Inhibitory substrate binding site of human indoleamine 2,3-dioxygenase.
Human indoleamine 2,3-dioxygenase (hIDO) is an intracellular heme-containing enzyme, which catalyzes the initial and rate-determining step of L-tryptophan (L-Trp) metabolism via the kynurenine pathway. Due to its immunosuppressive function, hIDO has been recognized as an important drug target for cancer. Here we report evidence supporting the presence of an inhibitory substrate binding site (S(i)) in hIDO that is capable of binding molecules with a wide variety of structures, including substrates (L-Trp and 1-methyl-L-tryptophan), an effector (3-indole ethanol), and an uncompetitive inhibitor (Mitomycin C). The data offer useful guidelines for future development of more potent hIDO inhibitors; they also call for the re-evaluation of the action mechanism of Mitomycin C (MtoC), a widely used antitumor chemotherapeutic agent.
Lu
Changyuan
C
Department of Physiology and Biophysics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
Lin
Yu
Y
Yeh
Syun-Ru
SR
D001665:Binding Sites; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000737:chemistry / Q000378:metabolism*; D007211:Indoles / Q000737:chemistry / Q000378:metabolism; D016685:Mitomycin / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D011485:Protein Binding; D013379:Substrate Specificity; D014364:Tryptophan / Q000031:analogs & derivatives / Q000378:metabolism; D000438:Alcohols
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007211:Indoles; D016685:Mitomycin; D014364:Tryptophan; C005949:tryptophol; D000438:Alcohols