investigaciones en Hidratos de Carbono; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Couto, Alicia Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Centro de Investigaciones en Hidratos de Carbono; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Perez Rojo, Fernando G.. Universidad Abierta Interamericana; Argentina
Fil: Fuchs, Alicia G.. Universidad Abierta Interamericana; Argentina. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud; Argentina
Fil: Dubin, Marta. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina
Fil: Elingold, Igal. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina
Fil: Rodriguez, Juan Bautista. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos Aplicados a la Química Orgánica (i); Argentina
Fil: Marcela Ferella. Uppsala University; Suecia
Fil: Esteva, Mónica I.. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio E Instituto de Salud; Argentina
Fil: Bontempi, Esteban J.. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio E Instituto de Salud; Argentina. Academy of Sciences of the Czech Republic; República Checa
Fil: Lukes, Julius. Academy of Sciences of the Czech Republic; República Checa. University Of South Bohemia; República Checa
Materia
Solanesyl Diphosphate Synthase
Trypanosoma Brucei
Ubiquinone 9
Bisphosphonates
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/11034
Acceder
id CONICETDig_708a7bd034a209275d8ed440f80d0a23
oai_identifier_str oai:ri.conicet.gov.ar:11336/11034
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Solanesyl diphosphate synthase, an enzyme of ubiquinone synthetic pathway, is required throughout the life cycle of Trypanosoma bruceiDe Hua, LaiPoropat, EstefaníaPravia, CarlosLandoni, MalenaCouto, Alicia SusanaPerez Rojo, Fernando G.Fuchs, Alicia G.Dubin, MartaElingold, IgalRodriguez, Juan BautistaMarcela FerellaEsteva, Mónica I.Bontempi, Esteban J.Lukes, JuliusSolanesyl Diphosphate SynthaseTrypanosoma BruceiUbiquinone 9Bisphosphonateshttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1Ubiquinone 9 (UQ9), the expected product of the long-chain solanesyl diphosphate synthase of Trypanosoma brucei (TbSPPS), has a central role in reoxidation of reducing equivalents in the mitochondrion of T. brucei. The ablation of TbSPPS gene expression by RNA interference increased the generation of reactive oxygen species and reduced cell growth and oxygen consumption. The addition of glycerol to the culture medium exacerbated the phenotype by blocking its endogenous generation and excretion. The participation of TbSPPS in UQ synthesis was further confirmed by growth rescue using UQ with 10 isoprenyl subunits (UQ10). Furthermore, the survival of infected mice was prolonged upon the downregulation of TbSPPS and/or the addition of glycerol to drinking water. TbSPPS is inhibited by 1-[(n-oct-1-ylamino)ethyl] 1,1-bisphosphonic acid, and treatment with this compound was lethal for the cells. The findings that both UQ9 and ATP pools were severely depleted by the drug and that exogenous UQ10 was able to fully rescue growth of the inhibited parasites strongly suggest that TbSPPS and UQ synthesis are the main targets of the drug. These two strategies highlight the importance of TbSPPS for T. brucei, justifying further efforts to validate it as a new drug targetFil: De Hua, Lai. Academy of Sciences of the Czech Republic; República Checa. University Of South Bohemia; República ChecaFil: Poropat, Estefanía. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio E Instituto de Salud; ArgentinaFil: Pravia, Carlos. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud; ArgentinaFil: Landoni, Malena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Centro de Investigaciones en Hidratos de Carbono; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Couto, Alicia Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Centro de Investigaciones en Hidratos de Carbono; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Perez Rojo, Fernando G.. Universidad Abierta Interamericana; ArgentinaFil: Fuchs, Alicia G.. Universidad Abierta Interamericana; Argentina. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud; ArgentinaFil: Dubin, Marta. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Elingold, Igal. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Rodriguez, Juan Bautista. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos Aplicados a la Química Orgánica (i); ArgentinaFil: Marcela Ferella. Uppsala University; SueciaFil: Esteva, Mónica I.. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio E Instituto de Salud; ArgentinaFil: Bontempi, Esteban J.. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio E Instituto de Salud; Argentina. Academy of Sciences of the Czech Republic; República ChecaFil: Lukes, Julius. Academy of Sciences of the Czech Republic; República Checa. University Of South Bohemia; República ChecaAmerican Society For Microbiology2014-02info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/11034De Hua, Lai; Poropat, Estefanía; Pravia, Carlos; Landoni, Malena; Couto, Alicia Susana; et al.; Solanesyl diphosphate synthase, an enzyme of ubiquinone synthetic pathway, is required throughout the life cycle of Trypanosoma brucei; American Society For Microbiology; Eukaryotic Cell; 13; 2; 2-2014; 320-3281535-9778enginfo:eu-repo/semantics/altIdentifier/url/http://ec.asm.org/content/13/2/320info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3910978/info:eu-repo/semantics/altIdentifier/doi/10.1128/EC.00271-13info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:44:51Zoai:ri.conicet.gov.ar:11336/11034instacron: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:34982025-09-03 09:44:52.173CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Solanesyl diphosphate synthase, an enzyme of ubiquinone synthetic pathway, is required throughout the life cycle of Trypanosoma brucei
title Solanesyl diphosphate synthase, an enzyme of ubiquinone synthetic pathway, is required throughout the life cycle of Trypanosoma brucei
spellingShingle Solanesyl diphosphate synthase, an enzyme of ubiquinone synthetic pathway, is required throughout the life cycle of Trypanosoma brucei
De Hua, Lai
Solanesyl Diphosphate Synthase
Trypanosoma Brucei
Ubiquinone 9
Bisphosphonates
title_short Solanesyl diphosphate synthase, an enzyme of ubiquinone synthetic pathway, is required throughout the life cycle of Trypanosoma brucei
title_full Solanesyl diphosphate synthase, an enzyme of ubiquinone synthetic pathway, is required throughout the life cycle of Trypanosoma brucei
title_fullStr Solanesyl diphosphate synthase, an enzyme of ubiquinone synthetic pathway, is required throughout the life cycle of Trypanosoma brucei
title_full_unstemmed Solanesyl diphosphate synthase, an enzyme of ubiquinone synthetic pathway, is required throughout the life cycle of Trypanosoma brucei
title_sort Solanesyl diphosphate synthase, an enzyme of ubiquinone synthetic pathway, is required throughout the life cycle of Trypanosoma brucei
dc.creator.none.fl_str_mv De Hua, Lai
Poropat, Estefanía
Pravia, Carlos
Landoni, Malena
Couto, Alicia Susana
Perez Rojo, Fernando G.
Fuchs, Alicia G.
Dubin, Marta
Elingold, Igal
Rodriguez, Juan Bautista
Marcela Ferella
Esteva, Mónica I.
Bontempi, Esteban J.
Lukes, Julius
author De Hua, Lai
author_facet De Hua, Lai
Poropat, Estefanía
Pravia, Carlos
Landoni, Malena
Couto, Alicia Susana
Perez Rojo, Fernando G.
Fuchs, Alicia G.
Dubin, Marta
Elingold, Igal
Rodriguez, Juan Bautista
Marcela Ferella
Esteva, Mónica I.
Bontempi, Esteban J.
Lukes, Julius
author_role author
author2 Poropat, Estefanía
Pravia, Carlos
Landoni, Malena
Couto, Alicia Susana
Perez Rojo, Fernando G.
Fuchs, Alicia G.
Dubin, Marta
Elingold, Igal
Rodriguez, Juan Bautista
Marcela Ferella
Esteva, Mónica I.
Bontempi, Esteban J.
