Clinical aspects of indoleamine 2,3-dioxygenase (IDO)-initiated tryptophan metabolism: IDO is a target of drug discovery for various diseases

Abstract

Indoleamine 2,3-dioxygenase (IDO) catalyzes the first and rate-limiting step in the major metabolic pathway of tryptophan (Trp) in mammals. In healthy conditions, IDO is modestly expressed in many tissues but highly up-regulated locally or systemically by immune activation and inflammation. Considerable attention has been focused on IDO because of its detrimental effects in a variety of diseases. The activity of IDO plays a role in: 1) the cytokine (IFN-γ/IL-12) cascade inducing dangerous systemic Trp depletion that possibly results in a reduction of serotonin synthesis, 2) the escape of malignant tumors from immune surveillance by inducing immune tolerance through localized Trp depletion and production of immunosuppressive Trp metabolites, 3) neurodegenerative disorders such as Alzheimer`s disease via aberrant production of the neurotoxin, quinolinic acid, and 4) age-related cataract due to “Kynurenilation,” a novel post-translational modification of lens proteins with Trp-derived UV filters. Therefore IDO is an ideal pharmacological target for intervention in these diseases. The properties of currently available IDO inhibitors are also described.