The Inhibitory Activity of Plants from Central Argentina on p-Hydroxyphenylpyruvate Dioxygenase: Isolation and Mechanism of Inhibition of a Flavanone from Flourensia oolepis

Autores
Chiari, Maria Eugenia; Tosoni, Leonardo Daniel; Joray, Mariana Belén; Diaz Napal, Georgina Natalia; Palacios, Sara Maria; Ruiz, Gustavo Miguel; Vera, Domingo Mariano Adolfo; Carpinella, Maria Cecilia
Año de publicación
2015
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The enzyme 4-hydroxyphenylpyruvate dioxygenase catalyzes the second step in the tyrosine degradation pathway. In mammals, this enzyme is the molecular target of drugs used for the treatment of metabolic disorders associated with defects in the tyrosine catabolism, mainly the fatal hereditary disease tyrosinemia type 1. This study evaluated the inhibitory effect of 91 extracts on 4-hydroxyphenylpyruvate dioxygenase from mostly native plants from central Argentina. Flourensia oolepis ethanol extract showed itself to be the most effective, and bioguided fractionation yielded pinocembrin (1) as its active principle. This flavanone, with an IC50 value of 73.1 µM and a KI of 13.7 µM, behaved as a reversible inhibitor of the enzyme and as a noncompetitive inhibitor. Molecular modeling studies confirmed the inhibitory potency of 1 and explained its activity by means of in silico determination of its binding mode in comparison to inhibitors of known activity, cocrystallized with 4-hydroxyphenylpyruvate dioxygenase. The main structural determinants that confer its potency are discussed. Analysis of the binding mode of the flavanone 1 with 4-hydroxyphenylpyruvate dioxygenase revealed the basis of the noncompetitive reversible mechanism of inhibition at the molecular level, which seems to be a common feature in this ubiquitous family of natural compounds. The resulting information may establish the basis for obtaining novel 4-hydroxyphenylpyruvate dioxygenase inhibitors for the treatment of tyrosinemia type 1 and other disorders associated with tyrosinase catabolism.
Fil: Chiari, Maria Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; Argentina
Fil: Tosoni, Leonardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Departamento de Química; Argentina
Fil: Joray, Mariana Belén. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; Argentina
Fil: Diaz Napal, Georgina Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; Argentina
Fil: Palacios, Sara Maria. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; Argentina
Fil: Ruiz, Gustavo Miguel. Universidad Católica de Córdoba. Facultad de Ciencias Agropecuarias; Argentina
Fil: Vera, Domingo Mariano Adolfo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata; Argentina. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Departamento de Química; Argentina
Fil: Carpinella, Maria Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; Argentina
Materia
Flourensia Oolepis
Hppd Inhibitors
Molecular Docking
Pinocembrin
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/51165
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/51165
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling The Inhibitory Activity of Plants from Central Argentina on p-Hydroxyphenylpyruvate Dioxygenase: Isolation and Mechanism of Inhibition of a Flavanone from Flourensia oolepisChiari, Maria EugeniaTosoni, Leonardo DanielJoray, Mariana BelénDiaz Napal, Georgina NataliaPalacios, Sara MariaRuiz, Gustavo MiguelVera, Domingo Mariano AdolfoCarpinella, Maria CeciliaFlourensia OolepisHppd InhibitorsMolecular DockingPinocembrinhttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1The enzyme 4-hydroxyphenylpyruvate dioxygenase catalyzes the second step in the tyrosine degradation pathway. In mammals, this enzyme is the molecular target of drugs used for the treatment of metabolic disorders associated with defects in the tyrosine catabolism, mainly the fatal hereditary disease tyrosinemia type 1. This study evaluated the inhibitory effect of 91 extracts on 4-hydroxyphenylpyruvate dioxygenase from mostly native plants from central Argentina. Flourensia oolepis ethanol extract showed itself to be the most effective, and bioguided fractionation yielded pinocembrin (1) as its active principle. This flavanone, with an IC50 value of 73.1 µM and a KI of 13.7 µM, behaved as a reversible inhibitor of the enzyme and as a noncompetitive inhibitor. Molecular modeling studies confirmed the inhibitory potency of 1 and explained its activity by means of in silico determination of its binding mode in comparison to inhibitors of known activity, cocrystallized with 4-hydroxyphenylpyruvate dioxygenase. The main structural determinants that confer its potency are discussed. Analysis of the binding mode of the flavanone 1 with 4-hydroxyphenylpyruvate dioxygenase revealed the basis of the noncompetitive reversible mechanism of inhibition at the molecular level, which seems to be a common feature in this ubiquitous family of natural compounds. The resulting information may establish the basis for obtaining novel 4-hydroxyphenylpyruvate dioxygenase inhibitors for the treatment of tyrosinemia type 1 and other disorders associated with tyrosinase catabolism.Fil: Chiari, Maria Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; ArgentinaFil: Tosoni, Leonardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Departamento de Química; ArgentinaFil: Joray, Mariana Belén. