Molecular basis for the substrate stereoselectivity in tryptophan dioxygenase

Autores
Capece, Luciana; Lewis-Ballester, Ariel; Marti, Marcelo Adrian; Estrin, Dario Ariel; Yeh, Syun-Ru
Año de publicación
2011
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Tryptophan dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) are the only two heme proteins that catalyze the oxidation reaction of tryptophan (Trp) to Nformylkynurenine.
While human IDO is able to oxidize both Land D-Trp, human TDO (hTDO) displays major specificity for L-Trp. In this work, we aim to interrogate the molecular basis for the substrate stereoselectivity of hTDO. Our previous molecular dynamics simulation studies of Xanthomonas campestris TDO (xcTDO) showed that a hydrogen bond between T254 (T342 in hTDO) and the ammonium group of the substrate is present in the L-Trp-bound enzyme, but not in the D-Trp-bound enzyme. The fact that this is the only notable structural alteration induced by the change in the stereo structure of the substrate prompted us to produce and characterize the T342A mutant of hTDO to evaluate the structural role of T342 in controlling the substrate stereoselectivity of the enzyme. The  experimental results indicate that the mutation only slightly perturbs the global structural properties of the enzyme but totally abolishes the substrate stereoselectivity. Molecular dynamics simulations of xcTDO show that T254 controls the substrate stereoselectivity of the enzyme by (i) modulating the hydrogen bonding interaction between the NH3+ group and epoxide oxygen of the ferryl−indole 2,3-epoxide intermediate of the enzyme and (ii) regulating the dynamics of two active site loops,
loop250−260 and loop117−130, critical for substrate binding.
Fil: Capece, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentina
Fil: Lewis-Ballester, Ariel. Yeshiva University; Estados Unidos
Fil: Marti, Marcelo Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Estrin, Dario Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentina
Fil: Yeh, Syun-Ru. Yeshiva University; Estados Unidos
Materia
Indeolamine Dioxygenase
Tryptophane Dioxygenase
Computer Simulation
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:11336/68712
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/68712
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Molecular basis for the substrate stereoselectivity in tryptophan dioxygenaseCapece, LucianaLewis-Ballester, ArielMarti, Marcelo AdrianEstrin, Dario ArielYeh, Syun-RuIndeolamine DioxygenaseTryptophane DioxygenaseComputer Simulationhttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1Tryptophan dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) are the only two heme proteins that catalyze the oxidation reaction of tryptophan (Trp) to Nformylkynurenine.<br />While human IDO is able to oxidize both Land D-Trp, human TDO (hTDO) displays major specificity for L-Trp. In this work, we aim to interrogate the molecular basis for the substrate stereoselectivity of hTDO. Our previous molecular dynamics simulation studies of Xanthomonas campestris TDO (xcTDO) showed that a hydrogen bond between T254 (T342 in hTDO) and the ammonium group of the substrate is present in the L-Trp-bound enzyme, but not in the D-Trp-bound enzyme. The fact that this is the only notable structural alteration induced by the change in the stereo structure of the substrate prompted us to produce and characterize the T342A mutant of hTDO to evaluate the structural role of T342 in controlling the substrate stereoselectivity of the enzyme. The  experimental results indicate that the mutation only slightly perturbs the global structural properties of the enzyme but totally abolishes the substrate stereoselectivity. Molecular dynamics simulations of xcTDO show that T254 controls the substrate stereoselectivity of the enzyme by (i) modulating the hydrogen bonding interaction between the NH3+ group and epoxide oxygen of the ferryl−indole 2,3-epoxide intermediate of the enzyme and (ii) regulating the dynamics of two active site loops,<br />loop250−260 and loop117−130, critical for substrate binding.Fil: Capece, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; ArgentinaFil: Lewis-Ballester, Ariel. Yeshiva University; Estados UnidosFil: Marti, Marcelo Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Estrin, Dario Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; ArgentinaFil: Yeh, Syun-Ru. Yeshiva University; Estados UnidosAmerican Chemical Society2011-11-23info: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/11336/68712Capece, Luciana; Lewis-Ballester, Ariel; Marti, Marcelo Adrian; Estrin, Dario Ariel; Yeh, Syun-Ru; Molecular basis for the substrate stereoselectivity in tryptophan dioxygenase; American Chemical Society; Biochemistry; 50; 50; 23-11-2011; 10910-109180006-2960CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/abs/10.1021/bi201439minfo:eu-repo/semantics/altIdentifier/doi/10.1021/bi201439minfo:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3237892/info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:04:55Zoai:ri.conicet.gov.ar:11336/68712instacron: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 11:04:56.196CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Molecular basis for the substrate stereoselectivity in tryptophan dioxygenase
title Molecular basis for the substrate stereoselectivity in tryptophan dioxygenase
spellingShingle Molecular basis for the substrate stereoselectivity in tryptophan dioxygenase
Capece, Luciana
Indeolamine Dioxygenase
Tryptophane Dioxygenase
Computer Simulation
