INSTITUTO DE QUIMICA, FISICA DE LOS MATERIALES, MEDIOAMBIENTE Y ENERGIA
Unidad Ejecutora - UE
Substrate Stereo-specificity in Tryptophan dioxygenase and Indoleamine 2,3- dioxygenase.
LUCIANA CAPECE; MERNOOSH ARRAR; ADRIÁN E. ROITBERG; SYUN-RU YEH; MARCELO A MARTI; DARIO A ESTRIN
PROTEINS: STRUCTURE, FUNCTION AND GENETICS
WILEY-LISS, DIV JOHN WILEY & SONS INC
Año: 2010 p. 2961 - 2961
The first and rate-limiting step of the kynurenine path-way, in which tryptophan (Trp) is converted to N-for-mylkynurenine is catalyzed by two heme-containingproteins, Indoleamine 2,3-dioxygenase (IDO), andTryptophan 2,3-dioxygenase (TDO). In mammals, TDOis found exclusively in liver tissue, IDO is found ubiq-uitously in all tissues. IDO has become increasinglypopular in pharmaceutical research as it was found tobe involved in many physiological situations, includingimmune escape of cancer. More importantly, small-mol-ecule inhibitors of IDO are currently utilized in cancertherapy. One of the main concerns for the design ofhuman IDO (hIDO) inhibitors is that they should beselective enough to avoid inhibition of TDO. In thiswork, we have used a combination of classical molecu-lar dynamics (MD) and hybrid quantum-classical (QM/MM) methodologies to establish the structural basisthat determine the differences in (a) the interactions ofTDO and IDO with small ligands (CO/O2) and (b) thesubstrate stereo-specificity in hIDO and TDO. Ourresults indicate that the differences in small ligandbound structures of IDO and TDO arise from slightdifferences in the structure of the bound substratecomplex. The results also show that substrate stereo-specificity of TDO is achieved by the perfect fit ofL-Trp, but not D-Trp, which exhibits weaker interac-tions with the protein matrix-. For hIDO, the presenceof multiple stable binding conformations for L/D-Trpreveal the presence of a large and dynamic active site.Taken together, our data allow determination of keyinteractions useful for the future design of more potenthIDO-selective inhibitors.