Inhibitory Substrate Binding Site of Human Indoleamine 2,3-Dioxygenase

摘要

Indoleamine 2,3-dioxygenase (IDO) is a nonhepatic intracellular heme-containing enzyme. It catalyzes the conversion of L-tryptophan (L-Trp) to N-formylkynurenine (NFK), the initial and rate-determining step of the kynurenine pathway, by inserting both atoms of dioxygen across the C_2=C_3 bond of the indole moiety of L-Trp. IDO was first discovered by Hayaishi et al. more than four decades ago. Since then, its structural and functional properties were extensively studied until the early 1990s. This field of research was invigorated recently due to the discoveries that IDO is linked to a variety of immune-related pathophysiological conditions and that IDO is a potential target for pharmacological intervention against cancer. Here we report evidence supporting the presence of an inhibitory substrate binding site (S_i site) in human IDO (hIDO), which is capable of binding substrates (L-Trp and 1-methy-L-tryptophan), an effector (3-indole ethanol), and an uncompetitive inhibitor (Mitomycin C). The structures of these molecules are illustrated in Scheme 1.