title_short Molecular basis for the substrate stereoselectivity in tryptophan dioxygenase
title_full Molecular basis for the substrate stereoselectivity in tryptophan dioxygenase
title_fullStr Molecular basis for the substrate stereoselectivity in tryptophan dioxygenase
title_full_unstemmed Molecular basis for the substrate stereoselectivity in tryptophan dioxygenase
title_sort Molecular basis for the substrate stereoselectivity in tryptophan dioxygenase
dc.creator.none.fl_str_mv Capece, Luciana
Lewis-Ballester, Ariel
Marti, Marcelo Adrian
Estrin, Dario Ariel
Yeh, Syun-Ru
author Capece, Luciana
author_facet Capece, Luciana
Lewis-Ballester, Ariel
Marti, Marcelo Adrian
Estrin, Dario Ariel
Yeh, Syun-Ru
author_role author
author2 Lewis-Ballester, Ariel
Marti, Marcelo Adrian
Estrin, Dario Ariel
Yeh, Syun-Ru
author2_role author
author
author
author
dc.subject.none.fl_str_mv Indeolamine Dioxygenase
Tryptophane Dioxygenase
Computer Simulation
topic Indeolamine Dioxygenase
Tryptophane Dioxygenase
Computer Simulation
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Tryptophan dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) are the only two heme proteins that catalyze the oxidation reaction of tryptophan (Trp) to Nformylkynurenine.<br />While human IDO is able to oxidize both Land D-Trp, human TDO (hTDO) displays major specificity for L-Trp. In this work, we aim to interrogate the molecular basis for the substrate stereoselectivity of hTDO. Our previous molecular dynamics simulation studies of Xanthomonas campestris TDO (xcTDO) showed that a hydrogen bond between T254 (T342 in hTDO) and the ammonium group of the substrate is present in the L-Trp-bound enzyme, but not in the D-Trp-bound enzyme. The fact that this is the only notable structural alteration induced by the change in the stereo structure of the substrate prompted us to produce and characterize the T342A mutant of hTDO to evaluate the structural role of T342 in controlling the substrate stereoselectivity of the enzyme. The  experimental results indicate that the mutation only slightly perturbs the global structural properties of the enzyme but totally abolishes the substrate stereoselectivity. Molecular dynamics simulations of xcTDO show that T254 controls the substrate stereoselectivity of the enzyme by (i) modulating the hydrogen bonding interaction between the NH3+ group and epoxide oxygen of the ferryl−indole 2,3-epoxide intermediate of the enzyme and (ii) regulating the dynamics of two active site loops,<br />loop250−260 and loop117−130, critical for substrate binding.
Fil: Capece, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentina
Fil: Lewis-Ballester, Ariel. Yeshiva University; Estados Unidos
Fil: Marti, Marcelo Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Estrin, Dario Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentina
Fil: Yeh, Syun-Ru. Yeshiva University; Estados Unidos
description Tryptophan dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) are the only two heme proteins that catalyze the oxidation reaction of tryptophan (Trp) to Nformylkynurenine.<br />While human IDO is able to oxidize both Land D-Trp, human TDO (hTDO) displays major specificity for L-Trp. In this work, we aim to interrogate the molecular basis for the substrate stereoselectivity of hTDO. Our previous molecular dynamics simulation studies of Xanthomonas campestris TDO (xcTDO) showed that a hydrogen bond between T254 (T342 in hTDO) and the ammonium group of the substrate is present in the L-Trp-bound enzyme, but not in the D-Trp-bound enzyme. The fact that this is the only notable structural alteration induced by the change in the stereo structure of the substrate prompted us to produce and characterize the T342A mutant of hTDO to evaluate the structural role of T342 in controlling the substrate stereoselectivity of the enzyme. The  experimental results indicate that the mutation only slightly perturbs the global structural properties of the enzyme but totally abolishes the substrate stereoselectivity. Molecular dynamics simulations of xcTDO show that T254 controls the substrate stereoselectivity of the enzyme by (i) modulating the hydrogen bonding interaction between the NH3+ group and epoxide oxygen of the ferryl−indole 2,3-epoxide intermediate of the enzyme and (ii) regulating the dynamics of two active site loops,<br />loop250−260 and loop117−130, critical for substrate binding.
publishDate 2011
dc.date.none.fl_str_mv 2011-11-23
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/11336/68712
Capece, Luciana; Lewis-Ballester, Ariel; Marti, Marcelo Adrian; Estrin, Dario Ariel; Yeh, Syun-Ru; Molecular basis for the substrate stereoselectivity in tryptophan dioxygenase; American Chemical Society; Biochemistry; 50; 50; 23-11-2011; 10910-10918
0006-2960
CONICET Digital
CONICET
url http://hdl.handle.net/11336/68712
identifier_str_mv Capece, Luciana; Lewis-Ballester, Ariel; Marti, Marcelo Adrian; Estrin, Dario Ariel; Yeh, Syun-Ru; Molecular basis for the substrate stereoselectivity in tryptophan dioxygenase; American Chemical Society; Biochemistry; 50; 50; 23-11-2011; 10910-10918
0006-2960
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://pubs.acs.org/doi/abs/10.1021/bi201439m
info:eu-repo/semantics/altIdentifier/doi/10.1021/bi201439m
info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3237892/
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 American Chemical Society
publisher.none.fl_str_mv American Chemical Society
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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