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

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• 作者：Changyuan Lu ; Yu Lin ; Syun-Ru Yeh
• 刊名：Journal of the American Chemical Society
• 出版年：2009
• 出版时间：September 16, 2009
• 年：2009
• 卷：131
• 期：36
• 页码：12866-12867
• 全文大小：141K
• 年卷期：v.131,no.36(September 16, 2009)
• ISSN：1520-5126

文摘

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.