QM/MM study of the C-C coupling reaction mechanism of CYP121, an essential Cytochrome p450 of Mycobacterium tuberculosis

Autores
Dumas, Victoria Gisel; Defelipe, Lucas Alfredo; Petruk, Ariel Alcides; Turjanski, Adrian; Marti, Marcelo Adrian
Año de publicación
2013
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Among 20 p450s of Mycobacterium tuberculosis (Mt), CYP121 has received an outstanding interest, not only due to its essentiality for bacterial viability but also because it catalyzes an unusual carbon-carbon coupling reaction. Based on the structure of the substrate bound enzyme, several reaction mechanisms were proposed involving first Tyr radical formation, second Tyr radical formation, and C?C coupling. Key and unknown features, being the nature of the species that generate the first and second radicals, and the role played by the protein scaffold each step. In the present work we have used classical and quantum based computer simulation methods to study in detail its reaction mechanism. Our results show that substrate binding promotes formation of the initial oxy complex, Compound I is the responsible for first Tyr radical formation, and that the second Tyr radical is formed subsequently, through a PCET reaction, promoted by the presence of key residue Arg386. The final C-C coupling reaction possibly occurs in bulk solution, thus yielding the product in one oxygen reduction cycle. Our results thus contribute to a better comprehension of MtCYP121 reaction mechanism, with direct implications for inhibitor design, and also contribute to our general understanding of these type of enzymes.
Fil: Dumas, Victoria Gisel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de Los Materiales, Medioambiente y Energía; Argentina. Universidad de Buenos Aires; Argentina
Fil: Defelipe, Lucas Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de Los Materiales, Medioambiente y Energía; Argentina. Universidad de Buenos Aires; Argentina
Fil: Petruk, Ariel Alcides. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentina
Fil: Turjanski, Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de Los Materiales, Medioambiente y Energía; Argentina. Universidad de Buenos Aires; Argentina
Fil: Marti, Marcelo Adrian. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentina
Materia
Cyp121
Mycobacterium Tuberculosis
Qm/Mm
Cytochrome P450
Cyclo-Di-Tyrosine
Reaction Mecanism
Molecular Dynamics
Electron Transfer
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:11336/7816
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/7816
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling QM/MM study of the C-C coupling reaction mechanism of CYP121, an essential Cytochrome p450 of Mycobacterium tuberculosisDumas, Victoria GiselDefelipe, Lucas AlfredoPetruk, Ariel AlcidesTurjanski, AdrianMarti, Marcelo AdrianCyp121Mycobacterium TuberculosisQm/MmCytochrome P450Cyclo-Di-TyrosineReaction MecanismMolecular DynamicsElectron Transferhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Among 20 p450s of Mycobacterium tuberculosis (Mt), CYP121 has received an outstanding interest, not only due to its essentiality for bacterial viability but also because it catalyzes an unusual carbon-carbon coupling reaction. Based on the structure of the substrate bound enzyme, several reaction mechanisms were proposed involving first Tyr radical formation, second Tyr radical formation, and C?C coupling. Key and unknown features, being the nature of the species that generate the first and second radicals, and the role played by the protein scaffold each step. In the present work we have used classical and quantum based computer simulation methods to study in detail its reaction mechanism. Our results show that substrate binding promotes formation of the initial oxy complex, Compound I is the responsible for first Tyr radical formation, and that the second Tyr radical is formed subsequently, through a PCET reaction, promoted by the presence of key residue Arg386. The final C-C coupling reaction possibly occurs in bulk solution, thus yielding the product in one oxygen reduction cycle. Our results thus contribute to a better comprehension of MtCYP121 reaction mechanism, with direct implications for inhibitor design, and also contribute to our general understanding of these type of enzymes.Fil: Dumas, Victoria Gisel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de Los Materiales, Medioambiente y Energía; Argentina. Universidad de Buenos Aires; ArgentinaFil: Defelipe, Lucas Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de Los Materiales, Medioambiente y Energía; Argentina. Universidad de Buenos Aires; ArgentinaFil: Petruk, Ariel Alcides. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía; ArgentinaFil: Turjanski, Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de Los Materiales, Medioambiente y Energía; Argentina. Universidad de Buenos Aires; ArgentinaFil: Marti, Marcelo Adrian. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía; ArgentinaWiley2013-12info: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/11336/7816Dumas, Victoria Gisel; Defelipe, Lucas Alfredo; Petruk, Ariel Alcides; Turjanski, Adrian; Marti, Marcelo Adrian; QM/MM study of the C-C coupling reaction mechanism of CYP121, an essential Cytochrome p450 of Mycobacterium tuberculosis; Wiley; Proteins: Structure, Function And Genetics; 82; 6; 12-2013; 1004-10210887-3585enginfo:eu-repo/semantics/altIdentifier/url/http://onlinelibrary.wiley.com/doi/10.1002/prot.24474/abstractinfo:eu-repo/semantics/altIdentifier/doi/10.1002/prot.24474info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:26:39Zoai:ri.conicet.gov.ar:11336/7816instacron: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:34982025-10-22 11:26:40.085CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv QM/MM study of the C-C coupling reaction mechanism of CYP121, an essential Cytochrome p450 of Mycobacterium tuberculosis
title QM/MM study of the C-C coupling reaction mechanism of CYP121, an essential Cytochrome p450 of Mycobacterium tuberculosis
spellingShingle QM/MM study of the C-C coupling reaction mechanism of CYP121, an essential Cytochrome p450 of Mycobacterium tuberculosis
