人吲哚胺 2,3-双加氧酶的抑制性底物结合位点。
Inhibitory substrate binding site of human indoleamine 2,3-dioxygenase.
机构信息
Department of Physiology and Biophysics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
出版信息
J Am Chem Soc. 2009 Sep 16;131(36):12866-7. doi: 10.1021/ja9029768.
Abstract
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.
摘要
人吲哚胺 2,3-双加氧酶（hIDO）是一种细胞内血红素酶，通过犬尿氨酸途径催化 L-色氨酸（L-Trp）代谢的初始和限速步骤。由于其免疫抑制功能，hIDO 已被认为是癌症的一个重要药物靶点。在这里，我们报告了支持 hIDO 中存在抑制性底物结合位点（S(i)）的证据，该位点能够结合具有各种结构的分子，包括底物（L-Trp 和 1-甲基-L-色氨酸）、效应物（3-吲哚乙醇）和非竞争性抑制剂（丝裂霉素 C）。这些数据为进一步开发更有效的 hIDO 抑制剂提供了有用的指导；它们还呼吁重新评估丝裂霉素 C（MtoC）的作用机制，MtoC 是一种广泛使用的抗肿瘤化疗药物。
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