Complete reaction mechanism of indoleamine 2,3-dioxygenase as revealed by QM/MM simulations
Indoleamine 2,3-dioxygenase (IDO) and tryptophan dioxygenase (TDO) are two heme proteins that catalyze the oxidation reaction of tryptophan (Trp) to N-formylkynurenine (NFK). Human IDO (hIDO) has recently been recognized as a potent anticancer drug target, a fact that triggered intense research on t...
Guardado en:
Autores principales: | , , , , |
---|---|
Formato: | JOUR |
Materias: | |
Acceso en línea: | http://hdl.handle.net/20.500.12110/paper_15206106_v116_n4_p1401_Capece |
Aporte de: |
id |
todo:paper_15206106_v116_n4_p1401_Capece |
---|---|
record_format |
dspace |
spelling |
todo:paper_15206106_v116_n4_p1401_Capece2023-10-03T16:20:24Z Complete reaction mechanism of indoleamine 2,3-dioxygenase as revealed by QM/MM simulations Capece, L. Lewis-Ballester, A. Yeh, S.-R. Estrin, D.A. Marti, M.A. Amino acids Chemical bonds Oxygen Porphyrins Proteins Proton transfer Acid catalyst Amino group Anticancer drug Bond cleavages Comparative studies Dioxygenases Dioxygens Enzyme reaction Epoxide ring opening Epoxide ring-opening reaction Heme proteins Indole rings Indoleamine 2 ,3-dioxygenase Inhibition mechanisms Nucleophilic attack Oxidation reactions Oxygen addition QM/MM method Reaction catalyzed Reaction mechanism Superoxides Transition state Reaction intermediates Indoleamine 2,3-dioxygenase (IDO) and tryptophan dioxygenase (TDO) are two heme proteins that catalyze the oxidation reaction of tryptophan (Trp) to N-formylkynurenine (NFK). Human IDO (hIDO) has recently been recognized as a potent anticancer drug target, a fact that triggered intense research on the reaction and inhibition mechanisms of hIDO. Our recent studies revealed that the dioxygenase reaction catalyzed by hIDO and TDO is initiated by addition of the ferric iron-bound superoxide to the C2=C3 bond of Trp to form a ferryl and Trp-epoxide intermediate, via a 2-indolenylperoxo radical transition state. The data demonstrate that the two atoms of dioxygen are inserted into the substrate in a stepwise fashion, challenging the paradigm of heme-based dioxygenase chemistry. In the current study, we used QM/MM methods to decipher the mechanism by which the second ferryl oxygen is inserted into the Trp-epoxide to form the NFK product in hIDO. Our results show that the most energetically favored pathway involves proton transfer from Trp-NH 3+ to the epoxide oxygen, triggering epoxide ring opening and a concerted nucleophilic attack of the ferryl oxygen to the C2 of Trp that leads to a metastable reaction intermediate. This intermediate subsequently converts to NFK, following C2-C3 bond cleavage and the associated back proton transfer from the oxygen to the amino group of Trp. A comparative study with Xantomonas campestris TDO (xcTDO) indicates that the reaction follows a similar pathway, although subtle differences distinguishing the two enzyme reactions are evident. The results underscore the importance of the NH3+ group of Trp in the two-step ferryl-based mechanism of hIDO and xcTDO, by acting as an acid catalyst to facilitate the epoxide ring-opening reaction and ferryl oxygen addition to the indole ring. © 2011 American Chemical Society. 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. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_15206106_v116_n4_p1401_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 |
Amino acids Chemical bonds Oxygen Porphyrins Proteins Proton transfer Acid catalyst Amino group Anticancer drug Bond cleavages Comparative studies Dioxygenases Dioxygens Enzyme reaction Epoxide ring opening Epoxide ring-opening reaction Heme proteins Indole rings Indoleamine 2 ,3-dioxygenase Inhibition mechanisms Nucleophilic attack Oxidation reactions Oxygen addition QM/MM method Reaction catalyzed Reaction mechanism Superoxides Transition state Reaction intermediates |
spellingShingle |
