文献类型：期刊文献

英文题名：Myricetin is a novel inhibitor of human inosine 5′-monophosphate dehydrogenase with anti-leukemia activity

作者：Pan, Huiling[1];Hu, Qian[1];Wang, Jingyuan[1];Liu, Zehui[1];Wu, Dang[1];Lu, Weiqiang[2,3];Huang, Jin[1]

机构：[1]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, 130 Mei Long Rd, Shanghai 200237, Peoples R China;[2]East China Normal Univ, Shanghai Key Lab Regulatory Biol, Inst Biomed Sci, 500 Dongchuan Rd, Shanghai 200241, Peoples R China;[3]East China Normal Univ, Sch Life Sci, 500 Dongchuan Rd, Shanghai 200241, Peoples R China

年份：2016

卷号：477

期号：4

起止页码：915

外文期刊名：BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000380969300061)】；

基金：We thank Professor Hedstorm Lizbeth (Department of Biology, Brandeis University, USA) for providing the cDNAs of hIMPDH1 and hIMPDH2. Financial support of this work provided by the National Natural Science Foundation of China (Grant 81402482), Shanghai Committee of Science and Technology (Grant 14ZR1411100 and 15431902000), China Postdoctoral Science Foundation Grant (2014M551361 and 2015T80415), and the Fundamental Research Funds for the Central Universities is gratefully acknowledged.

语种：英文

外文关键词：Inosine 5 '-monophosphate dehydrogenase; Myricetin; Leukemia; Guanine nucleotide; Anti-cancer

摘要：Human inosine 5'-monophosphate dehydrogenase (hIMPDH) is a rate-limiting enzyme in the de novo biosynthetic pathway of purine nucleotides, playing crucial roles in cellular proliferation, differentiation, and transformation. Dysregulation of hIMPDH expression and activity have been found in a variety of human cancers including leukemia. In this study, we found that myricetin, a naturally occurring phytochemical existed in berries, wine and tea, was a novel inhibitor of human type 1 and type 2 IMPDH (hIMPDH1/2) with IC50 values of 6.98 +/- 0.22 mu M and 4.10 +/- 0.14 mu M, respectively. Enzyme kinetic analysis using Lineweaver-Burk plot revealed that myricetin is a mix-type inhibitor for hIMPDH1/2. Differential scanning fluorimetry and molecular docking simulation data demonstrate that myricetin is capable of binding with hIMPDH1/2. Myricetin treatment exerts potent anti-proliferative and pro-apoptotic effects on K562 human leukemia cells in a dose-dependent manner. Importantly, cytotoxicity of myricetin on K562 cells were markedly attenuated by exogenous addition of guanosine, a salvage pathway of maintaining intracellular pool of guanine nucleotides. Taking together, these results indicate that natural product myricetin exhibits potent anti-leukemia activity by interfering with purine nucleotides biosynthetic pathway through the suppression of hIMPDH1/2 catalytic activity. (C) 2016 Elsevier Inc. All rights reserved.