The first step of the dioxygenation reaction carried out by tryptophan dioxygenase and indoleamine 2,3-dioxygenase as revealed by quantum mechanical/molecular mechanical studies
Tryptophan dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) are two heme-containing enzymes which catalyze the conversion of L-tryptophan to N-formylkynurenine (NFK). In mammals, TDO is mostly expressed in liver and is involved in controlling homeostatic serum tryptophan concentrations, where...
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2010
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09498257_v15_n6_p811_Capece http://hdl.handle.net/20.500.12110/paper_09498257_v15_n6_p811_Capece |
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paper:paper_09498257_v15_n6_p811_Capece2023-06-08T15:54:04Z The first step of the dioxygenation reaction carried out by tryptophan dioxygenase and indoleamine 2,3-dioxygenase as revealed by quantum mechanical/molecular mechanical studies Capece, Luciana Estrin, Dario Ariel Martí, Marcelo Adrián 3-dioxygenase Indoleamine 2 Molecular dynamics Quantum mechanics/molecular mechanics Tryptophan dioxygenase Tryptophan dioxygenation formylkynurenine histidine indoleamine 2,3 dioxygenase kynurenine tryptophan 2,3 dioxygenase unclassified drug article catalysis chemical bond chemical composition chemical modification chemical reaction kinetics molecular mechanics oxygenation priority journal proton transport quantum mechanics Amines Biocatalysis Electrons Feasibility Studies Humans Indoleamine-Pyrrole 2,3,-Dioxygenase Ligands Molecular Dynamics Simulation Oxygen Protein Conformation Protons Quantum Theory Tryptophan Oxygenase Xanthomonas campestris Mammalia Tryptophan dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) are two heme-containing enzymes which catalyze the conversion of L-tryptophan to N-formylkynurenine (NFK). In mammals, TDO is mostly expressed in liver and is involved in controlling homeostatic serum tryptophan concentrations, whereas IDO is ubiquitous and is involved in modulating immune responses. Previous studies suggested that the first step of the dioxygenase reaction involves the deprotonation of the indoleamine group of the substrate by an evolutionarily conserved distal histidine residue in TDO and the hemebound dioxygen in IDO. Here, we used classical molecular dynamics and hybrid quantum mechanical/molecular mechanical methods to evaluate the base-catalyzed mechanism. Our data suggest that the deprotonation of the indoleamine group of the substrate by either histidine in TDO or heme-bound dioxygen in IDO is not energetically favorable. Instead, the dioxygenase reaction can be initiated by a direct attack of heme-bound dioxygen on the C 2=C 3 bond of the indole ring, leading to a protein-stabilized 2,3-alkylperoxide transition state and a ferryl epoxide intermediate, which subsequently recombine to generate NFK. The novel sequential two-step oxygen addition mechanism is fully supported by our recent resonance Raman data that allowed identification of the ferryl intermediate (Lewis-Ballester et al. in Proc Natl Acad Sci USA 106:17371-17376, 2009). The results reveal the subtle differences between the TDO and IDO reactions and highlight the importance of protein matrix in modulating stereoelectronic factors for oxygen activation and the stabilization of both transition and intermediate states. © SBIC 2010. Fil:Capece, L. 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. Fil:Marti, M.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2010 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09498257_v15_n6_p811_Capece http://hdl.handle.net/20.500.12110/paper_09498257_v15_n6_p811_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 |
3-dioxygenase Indoleamine 2 Molecular dynamics Quantum mechanics/molecular mechanics Tryptophan dioxygenase Tryptophan dioxygenation formylkynurenine histidine indoleamine 2,3 dioxygenase kynurenine tryptophan 2,3 dioxygenase unclassified drug article catalysis chemical bond chemical composition chemical modification chemical reaction kinetics molecular mechanics oxygenation priority journal proton transport quantum mechanics Amines Biocatalysis Electrons Feasibility Studies Humans Indoleamine-Pyrrole 2,3,-Dioxygenase Ligands Molecular Dynamics Simulation Oxygen Protein Conformation Protons Quantum Theory Tryptophan Oxygenase Xanthomonas campestris Mammalia |
| spellingShingle |