Amino acids Chemical bonds Oxygen Porphyrins Proteins Proton transfer Acid catalyst Amino group Anticancer drug Bond cleavages Comparative studies Dioxygenases Dioxygens Enzyme reaction Epoxide ring opening Epoxide ring-opening reaction Heme proteins Indole rings Indoleamine 2 ,3-dioxygenase Inhibition mechanisms Nucleophilic attack Oxidation reactions Oxygen addition QM/MM method Reaction catalyzed Reaction mechanism Superoxides Transition state Reaction intermediates Capece, L. Lewis-Ballester, A. Yeh, S.-R. Estrin, D.A. Marti, M.A. Complete reaction mechanism of indoleamine 2,3-dioxygenase as revealed by QM/MM simulations |
topic_facet |
Amino acids Chemical bonds Oxygen Porphyrins Proteins Proton transfer Acid catalyst Amino group Anticancer drug Bond cleavages Comparative studies Dioxygenases Dioxygens Enzyme reaction Epoxide ring opening Epoxide ring-opening reaction Heme proteins Indole rings Indoleamine 2 ,3-dioxygenase Inhibition mechanisms Nucleophilic attack Oxidation reactions Oxygen addition QM/MM method Reaction catalyzed Reaction mechanism Superoxides Transition state Reaction intermediates |
description |
Indoleamine 2,3-dioxygenase (IDO) and tryptophan dioxygenase (TDO) are two heme proteins that catalyze the oxidation reaction of tryptophan (Trp) to N-formylkynurenine (NFK). Human IDO (hIDO) has recently been recognized as a potent anticancer drug target, a fact that triggered intense research on the reaction and inhibition mechanisms of hIDO. Our recent studies revealed that the dioxygenase reaction catalyzed by hIDO and TDO is initiated by addition of the ferric iron-bound superoxide to the C2=C3 bond of Trp to form a ferryl and Trp-epoxide intermediate, via a 2-indolenylperoxo radical transition state. The data demonstrate that the two atoms of dioxygen are inserted into the substrate in a stepwise fashion, challenging the paradigm of heme-based dioxygenase chemistry. In the current study, we used QM/MM methods to decipher the mechanism by which the second ferryl oxygen is inserted into the Trp-epoxide to form the NFK product in hIDO. Our results show that the most energetically favored pathway involves proton transfer from Trp-NH 3+ to the epoxide oxygen, triggering epoxide ring opening and a concerted nucleophilic attack of the ferryl oxygen to the C2 of Trp that leads to a metastable reaction intermediate. This intermediate subsequently converts to NFK, following C2-C3 bond cleavage and the associated back proton transfer from the oxygen to the amino group of Trp. A comparative study with Xantomonas campestris TDO (xcTDO) indicates that the reaction follows a similar pathway, although subtle differences distinguishing the two enzyme reactions are evident. The results underscore the importance of the NH3+ group of Trp in the two-step ferryl-based mechanism of hIDO and xcTDO, by acting as an acid catalyst to facilitate the epoxide ring-opening reaction and ferryl oxygen addition to the indole ring. © 2011 American Chemical Society. |
format |
JOUR |
author |
Capece, L. Lewis-Ballester, A. Yeh, S.-R. Estrin, D.A. Marti, M.A. |
author_facet |
Capece, L. Lewis-Ballester, A. Yeh, S.-R. Estrin, D.A. Marti, M.A. |
author_sort |
Capece, L. |
title |
Complete reaction mechanism of indoleamine 2,3-dioxygenase as revealed by QM/MM simulations |
title_short |
Complete reaction mechanism of indoleamine 2,3-dioxygenase as revealed by QM/MM simulations |
title_full |
Complete reaction mechanism of indoleamine 2,3-dioxygenase as revealed by QM/MM simulations |
title_fullStr |
Complete reaction mechanism of indoleamine 2,3-dioxygenase as revealed by QM/MM simulations |
title_full_unstemmed |
Complete reaction mechanism of indoleamine 2,3-dioxygenase as revealed by QM/MM simulations |
title_sort |
complete reaction mechanism of indoleamine 2,3-dioxygenase as revealed by qm/mm simulations |
url |
http://hdl.handle.net/20.500.12110/paper_15206106_v116_n4_p1401_Capece |
work_keys_str_mv |
AT capecel completereactionmechanismofindoleamine23dioxygenaseasrevealedbyqmmmsimulations AT lewisballestera completereactionmechanismofindoleamine23dioxygenaseasrevealedbyqmmmsimulations AT yehsr completereactionmechanismofindoleamine23dioxygenaseasrevealedbyqmmmsimulations AT estrinda completereactionmechanismofindoleamine23dioxygenaseasrevealedbyqmmmsimulations AT martima completereactionmechanismofindoleamine23dioxygenaseasrevealedbyqmmmsimulations |
_version_ |
1782027731202998272 |