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

Luciana Capece, Mehrnoosh Arrar, Adrian E. Roitberg, Syun-Ru Yeh, Marcelo A. Marti, Dario A. Estrin

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

The first and rate-limiting step of the kynurenine pathway, in which tryptophan (Trp) is converted to N-formylkynurenine is catalyzed by two heme-containing proteins, Indoleamine 2,3-dioxygenase (IDO), and Tryptophan 2,3-dioxygenase (TDO). In mammals, TDO is found exclusively in liver tissue, IDO is found ubiquitously in all tissues. IDO has become increasingly popular in pharmaceutical research as it was found to be involved in many physiological situations, including immune escape of cancer. More importantly, small-molecule inhibitors of IDO are currently utilized in cancer therapy. One of the main concerns for the design of human IDO (hIDO) inhibitors is that they should be selective enough to avoid inhibition of TDO. In this work, we have used a combination of classical molecular dynamics (MD) and hybrid quantum-classical (QM/MM) methodologies to establish the structural basis that determine the differences in (a) the interactions of TDO and IDO with small ligands (CO/O 2) and (b) the substrate stereo-specificity in hIDO and TDO. Our results indicate that the differences in small ligand bound structures of IDO and TDO arise from slight differences in the structure of the bound substrate complex. The results also show that substrate stereospecificity of TDO is achieved by the perfect fit of L-Trp, but not D-Trp, which exhibits weaker interactions with the protein matrix. For hIDO, the presence of multiple stable binding conformations for L/D-Trp reveal the existence of a large and dynamic active site. Taken together, our data allow determination of key interactions useful for the future design of more potent hIDO-selective inhibitors.

Original languageEnglish (US)
Pages (from-to)2961-2972
Number of pages12
JournalProteins: Structure, Function and Bioinformatics
Volume78
Issue number14
DOIs
StatePublished - Nov 1 2010

Fingerprint

Tryptophan Oxygenase
Indoleamine-Pyrrole 2,3,-Dioxygenase
Dioxygenases
Substrate Specificity
Tryptophan
Substrates
Tissue
Ligands
Kynurenine
Mammals
Molecular Dynamics Simulation
Carbon Monoxide
Heme
Liver
Conformations
Molecular dynamics
Catalytic Domain
Neoplasms
Proteins
Molecules

Keywords

  • Affinity
  • CO
  • Dioxygenase
  • IDO
  • Inhibitors
  • Molecular dynamics
  • Oxygen
  • Structure
  • TDO

ASJC Scopus subject areas

  • Biochemistry
  • Structural Biology
  • Molecular Biology

Cite this

Substrate stereo-specificity in tryptophan dioxygenase and indoleamine 2,3-dioxygenase. / Capece, Luciana; Arrar, Mehrnoosh; Roitberg, Adrian E.; Yeh, Syun-Ru; Marti, Marcelo A.; Estrin, Dario A.

In: Proteins: Structure, Function and Bioinformatics, Vol. 78, No. 14, 01.11.2010, p. 2961-2972.

Research output: Contribution to journalArticle

Capece, Luciana ; Arrar, Mehrnoosh ; Roitberg, Adrian E. ; Yeh, Syun-Ru ; Marti, Marcelo A. ; Estrin, Dario A. / Substrate stereo-specificity in tryptophan dioxygenase and indoleamine 2,3-dioxygenase. In: Proteins: Structure, Function and Bioinformatics. 2010 ; Vol. 78, No. 14. pp. 2961-2972.
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AU - Yeh, Syun-Ru

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AU - Estrin, Dario A.

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AB - The first and rate-limiting step of the kynurenine pathway, in which tryptophan (Trp) is converted to N-formylkynurenine is catalyzed by two heme-containing proteins, Indoleamine 2,3-dioxygenase (IDO), and Tryptophan 2,3-dioxygenase (TDO). In mammals, TDO is found exclusively in liver tissue, IDO is found ubiquitously in all tissues. IDO has become increasingly popular in pharmaceutical research as it was found to be involved in many physiological situations, including immune escape of cancer. More importantly, small-molecule inhibitors of IDO are currently utilized in cancer therapy. One of the main concerns for the design of human IDO (hIDO) inhibitors is that they should be selective enough to avoid inhibition of TDO. In this work, we have used a combination of classical molecular dynamics (MD) and hybrid quantum-classical (QM/MM) methodologies to establish the structural basis that determine the differences in (a) the interactions of TDO and IDO with small ligands (CO/O 2) and (b) the substrate stereo-specificity in hIDO and TDO. Our results indicate that the differences in small ligand bound structures of IDO and TDO arise from slight differences in the structure of the bound substrate complex. The results also show that substrate stereospecificity of TDO is achieved by the perfect fit of L-Trp, but not D-Trp, which exhibits weaker interactions with the protein matrix. For hIDO, the presence of multiple stable binding conformations for L/D-Trp reveal the existence of a large and dynamic active site. Taken together, our data allow determination of key interactions useful for the future design of more potent hIDO-selective inhibitors.

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