Substrate Stereo-specificity in Tryptophan dioxygenase and Indoleamine 2,3- dioxygenase

CAPECE, L.; ARRAR, M.; ROITBERG, A.E.; YEH, S.R.; MARTI, M.A.; ESTRIN, D.A.

PROTEINS: STRUCTURE, FUNCTION AND GENETICS

WILEY-LISS, DIV JOHN WILEY & SONS INC

Año: 2010 vol. 78 p. 2961 - 2972

0887-3585

The first and rate-limiting step of the kynurenine pathway, in which tryptophan (Trp) isconverted to N-formylkynurenine is catalyzed by two heme-containing proteins, Indoleamine2,3-dioxygenase (IDO) and Tryptophan 2,3-dioxygenase (TDO). In mammals, TDO is foundexclusively in liver tissue, IDO is found ubiquitously in all tissues. IDO has becomeincreasingly popular in pharmaceutical research as it was found to be involved in manyphysiological situations, including immune escape of cancer. More importantly, small-moleculeinhibitors of IDO are currently utilized in cancer therapy. One of the main concerns for thedesign 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/O2) and b) the substrate stereo-specificity in hIDO and TDO. Our results indicate that the differences in smallligand bound structures of IDO and TDO arise from slight differences in the structure of the bound substrate complex. The results also show that substrate stereo-specificity of TDO isachieved 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 presence 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-selectiveinhibitors.