3-dioxygenase Indoleamine 2 Molecular dynamics Quantum mechanics/molecular mechanics Tryptophan dioxygenase Tryptophan dioxygenation formylkynurenine histidine indoleamine 2,3 dioxygenase kynurenine tryptophan 2,3 dioxygenase unclassified drug article catalysis chemical bond chemical composition chemical modification chemical reaction kinetics molecular mechanics oxygenation priority journal proton transport quantum mechanics Amines Biocatalysis Electrons Feasibility Studies Humans Indoleamine-Pyrrole 2,3,-Dioxygenase Ligands Molecular Dynamics Simulation Oxygen Protein Conformation Protons Quantum Theory Tryptophan Oxygenase Xanthomonas campestris Mammalia Capece, Luciana Estrin, Dario Ariel Martí, Marcelo Adrián The first step of the dioxygenation reaction carried out by tryptophan dioxygenase and indoleamine 2,3-dioxygenase as revealed by quantum mechanical/molecular mechanical studies |
| topic_facet |
3-dioxygenase Indoleamine 2 Molecular dynamics Quantum mechanics/molecular mechanics Tryptophan dioxygenase Tryptophan dioxygenation formylkynurenine histidine indoleamine 2,3 dioxygenase kynurenine tryptophan 2,3 dioxygenase unclassified drug article catalysis chemical bond chemical composition chemical modification chemical reaction kinetics molecular mechanics oxygenation priority journal proton transport quantum mechanics Amines Biocatalysis Electrons Feasibility Studies Humans Indoleamine-Pyrrole 2,3,-Dioxygenase Ligands Molecular Dynamics Simulation Oxygen Protein Conformation Protons Quantum Theory Tryptophan Oxygenase Xanthomonas campestris Mammalia |
| description |
Tryptophan dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) are two heme-containing enzymes which catalyze the conversion of L-tryptophan to N-formylkynurenine (NFK). In mammals, TDO is mostly expressed in liver and is involved in controlling homeostatic serum tryptophan concentrations, whereas IDO is ubiquitous and is involved in modulating immune responses. Previous studies suggested that the first step of the dioxygenase reaction involves the deprotonation of the indoleamine group of the substrate by an evolutionarily conserved distal histidine residue in TDO and the hemebound dioxygen in IDO. Here, we used classical molecular dynamics and hybrid quantum mechanical/molecular mechanical methods to evaluate the base-catalyzed mechanism. Our data suggest that the deprotonation of the indoleamine group of the substrate by either histidine in TDO or heme-bound dioxygen in IDO is not energetically favorable. Instead, the dioxygenase reaction can be initiated by a direct attack of heme-bound dioxygen on the C 2=C 3 bond of the indole ring, leading to a protein-stabilized 2,3-alkylperoxide transition state and a ferryl epoxide intermediate, which subsequently recombine to generate NFK. The novel sequential two-step oxygen addition mechanism is fully supported by our recent resonance Raman data that allowed identification of the ferryl intermediate (Lewis-Ballester et al. in Proc Natl Acad Sci USA 106:17371-17376, 2009). The results reveal the subtle differences between the TDO and IDO reactions and highlight the importance of protein matrix in modulating stereoelectronic factors for oxygen activation and the stabilization of both transition and intermediate states. © SBIC 2010. |
| author |
Capece, Luciana Estrin, Dario Ariel Martí, Marcelo Adrián |
| author_facet |
Capece, Luciana Estrin, Dario Ariel Martí, Marcelo Adrián |
| author_sort |
Capece, Luciana |
| title |
The first step of the dioxygenation reaction carried out by tryptophan dioxygenase and indoleamine 2,3-dioxygenase as revealed by quantum mechanical/molecular mechanical studies |
| title_short |
The first step of the dioxygenation reaction carried out by tryptophan dioxygenase and indoleamine 2,3-dioxygenase as revealed by quantum mechanical/molecular mechanical studies |
| title_full |
The first step of the dioxygenation reaction carried out by tryptophan dioxygenase and indoleamine 2,3-dioxygenase as revealed by quantum mechanical/molecular mechanical studies |
| title_fullStr |
The first step of the dioxygenation reaction carried out by tryptophan dioxygenase and indoleamine 2,3-dioxygenase as revealed by quantum mechanical/molecular mechanical studies |
| title_full_unstemmed |
The first step of the dioxygenation reaction carried out by tryptophan dioxygenase and indoleamine 2,3-dioxygenase as revealed by quantum mechanical/molecular mechanical studies |
| title_sort |
first step of the dioxygenation reaction carried out by tryptophan dioxygenase and indoleamine 2,3-dioxygenase as revealed by quantum mechanical/molecular mechanical studies |
| publishDate |
2010 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09498257_v15_n6_p811_Capece http://hdl.handle.net/20.500.12110/paper_09498257_v15_n6_p811_Capece |
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