Lukes, Julius
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Solanesyl Diphosphate Synthase
Trypanosoma Brucei
Ubiquinone 9
Bisphosphonates
topic Solanesyl Diphosphate Synthase
Trypanosoma Brucei
Ubiquinone 9
Bisphosphonates
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Ubiquinone 9 (UQ9), the expected product of the long-chain solanesyl diphosphate synthase of Trypanosoma brucei (TbSPPS), has a central role in reoxidation of reducing equivalents in the mitochondrion of T. brucei. The ablation of TbSPPS gene expression by RNA interference increased the generation of reactive oxygen species and reduced cell growth and oxygen consumption. The addition of glycerol to the culture medium exacerbated the phenotype by blocking its endogenous generation and excretion. The participation of TbSPPS in UQ synthesis was further confirmed by growth rescue using UQ with 10 isoprenyl subunits (UQ10). Furthermore, the survival of infected mice was prolonged upon the downregulation of TbSPPS and/or the addition of glycerol to drinking water. TbSPPS is inhibited by 1-[(n-oct-1-ylamino)ethyl] 1,1-bisphosphonic acid, and treatment with this compound was lethal for the cells. The findings that both UQ9 and ATP pools were severely depleted by the drug and that exogenous UQ10 was able to fully rescue growth of the inhibited parasites strongly suggest that TbSPPS and UQ synthesis are the main targets of the drug. These two strategies highlight the importance of TbSPPS for T. brucei, justifying further efforts to validate it as a new drug target
Fil: De Hua, Lai. Academy of Sciences of the Czech Republic; República Checa. University Of South Bohemia; República Checa
Fil: Poropat, Estefanía. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio E Instituto de Salud; Argentina
Fil: Pravia, Carlos. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud; Argentina
Fil: Landoni, Malena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Centro de Investigaciones en Hidratos de Carbono; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Couto, Alicia Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Centro de Investigaciones en Hidratos de Carbono; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Perez Rojo, Fernando G.. Universidad Abierta Interamericana; Argentina
Fil: Fuchs, Alicia G.. Universidad Abierta Interamericana; Argentina. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud; Argentina
Fil: Dubin, Marta. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina
Fil: Elingold, Igal. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina
Fil: Rodriguez, Juan Bautista. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos Aplicados a la Química Orgánica (i); Argentina
Fil: Marcela Ferella. Uppsala University; Suecia
Fil: Esteva, Mónica I.. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio E Instituto de Salud; Argentina
Fil: Bontempi, Esteban J.. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio E Instituto de Salud; Argentina. Academy of Sciences of the Czech Republic; República Checa
Fil: Lukes, Julius. Academy of Sciences of the Czech Republic; República Checa. University Of South Bohemia; República Checa
description Ubiquinone 9 (UQ9), the expected product of the long-chain solanesyl diphosphate synthase of Trypanosoma brucei (TbSPPS), has a central role in reoxidation of reducing equivalents in the mitochondrion of T. brucei. The ablation of TbSPPS gene expression by RNA interference increased the generation of reactive oxygen species and reduced cell growth and oxygen consumption. The addition of glycerol to the culture medium exacerbated the phenotype by blocking its endogenous generation and excretion. The participation of TbSPPS in UQ synthesis was further confirmed by growth rescue using UQ with 10 isoprenyl subunits (UQ10). Furthermore, the survival of infected mice was prolonged upon the downregulation of TbSPPS and/or the addition of glycerol to drinking water. TbSPPS is inhibited by 1-[(n-oct-1-ylamino)ethyl] 1,1-bisphosphonic acid, and treatment with this compound was lethal for the cells. The findings that both UQ9 and ATP pools were severely depleted by the drug and that exogenous UQ10 was able to fully rescue growth of the inhibited parasites strongly suggest that TbSPPS and UQ synthesis are the main targets of the drug. These two strategies highlight the importance of TbSPPS for T. brucei, justifying further efforts to validate it as a new drug target
publishDate 2014
dc.date.none.fl_str_mv 2014-02
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/11336/11034
De Hua, Lai; Poropat, Estefanía; Pravia, Carlos; Landoni, Malena; Couto, Alicia Susana; et al.; Solanesyl diphosphate synthase, an enzyme of ubiquinone synthetic pathway, is required throughout the life cycle of Trypanosoma brucei; American Society For Microbiology; Eukaryotic Cell; 13; 2; 2-2014; 320-328
1535-9778
url http://hdl.handle.net/11336/11034
identifier_str_mv De Hua, Lai; Poropat, Estefanía; Pravia, Carlos; Landoni, Malena; Couto, Alicia Susana; et al.; Solanesyl diphosphate synthase, an enzyme of ubiquinone synthetic pathway, is required throughout the life cycle of Trypanosoma brucei; American Society For Microbiology; Eukaryotic Cell; 13; 2; 2-2014; 320-328
1535-9778
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://ec.asm.org/content/13/2/320
info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3910978/
info:eu-repo/semantics/altIdentifier/doi/10.1128/EC.00271-13
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Society For Microbiology
publisher.none.fl_str_mv American Society For Microbiology
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 13.13397

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