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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

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Abstract

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 heme-bound 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 C2=C3 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.

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Abbreviations

Cf1 :

Conformation 1

Cf2 :

Conformation 1

DFT:

Density functional theory

hIDO:

Human indoleamine 2,3-dioxygenase

hTDO:

Human tryptophan dioxygenase

IDO:

Indoleamine 2,3-dioxygenase

MD:

Molecular dynamics

MM:

Molecular mechanical

NFK:

N-Formylkynurenine

PDB:

Protein Data Bank

PBE:

Generalized gradient approximation functional proposed by Perdew, Burke, and Ernzerhof

QM:

Quantum mechanical

TDO:

Tryptophan dioxygenase

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Acknowledgments

This work was partially supported by grants from Universidad de Buenos Aires 08-X625 to M.A.M. and 08-X074 to D.A.E., ANPCYT 07-1650 to M.A.M. and 06-25667 to D.A.E., Conicet PIP 01207 and a Guggenheim Foundation grant awarded to D.A.E, and NIH Molecular Biophysics Training Grant GM008572 to A.L.-B. D.A.E., and M.A.M. are members of CONICET, L.C. holds a CONICET Ph.D. fellowship. Computer power was provided by the Centro de Computacion de Alto Rendimiento (CECAR) at Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires. We thank Pau Arroyo Mañez for useful discussions.

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Authors and Affiliations

  1. Departamento de Química Inorgánica, Analítica y Química Física/INQUIMAE-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón 2, C1428EHA, Buenos Aires, Argentina

    Luciana Capece, Natali Di Russo, Dario A. Estrin & Marcelo A. Marti

  2. Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón 2, C1428EHA, Buenos Aires, Argentina

    Marcelo A. Marti

  3. Department of Physiology and Biophysics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, New York, NY, 10461, USA

    Ariel Lewis-Ballester, Dipanwita Batabyal & Syun-Ru Yeh

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  1. Luciana Capece
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  2. Ariel Lewis-Ballester
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  7. Marcelo A. Marti
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Correspondence to Syun-Ru Yeh or Marcelo A. Marti.

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Capece, L., Lewis-Ballester, A., Batabyal, D. et al. 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. J Biol Inorg Chem 15, 811–823 (2010). https://doi.org/10.1007/s00775-010-0646-x

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