Comparative Studies of Human Indoleamine 2,3-Dioxygenase (IDO) and Tryptophan Dioxygenase (TDO)

Abstract

The majority of our dietary Tryptophan (L-Trp) is oxidized to NAD via the the kynurenine pathway. The first and rate-limiting step of the pathway, the conversion of L-Try to N-formyl kynurenine, is catalyzed by two heme-based dioxygenases, tryptophan dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO). Although the two enzymes catalyze the same chemical reaction and exhibit high structural similarity, they perform distinct physiological functions: TDO is a hepatic enzyme that is linked to Trp homeostasis, while IDO is an ubiquitous enzyme that is involved in a variety of important immune related conditions, such as fetal tolerance and cancer immune escape. Recently, IDO has attracted a great deal of attention owing to its potential as a therapeutic target for cancer. Despite of intense reserach, the dioxygenase reaction mechanisms of IDO and TDO are poorly understood. Our recent spectroscopic and kinetic studies indicate that the two reactions follow the same ferryl-based two-step mechanism, challenging the general conception that the two atoms of dioxygen are inserted into the substrate simultaneoiusly. In this work, the structural differences between IDO and TDO are systematically evaluated. The implication of the data on the functional differences between the two enzymes will be discussed.