Molecular basis for the substrate stereoselectivity in tryptophan dioxygenase

Tryptophan dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) are the only two heme proteins that catalyze the oxidation reaction of tryptophan (Trp) to N-formylkynurenine. While human IDO is able to oxidize both l- and d-Trp, human TDO (hTDO) displays major specificity for l-Trp. In this work,...

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Autores principales:	Capece, Luciana, Martí, Marcelo Adrián, Estrin, Dario Ariel
Publicado:	2011
Materias:	Active site Ammonium groups Dioxygenases Heme proteins Hydrogen bonding interactions Indoleamine 2 ,3-dioxygenase Molecular basis Molecular dynamics simulations Oxidation reactions Stereostructure Structural alterations Substrate binding Xanthomonas campestris Amino acids Ammonium compounds Dynamics Enzymes Hydrogen bonds Molecular dynamics Molecular oxygen Porphyrins Proteins Reaction kinetics Stereoselectivity Substrates enzyme ferryl indole 2,3 epoxide formylkynurenine indoleamine 2,3 dioxygenase tryptophan 2,3 dioxygenase unclassified drug article catalysis controlled study enzyme binding gene mutation hydrogen bond molecular dynamics nonhuman oxidation priority journal protein analysis protein structure stereochemistry Amino Acid Substitution Binding Sites Biocatalysis Humans Hydrogen Bonding Kinetics Models, Molecular Molecular Dynamics Simulation Mutant Proteins Oxidation-Reduction Protein Binding Protein Conformation Recombinant Proteins Spectrophotometry Spectrum Analysis, Raman Stereoisomerism Substrate Specificity Threonine Tryptophan Tryptophan Oxygenase
Acceso en línea:	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00062960_v50_n50_p10910_Capece http://hdl.handle.net/20.500.12110/paper_00062960_v50_n50_p10910_Capece
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