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; ArgentinaFil: Diaz Napal, Georgina Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; ArgentinaFil: Palacios, Sara Maria. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; ArgentinaFil: Ruiz, Gustavo Miguel. Universidad Católica de Córdoba. Facultad de Ciencias Agropecuarias; ArgentinaFil: Vera, Domingo Mariano Adolfo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata; Argentina. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Departamento de Química; ArgentinaFil: Carpinella, Maria Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; ArgentinaGeorg Thieme Verlag Kg2015-10info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/51165Chiari, Maria Eugenia; Tosoni, Leonardo Daniel; Joray, Mariana Belén; Diaz Napal, Georgina Natalia; Palacios, Sara Maria; et al.; The Inhibitory Activity of Plants from Central Argentina on p-Hydroxyphenylpyruvate Dioxygenase: Isolation and Mechanism of Inhibition of a Flavanone from Flourensia oolepis; Georg Thieme Verlag Kg; Planta Medica; 81; 15; 10-2015; 1382-13910032-09431439-0221CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1055/s-0035-1557864info:eu-repo/semantics/altIdentifier/url/https://www.thieme-connect.de/DOI/DOI?10.1055/s-0035-1557864info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:10:41Zoai:ri.conicet.gov.ar:11336/51165instacron: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 10:10:41.511CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv The Inhibitory Activity of Plants from Central Argentina on p-Hydroxyphenylpyruvate Dioxygenase: Isolation and Mechanism of Inhibition of a Flavanone from Flourensia oolepis
title The Inhibitory Activity of Plants from Central Argentina on p-Hydroxyphenylpyruvate Dioxygenase: Isolation and Mechanism of Inhibition of a Flavanone from Flourensia oolepis
spellingShingle The Inhibitory Activity of Plants from Central Argentina on p-Hydroxyphenylpyruvate Dioxygenase: Isolation and Mechanism of Inhibition of a Flavanone from Flourensia oolepis
Chiari, Maria Eugenia
Flourensia Oolepis
Hppd Inhibitors
Molecular Docking
Pinocembrin
title_short The Inhibitory Activity of Plants from Central Argentina on p-Hydroxyphenylpyruvate Dioxygenase: Isolation and Mechanism of Inhibition of a Flavanone from Flourensia oolepis
title_full The Inhibitory Activity of Plants from Central Argentina on p-Hydroxyphenylpyruvate Dioxygenase: Isolation and Mechanism of Inhibition of a Flavanone from Flourensia oolepis
title_fullStr The Inhibitory Activity of Plants from Central Argentina on p-Hydroxyphenylpyruvate Dioxygenase: Isolation and Mechanism of Inhibition of a Flavanone from Flourensia oolepis
title_full_unstemmed The Inhibitory Activity of Plants from Central Argentina on p-Hydroxyphenylpyruvate Dioxygenase: Isolation and Mechanism of Inhibition of a Flavanone from Flourensia oolepis
title_sort The Inhibitory Activity of Plants from Central Argentina on p-Hydroxyphenylpyruvate Dioxygenase: Isolation and Mechanism of Inhibition of a Flavanone from Flourensia oolepis
dc.creator.none.fl_str_mv Chiari, Maria Eugenia
Tosoni, Leonardo Daniel
Joray, Mariana Belén
Diaz Napal, Georgina Natalia
Palacios, Sara Maria
Ruiz, Gustavo Miguel
Vera, Domingo Mariano Adolfo
Carpinella, Maria Cecilia
author Chiari, Maria Eugenia
author_facet Chiari, Maria Eugenia
Tosoni, Leonardo Daniel
Joray, Mariana Belén
Diaz Napal, Georgina Natalia
Palacios, Sara Maria
Ruiz, Gustavo Miguel
Vera, Domingo Mariano Adolfo
Carpinella, Maria Cecilia
author_role author
author2 Tosoni, Leonardo Daniel
Joray, Mariana Belén
Diaz Napal, Georgina Natalia
Palacios, Sara Maria
Ruiz, Gustavo Miguel
Vera, Domingo Mariano Adolfo
Carpinella, Maria Cecilia
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Flourensia Oolepis
Hppd Inhibitors
Molecular Docking
Pinocembrin
topic Flourensia Oolepis
Hppd Inhibitors
Molecular Docking
Pinocembrin
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv The enzyme 4-hydroxyphenylpyruvate dioxygenase catalyzes the second step in the tyrosine degradation pathway. In mammals, this enzyme is the molecular target of drugs used for the treatment of metabolic disorders associated with defects in the tyrosine catabolism, mainly the fatal hereditary disease tyrosinemia type 1. This study evaluated the inhibitory effect of 91 extracts on 4-hydroxyphenylpyruvate dioxygenase from mostly native plants from central Argentina. Flourensia oolepis ethanol extract showed itself to be the most effective, and bioguided fractionation yielded pinocembrin (1) as its active principle. This flavanone, with an IC50 value of 73.1 µM and a KI of 13.7 µM, behaved as a reversible inhibitor of the enzyme and as a noncompetitive inhibitor. Molecular modeling studies confirmed the inhibitory potency of 1 and explained its activity by means of in silico determination of its binding mode in comparison to inhibitors of known activity, cocrystallized with 4-hydroxyphenylpyruvate dioxygenase. The main structural determinants that confer its potency are discussed. Analysis of the binding mode of the flavanone 1 with 4-hydroxyphenylpyruvate dioxygenase revealed the basis of the noncompetitive reversible mechanism of inhibition at the molecular level, which seems to be a common feature in this ubiquitous family of natural compounds. The resulting information may establish the basis for obtaining novel 4-hydroxyphenylpyruvate dioxygenase inhibitors for the treatment of tyrosinemia type 1 and other disorders associated with tyrosinase catabolism.
