Substrate stereo-specificity in tryptophan dioxygenase and indoleamine 2,3-dioxygenase

The first and rate-limiting step of the kynurenine pathway, in which tryptophan (Trp) is converted to N-formylkynurenine is catalyzed by two heme-containing proteins, Indoleamine 2,3-dioxygenase (IDO), and Tryptophan 2,3-dioxygenase (TDO). In mammals, TDO is found exclusively in liver tissue, IDO is...

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Autores principales:	Capece, L., Arrar, M., Roitberg, A.E., Yeh, S.-R., Marti, M.A., Estrin, D.A.
Formato:	JOUR
Materias:	Affinity CO Dioxygenase IDO Inhibitors Molecular dynamics Oxygen Structure TDO carbon monoxide indoleamine 2,3 dioxygenase oxygen tryptophan 2,3 dioxygenase article enzyme binding enzyme specificity enzyme substrate complex molecular dynamics molecular interaction priority journal protein conformation quantum chemistry stereospecificity Binding Sites Catalysis Humans Indoleamine-Pyrrole 2,3,-Dioxygenase Models, Molecular Molecular Dynamics Simulation Protein Conformation Stereoisomerism Substrate Specificity Tryptophan Tryptophan Oxygenase Mammalia
Acceso en línea:	http://hdl.handle.net/20.500.12110/paper_08873585_v78_n14_p2961_Capece
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