id	paper:paper_00062960_v50_n50_p10910_Capece
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spelling	paper:paper_00062960_v50_n50_p10910_Capece2023-06-08T14:30:47Z Molecular basis for the substrate stereoselectivity in tryptophan dioxygenase Capece, Luciana Martí, Marcelo Adrián Estrin, Dario Ariel Active site Ammonium groups Dioxygenases Heme proteins Hydrogen bonding interactions Indoleamine 2 ,3-dioxygenase Molecular basis Molecular dynamics simulations Oxidation reactions Stereostructure Structural alterations Substrate binding Xanthomonas campestris Amino acids Ammonium compounds Dynamics Enzymes Hydrogen bonds Molecular dynamics Molecular oxygen Porphyrins Proteins Reaction kinetics Stereoselectivity Substrates enzyme ferryl indole 2,3 epoxide formylkynurenine indoleamine 2,3 dioxygenase tryptophan 2,3 dioxygenase unclassified drug article catalysis controlled study enzyme binding gene mutation hydrogen bond molecular dynamics nonhuman oxidation priority journal protein analysis protein structure stereochemistry Xanthomonas campestris Amino Acid Substitution Binding Sites Biocatalysis Humans Hydrogen Bonding Kinetics Models, Molecular Molecular Dynamics Simulation Mutant Proteins Oxidation-Reduction Protein Binding Protein Conformation Recombinant Proteins Spectrophotometry Spectrum Analysis, Raman Stereoisomerism Substrate Specificity Threonine Tryptophan Tryptophan Oxygenase Tryptophan dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) are the only two heme proteins that catalyze the oxidation reaction of tryptophan (Trp) to N-formylkynurenine. While human IDO is able to oxidize both l- and 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 NH 3 + 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, loop 250-260 and loop 117-130, critical for substrate binding. © 2011 American Chemical Society. Fil:Capece, L. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Marti, M.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Estrin, D.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2011 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00062960_v50_n50_p10910_Capece http://hdl.handle.net/20.500.12110/paper_00062960_v50_n50_p10910_Capece
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	Active site Ammonium groups Dioxygenases Heme proteins Hydrogen bonding interactions Indoleamine 2 ,3-dioxygenase Molecular basis Molecular dynamics simulations Oxidation reactions Stereostructure Structural alterations Substrate binding Xanthomonas campestris Amino acids Ammonium compounds Dynamics Enzymes Hydrogen bonds Molecular dynamics Molecular oxygen Porphyrins Proteins Reaction kinetics Stereoselectivity Substrates enzyme ferryl indole 2,3 epoxide formylkynurenine indoleamine 2,3 dioxygenase tryptophan 2,3 dioxygenase unclassified drug article catalysis controlled study enzyme binding gene mutation hydrogen bond molecular dynamics nonhuman oxidation priority journal protein analysis protein structure stereochemistry Xanthomonas campestris Amino Acid Substitution Binding Sites Biocatalysis Humans Hydrogen Bonding Kinetics Models, Molecular Molecular Dynamics Simulation Mutant Proteins Oxidation-Reduction Protein Binding Protein Conformation Recombinant Proteins Spectrophotometry Spectrum Analysis, Raman Stereoisomerism Substrate Specificity Threonine Tryptophan Tryptophan Oxygenase
spellingShingle	Active site Ammonium groups Dioxygenases Heme proteins Hydrogen bonding interactions Indoleamine 2 ,3-dioxygenase Molecular basis Molecular dynamics simulations Oxidation reactions Stereostructure Structural alterations Substrate binding Xanthomonas campestris Amino acids Ammonium compounds Dynamics Enzymes Hydrogen bonds Molecular dynamics Molecular oxygen Porphyrins Proteins Reaction kinetics Stereoselectivity Substrates enzyme ferryl indole 2,3 epoxide formylkynurenine indoleamine 2,3 dioxygenase tryptophan 2,3 dioxygenase unclassified drug article catalysis controlled study enzyme binding gene mutation hydrogen bond molecular dynamics nonhuman oxidation priority journal protein analysis protein structure stereochemistry Xanthomonas campestris Amino Acid Substitution Binding Sites Biocatalysis Humans Hydrogen Bonding Kinetics Models, Molecular Molecular Dynamics Simulation Mutant Proteins Oxidation-Reduction Protein Binding Protein Conformation Recombinant Proteins Spectrophotometry Spectrum Analysis, Raman Stereoisomerism Substrate Specificity Threonine Tryptophan Tryptophan Oxygenase Capece, Luciana Martí, Marcelo Adrián Estrin, Dario Ariel Molecular basis for the substrate stereoselectivity in tryptophan dioxygenase
topic_facet	Active site Ammonium groups Dioxygenases Heme proteins Hydrogen bonding interactions Indoleamine 2 ,3-dioxygenase Molecular basis Molecular dynamics simulations Oxidation reactions Stereostructure Structural alterations Substrate binding Xanthomonas campestris Amino acids Ammonium compounds Dynamics Enzymes Hydrogen bonds Molecular dynamics Molecular oxygen Porphyrins Proteins Reaction kinetics Stereoselectivity Substrates enzyme ferryl indole 2,3 epoxide formylkynurenine indoleamine 2,3 dioxygenase tryptophan 2,3 dioxygenase unclassified drug article catalysis controlled study enzyme binding gene mutation hydrogen bond molecular dynamics nonhuman oxidation priority journal protein analysis protein structure stereochemistry Xanthomonas campestris Amino Acid Substitution Binding Sites Biocatalysis Humans Hydrogen Bonding Kinetics Models, Molecular Molecular Dynamics Simulation Mutant Proteins Oxidation-Reduction Protein Binding Protein Conformation Recombinant Proteins Spectrophotometry Spectrum Analysis, Raman Stereoisomerism Substrate Specificity Threonine Tryptophan Tryptophan Oxygenase
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 N-formylkynurenine. While human IDO is able to oxidize both l- and 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 NH 3 + 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, loop 250-260 and loop 117-130, critical for substrate binding. © 2011 American Chemical Society.
author	Capece, Luciana Martí, Marcelo Adrián Estrin, Dario Ariel
author_facet	Capece, Luciana Martí, Marcelo Adrián Estrin, Dario Ariel
author_sort	Capece, Luciana
title	Molecular basis for the substrate stereoselectivity in tryptophan dioxygenase
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
publishDate	2011
url	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00062960_v50_n50_p10910_Capece http://hdl.handle.net/20.500.12110/paper_00062960_v50_n50_p10910_Capece
work_keys_str_mv	AT capeceluciana molecularbasisforthesubstratestereoselectivityintryptophandioxygenase AT martimarceloadrian molecularbasisforthesubstratestereoselectivityintryptophandioxygenase AT estrindarioariel molecularbasisforthesubstratestereoselectivityintryptophandioxygenase
_version_	1768543065676447744

Molecular basis for the substrate stereoselectivity in tryptophan dioxygenase

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