Fil: Chiari, Maria Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; Argentina
Fil: Tosoni, Leonardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Departamento de Química; Argentina
Fil: Joray, Mariana Belén. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; Argentina
Fil: Diaz Napal, Georgina Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; Argentina
Fil: Palacios, Sara Maria. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; Argentina
Fil: Ruiz, Gustavo Miguel. Universidad Católica de Córdoba. Facultad de Ciencias Agropecuarias; Argentina
Fil: Vera, Domingo Mariano Adolfo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata; Argentina. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Departamento de Química; Argentina
Fil: Carpinella, Maria Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina. Universidad Católica de Córdoba. Facultad de Ciencias Químicas; Argentina
description The enzyme 4-hydroxyphenylpyruvate dioxygenase catalyzes the second step in the tyrosine degradation pathway. In mammals, this enzyme is the molecular target of drugs used for the treatment of metabolic disorders associated with defects in the tyrosine catabolism, mainly the fatal hereditary disease tyrosinemia type 1. This study evaluated the inhibitory effect of 91 extracts on 4-hydroxyphenylpyruvate dioxygenase from mostly native plants from central Argentina. Flourensia oolepis ethanol extract showed itself to be the most effective, and bioguided fractionation yielded pinocembrin (1) as its active principle. This flavanone, with an IC50 value of 73.1 µM and a KI of 13.7 µM, behaved as a reversible inhibitor of the enzyme and as a noncompetitive inhibitor. Molecular modeling studies confirmed the inhibitory potency of 1 and explained its activity by means of in silico determination of its binding mode in comparison to inhibitors of known activity, cocrystallized with 4-hydroxyphenylpyruvate dioxygenase. The main structural determinants that confer its potency are discussed. Analysis of the binding mode of the flavanone 1 with 4-hydroxyphenylpyruvate dioxygenase revealed the basis of the noncompetitive reversible mechanism of inhibition at the molecular level, which seems to be a common feature in this ubiquitous family of natural compounds. The resulting information may establish the basis for obtaining novel 4-hydroxyphenylpyruvate dioxygenase inhibitors for the treatment of tyrosinemia type 1 and other disorders associated with tyrosinase catabolism.
publishDate 2015
dc.date.none.fl_str_mv 2015-10
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/11336/51165
Chiari, Maria Eugenia; Tosoni, Leonardo Daniel; Joray, Mariana Belén; Diaz Napal, Georgina Natalia; Palacios, Sara Maria; et al.; The Inhibitory Activity of Plants from Central Argentina on p-Hydroxyphenylpyruvate Dioxygenase: Isolation and Mechanism of Inhibition of a Flavanone from Flourensia oolepis; Georg Thieme Verlag Kg; Planta Medica; 81; 15; 10-2015; 1382-1391
0032-0943
1439-0221
CONICET Digital
CONICET
url http://hdl.handle.net/11336/51165
identifier_str_mv Chiari, Maria Eugenia; Tosoni, Leonardo Daniel; Joray, Mariana Belén; Diaz Napal, Georgina Natalia; Palacios, Sara Maria; et al.; The Inhibitory Activity of Plants from Central Argentina on p-Hydroxyphenylpyruvate Dioxygenase: Isolation and Mechanism of Inhibition of a Flavanone from Flourensia oolepis; Georg Thieme Verlag Kg; Planta Medica; 81; 15; 10-2015; 1382-1391
0032-0943
1439-0221
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1055/s-0035-1557864
info:eu-repo/semantics/altIdentifier/url/https://www.thieme-connect.de/DOI/DOI?10.1055/s-0035-1557864
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Georg Thieme Verlag Kg
publisher.none.fl_str_mv Georg Thieme Verlag Kg
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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