id	todo:paper_08873585_v78_n14_p2961_Capece
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spelling	todo:paper_08873585_v78_n14_p2961_Capece2023-10-03T15:40:51Z Substrate stereo-specificity in tryptophan dioxygenase and indoleamine 2,3-dioxygenase Capece, L. Arrar, M. Roitberg, A.E. Yeh, S.-R. Marti, M.A. Estrin, D.A. Affinity CO Dioxygenase IDO Inhibitors Molecular dynamics Oxygen Structure TDO carbon monoxide indoleamine 2,3 dioxygenase oxygen tryptophan 2,3 dioxygenase article enzyme binding enzyme specificity enzyme substrate complex molecular dynamics molecular interaction priority journal protein conformation quantum chemistry stereospecificity Binding Sites Catalysis Humans Indoleamine-Pyrrole 2,3,-Dioxygenase Models, Molecular Molecular Dynamics Simulation Protein Conformation Stereoisomerism Substrate Specificity Tryptophan Tryptophan Oxygenase Mammalia The first and rate-limiting step of the kynurenine pathway, in which tryptophan (Trp) is converted to N-formylkynurenine is catalyzed by two heme-containing proteins, Indoleamine 2,3-dioxygenase (IDO), and Tryptophan 2,3-dioxygenase (TDO). In mammals, TDO is found exclusively in liver tissue, IDO is found ubiquitously in all tissues. IDO has become increasingly popular in pharmaceutical research as it was found to be involved in many physiological situations, including immune escape of cancer. More importantly, small-molecule inhibitors of IDO are currently utilized in cancer therapy. One of the main concerns for the design of human IDO (hIDO) inhibitors is that they should be selective enough to avoid inhibition of TDO. In this work, we have used a combination of classical molecular dynamics (MD) and hybrid quantum-classical (QM/MM) methodologies to establish the structural basis that determine the differences in (a) the interactions of TDO and IDO with small ligands (CO/O 2) and (b) the substrate stereo-specificity in hIDO and TDO. Our results indicate that the differences in small ligand bound structures of IDO and TDO arise from slight differences in the structure of the bound substrate complex. The results also show that substrate stereospecificity of TDO is achieved by the perfect fit of L-Trp, but not D-Trp, which exhibits weaker interactions with the protein matrix. For hIDO, the presence of multiple stable binding conformations for L/D-Trp reveal the existence of a large and dynamic active site. Taken together, our data allow determination of key interactions useful for the future design of more potent hIDO-selective inhibitors. © 2010 Wiley-Liss, Inc. 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. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_08873585_v78_n14_p2961_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	Affinity CO Dioxygenase IDO Inhibitors Molecular dynamics Oxygen Structure TDO carbon monoxide indoleamine 2,3 dioxygenase oxygen tryptophan 2,3 dioxygenase article enzyme binding enzyme specificity enzyme substrate complex molecular dynamics molecular interaction priority journal protein conformation quantum chemistry stereospecificity Binding Sites Catalysis Humans Indoleamine-Pyrrole 2,3,-Dioxygenase Models, Molecular Molecular Dynamics Simulation Protein Conformation Stereoisomerism Substrate Specificity Tryptophan Tryptophan Oxygenase Mammalia
spellingShingle	Affinity CO Dioxygenase IDO Inhibitors Molecular dynamics Oxygen Structure TDO carbon monoxide indoleamine 2,3 dioxygenase oxygen tryptophan 2,3 dioxygenase article enzyme binding enzyme specificity enzyme substrate complex molecular dynamics molecular interaction priority journal protein conformation quantum chemistry stereospecificity Binding Sites Catalysis Humans Indoleamine-Pyrrole 2,3,-Dioxygenase Models, Molecular Molecular Dynamics Simulation Protein Conformation Stereoisomerism Substrate Specificity Tryptophan Tryptophan Oxygenase Mammalia Capece, L. Arrar, M. Roitberg, A.E. Yeh, S.-R. Marti, M.A. Estrin, D.A. Substrate stereo-specificity in tryptophan dioxygenase and indoleamine 2,3-dioxygenase
topic_facet	Affinity CO Dioxygenase IDO Inhibitors Molecular dynamics Oxygen Structure TDO carbon monoxide indoleamine 2,3 dioxygenase oxygen tryptophan 2,3 dioxygenase article enzyme binding enzyme specificity enzyme substrate complex molecular dynamics molecular interaction priority journal protein conformation quantum chemistry stereospecificity Binding Sites Catalysis Humans Indoleamine-Pyrrole 2,3,-Dioxygenase Models, Molecular Molecular Dynamics Simulation Protein Conformation Stereoisomerism Substrate Specificity Tryptophan Tryptophan Oxygenase Mammalia
description	The first and rate-limiting step of the kynurenine pathway, in which tryptophan (Trp) is converted to N-formylkynurenine is catalyzed by two heme-containing proteins, Indoleamine 2,3-dioxygenase (IDO), and Tryptophan 2,3-dioxygenase (TDO). In mammals, TDO is found exclusively in liver tissue, IDO is found ubiquitously in all tissues. IDO has become increasingly popular in pharmaceutical research as it was found to be involved in many physiological situations, including immune escape of cancer. More importantly, small-molecule inhibitors of IDO are currently utilized in cancer therapy. One of the main concerns for the design of human IDO (hIDO) inhibitors is that they should be selective enough to avoid inhibition of TDO. In this work, we have used a combination of classical molecular dynamics (MD) and hybrid quantum-classical (QM/MM) methodologies to establish the structural basis that determine the differences in (a) the interactions of TDO and IDO with small ligands (CO/O 2) and (b) the substrate stereo-specificity in hIDO and TDO. Our results indicate that the differences in small ligand bound structures of IDO and TDO arise from slight differences in the structure of the bound substrate complex. The results also show that substrate stereospecificity of TDO is achieved by the perfect fit of L-Trp, but not D-Trp, which exhibits weaker interactions with the protein matrix. For hIDO, the presence of multiple stable binding conformations for L/D-Trp reveal the existence of a large and dynamic active site. Taken together, our data allow determination of key interactions useful for the future design of more potent hIDO-selective inhibitors. © 2010 Wiley-Liss, Inc.
format	JOUR
author	Capece, L. Arrar, M. Roitberg, A.E. Yeh, S.-R. Marti, M.A. Estrin, D.A.
author_facet	Capece, L. Arrar, M. Roitberg, A.E. Yeh, S.-R. Marti, M.A. Estrin, D.A.
author_sort	Capece, L.
title	Substrate stereo-specificity in tryptophan dioxygenase and indoleamine 2,3-dioxygenase
title_short	Substrate stereo-specificity in tryptophan dioxygenase and indoleamine 2,3-dioxygenase
title_full	Substrate stereo-specificity in tryptophan dioxygenase and indoleamine 2,3-dioxygenase
title_fullStr	Substrate stereo-specificity in tryptophan dioxygenase and indoleamine 2,3-dioxygenase
title_full_unstemmed	Substrate stereo-specificity in tryptophan dioxygenase and indoleamine 2,3-dioxygenase
title_sort	substrate stereo-specificity in tryptophan dioxygenase and indoleamine 2,3-dioxygenase
url	http://hdl.handle.net/20.500.12110/paper_08873585_v78_n14_p2961_Capece
work_keys_str_mv	AT capecel substratestereospecificityintryptophandioxygenaseandindoleamine23dioxygenase AT arrarm substratestereospecificityintryptophandioxygenaseandindoleamine23dioxygenase AT roitbergae substratestereospecificityintryptophandioxygenaseandindoleamine23dioxygenase AT yehsr substratestereospecificityintryptophandioxygenaseandindoleamine23dioxygenase AT martima substratestereospecificityintryptophandioxygenaseandindoleamine23dioxygenase AT estrinda substratestereospecificityintryptophandioxygenaseandindoleamine23dioxygenase
_version_	1782025362296799232

Substrate stereo-specificity in tryptophan dioxygenase and indoleamine 2,3-dioxygenase

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