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Abstract:

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.

Registro:

Documento: Artículo
Título:Complete reaction mechanism of indoleamine 2,3-dioxygenase as revealed by QM/MM simulations
Autor:Capece, L.; Lewis-Ballester, A.; Yeh, S.-R.; Estrin, D.A.; Marti, M.A.
Filiación:Departamento de Química Inorgánica, Analítica y Química Física, INQUIMAE-CONICET, Universidad de Buenos Aires, Buenos Aires, C1428EHA, Argentina
Department of Physiology and Biophysics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, United States
Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, C1428EHA, Argentina
German Research School for Simulation Sciences, FZ-Juelich, RWTH Aachen, Juelich, Germany
Palabras clave: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
Año:2012
Volumen:116
Número:4
Página de inicio:1401
Página de fin:1413
DOI: http://dx.doi.org/10.1021/jp2082825
Título revista:Journal of Physical Chemistry B
Título revista abreviado:J Phys Chem B
ISSN:15206106
CODEN:JPCBF
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_15206106_v116_n4_p1401_Capece

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Citas:

---------- APA ----------
Capece, L., Lewis-Ballester, A., Yeh, S.-R., Estrin, D.A. & Marti, M.A. (2012) . Complete reaction mechanism of indoleamine 2,3-dioxygenase as revealed by QM/MM simulations. Journal of Physical Chemistry B, 116(4), 1401-1413.
http://dx.doi.org/10.1021/jp2082825
---------- CHICAGO ----------
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" . Journal of Physical Chemistry B 116, no. 4 (2012) : 1401-1413.
http://dx.doi.org/10.1021/jp2082825
---------- MLA ----------
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" . Journal of Physical Chemistry B, vol. 116, no. 4, 2012, pp. 1401-1413.
http://dx.doi.org/10.1021/jp2082825
---------- VANCOUVER ----------
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. J Phys Chem B. 2012;116(4):1401-1413.
http://dx.doi.org/10.1021/jp2082825