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

Luciana Capece, Ariel Lewis-Ballester, Dipanwita Batabyal, Natali Di Russo, Syun-Ru Yeh, Dario A. Estrin, Marcelo A. Marti

Research output: Contribution to journalArticle

41 Citations (Scopus)

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 hemebound 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 C 2=C 3 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.

Original languageEnglish (US)
Pages (from-to)811-823
Number of pages13
JournalJournal of Biological Inorganic Chemistry
Volume15
Issue number6
DOIs
StatePublished - Aug 2010

Fingerprint

Indoleamine-Pyrrole 2,3,-Dioxygenase
Dioxygenases
Tryptophan
Oxygen
Heme
Deprotonation
Histidine
Mammals
Epoxy Compounds
Substrates
Molecular Dynamics Simulation
Liver
Molecular dynamics
Proteins
Stabilization
Chemical activation
Enzymes
Serum

Keywords

  • 3-dioxygenase
  • Indoleamine 2
  • Molecular dynamics
  • Quantum mechanics/molecular mechanics
  • Tryptophan dioxygenase
  • Tryptophan dioxygenation

ASJC Scopus subject areas

  • Biochemistry
  • Inorganic Chemistry

Cite this

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. / Capece, Luciana; Lewis-Ballester, Ariel; Batabyal, Dipanwita; Di Russo, Natali; Yeh, Syun-Ru; Estrin, Dario A.; Marti, Marcelo A.

In: Journal of Biological Inorganic Chemistry, Vol. 15, No. 6, 08.2010, p. 811-823.

Research output: Contribution to journalArticle

Capece, Luciana ; Lewis-Ballester, Ariel ; Batabyal, Dipanwita ; Di Russo, Natali ; Yeh, Syun-Ru ; Estrin, Dario A. ; Marti, Marcelo A. / 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. In: Journal of Biological Inorganic Chemistry. 2010 ; Vol. 15, No. 6. pp. 811-823.
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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 hemebound 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 C 2=C 3 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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AU - Yeh, Syun-Ru

AU - Estrin, Dario A.

AU - Marti, Marcelo A.

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