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The Complete Reaction Mechanism of Indoleamine 2,3-Dioxygenase as Revealed by QM/MM Simulations

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Lewis-ballester, Ariel Marti, Marcelo A. Capece, Luciana Yeh, Syun-ru Estrin, Dario A.
Description	Author Affiliation: Capece L ( Departamento de Química Inorgánica, Analítica y Química Física/INQUIMAE-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón 2, Buenos Aires, C1428EHA, Argentina.)
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 C(2)â C(3) 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 C(2) of Trp that leads to a metastable reaction intermediate. This intermediate subsequently converts to NFK, following C(2)-C(3) 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 NH(3)(+) 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.
ISSN	15206106
e-ISSN	15205207
Journal	The Journal of Physical Chemistry B
Issue Number	4
Volume Number	116
Language	English
Publisher	American Chemical Society (United States)
Publisher Date	2012-02-02
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Indoleamine-Pyrrole 2,3,-Dioxygenase Chemistry Quantum Theory Epoxy Compounds Ethers, Cyclic Metabolism Kynurenine Analogs & Derivatives Models, Molecular Molecular Conformation Oxygen Protons Thermodynamics Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Physical chemistry
Content Type	Text
Resource Type	Article
Subject	Surfaces, Coatings and Films Materials Chemistry Medicine Physical and Theoretical Chemistry

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Substrate Oxidation by Indoleamine 2,3-Dioxygenase

The Complete Reaction Mechanism of Indoleamine 2,3-Dioxygenase as Revealed by QM/MM Simulations

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.

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

Ligand and substrate migration in human indoleamine 2,3-dioxygenase.

Intact indoleamine 2,3-dioxygenase activity in human chronic granulomatous disease.

Indoleamine 2,3-dioxygenase activity and expression in patients with chronic lymphocytic leukemia.

Human Indoleamine 2,3-Dioxygenase Is a Catalyst of Physiological Heme Peroxidase Reactions: IMPLICATIONS FOR THE INHIBITION OF DIOXYGENASE ACTIVITY BY HYDROGEN PEROXIDE

Identification and Characterization of a Novel Dual Inhibitor of Indoleamine 2,3-dioxygenase 1 and Tryptophan 2,3-dioxygenase

The Complete Reaction Mechanism of Indoleamine 2,3-Dioxygenase as Revealed by QM/MM Simulations

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