Dumas, Victoria Gisel
Cyp121
Mycobacterium Tuberculosis
Qm/Mm
Cytochrome P450
Cyclo-Di-Tyrosine
Reaction Mecanism
Molecular Dynamics
Electron Transfer
title_short QM/MM study of the C-C coupling reaction mechanism of CYP121, an essential Cytochrome p450 of Mycobacterium tuberculosis
title_full QM/MM study of the C-C coupling reaction mechanism of CYP121, an essential Cytochrome p450 of Mycobacterium tuberculosis
title_fullStr QM/MM study of the C-C coupling reaction mechanism of CYP121, an essential Cytochrome p450 of Mycobacterium tuberculosis
title_full_unstemmed QM/MM study of the C-C coupling reaction mechanism of CYP121, an essential Cytochrome p450 of Mycobacterium tuberculosis
title_sort QM/MM study of the C-C coupling reaction mechanism of CYP121, an essential Cytochrome p450 of Mycobacterium tuberculosis
dc.creator.none.fl_str_mv Dumas, Victoria Gisel
Defelipe, Lucas Alfredo
Petruk, Ariel Alcides
Turjanski, Adrian
Marti, Marcelo Adrian
author Dumas, Victoria Gisel
author_facet Dumas, Victoria Gisel
Defelipe, Lucas Alfredo
Petruk, Ariel Alcides
Turjanski, Adrian
Marti, Marcelo Adrian
author_role author
author2 Defelipe, Lucas Alfredo
Petruk, Ariel Alcides
Turjanski, Adrian
Marti, Marcelo Adrian
author2_role author
author
author
author
dc.subject.none.fl_str_mv Cyp121
Mycobacterium Tuberculosis
Qm/Mm
Cytochrome P450
Cyclo-Di-Tyrosine
Reaction Mecanism
Molecular Dynamics
Electron Transfer
topic Cyp121
Mycobacterium Tuberculosis
Qm/Mm
Cytochrome P450
Cyclo-Di-Tyrosine
Reaction Mecanism
Molecular Dynamics
Electron Transfer
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Among 20 p450s of Mycobacterium tuberculosis (Mt), CYP121 has received an outstanding interest, not only due to its essentiality for bacterial viability but also because it catalyzes an unusual carbon-carbon coupling reaction. Based on the structure of the substrate bound enzyme, several reaction mechanisms were proposed involving first Tyr radical formation, second Tyr radical formation, and C?C coupling. Key and unknown features, being the nature of the species that generate the first and second radicals, and the role played by the protein scaffold each step. In the present work we have used classical and quantum based computer simulation methods to study in detail its reaction mechanism. Our results show that substrate binding promotes formation of the initial oxy complex, Compound I is the responsible for first Tyr radical formation, and that the second Tyr radical is formed subsequently, through a PCET reaction, promoted by the presence of key residue Arg386. The final C-C coupling reaction possibly occurs in bulk solution, thus yielding the product in one oxygen reduction cycle. Our results thus contribute to a better comprehension of MtCYP121 reaction mechanism, with direct implications for inhibitor design, and also contribute to our general understanding of these type of enzymes.
Fil: Dumas, Victoria Gisel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de Los Materiales, Medioambiente y Energía; Argentina. Universidad de Buenos Aires; Argentina
Fil: Defelipe, Lucas Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de Los Materiales, Medioambiente y Energía; Argentina. Universidad de Buenos Aires; Argentina
Fil: Petruk, Ariel Alcides. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentina
Fil: Turjanski, Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de Los Materiales, Medioambiente y Energía; Argentina. Universidad de Buenos Aires; Argentina
Fil: Marti, Marcelo Adrian. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentina
description Among 20 p450s of Mycobacterium tuberculosis (Mt), CYP121 has received an outstanding interest, not only due to its essentiality for bacterial viability but also because it catalyzes an unusual carbon-carbon coupling reaction. Based on the structure of the substrate bound enzyme, several reaction mechanisms were proposed involving first Tyr radical formation, second Tyr radical formation, and C?C coupling. Key and unknown features, being the nature of the species that generate the first and second radicals, and the role played by the protein scaffold each step. In the present work we have used classical and quantum based computer simulation methods to study in detail its reaction mechanism. Our results show that substrate binding promotes formation of the initial oxy complex, Compound I is the responsible for first Tyr radical formation, and that the second Tyr radical is formed subsequently, through a PCET reaction, promoted by the presence of key residue Arg386. The final C-C coupling reaction possibly occurs in bulk solution, thus yielding the product in one oxygen reduction cycle. Our results thus contribute to a better comprehension of MtCYP121 reaction mechanism, with direct implications for inhibitor design, and also contribute to our general understanding of these type of enzymes.
publishDate 2013
dc.date.none.fl_str_mv 2013-12
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/11336/7816
Dumas, Victoria Gisel; Defelipe, Lucas Alfredo; Petruk, Ariel Alcides; Turjanski, Adrian; Marti, Marcelo Adrian; QM/MM study of the C-C coupling reaction mechanism of CYP121, an essential Cytochrome p450 of Mycobacterium tuberculosis; Wiley; Proteins: Structure, Function And Genetics; 82; 6; 12-2013; 1004-1021
0887-3585
url http://hdl.handle.net/11336/7816
identifier_str_mv Dumas, Victoria Gisel; Defelipe, Lucas Alfredo; Petruk, Ariel Alcides; Turjanski, Adrian; Marti, Marcelo Adrian; QM/MM study of the C-C coupling reaction mechanism of CYP121, an essential Cytochrome p450 of Mycobacterium tuberculosis; Wiley; Proteins: Structure, Function And Genetics; 82; 6; 12-2013; 1004-1021
0887-3585
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://onlinelibrary.wiley.com/doi/10.1002/prot.24474/abstract
info:eu-repo/semantics/altIdentifier/doi/10.1002/prot.24474
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
application/pdf
dc.publisher.none.fl_str_mv Wiley
publisher.none.fl_str_mv Wiley
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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