Myricetin is a novel inhibitor of human inosine 5 '-monophosphate dehydrogenase with anti-leukemia activity
Myricetin is a novel inhibitor of human inosine 5 '-monophosphate dehydrogenase with anti-leukemia activity
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DOI：
10.1016/j.bbrc.2016.06.158
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发表时间：
2016
影响因子：
3.1
通讯作者：
Huang Jin
中科院分区：
文献类型：
--
作者：
Pan Huiling;Hu Qian;Wang Jingyuan;Liu Zehui;Wu Dang;Lu Weiqiang;Huang Jin
Human inosine 5′-monophosphate dehydrogenase (hIMPDH) is a rate-limiting enzyme in the de novobiosynthetic pathway of purine nucleotides, playing crucial roles in cellular proliferation, differentiation, and transformation. Dysregulation ofhIMPDH 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 IC50values of 6.98 ± 0.22 μM and 4.10 ± 0.14 μM, respectively. Enzyme kinetic analysis using Lineweaver-Burk plot revealed that myricetin is a mix-type inhibitor forhIMPDH1/2. Differential scanning fluorimetry and molecular docking simulation data demonstrate that myricetin is capable of binding withhIMPDH1/2. 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 ofhIMPDH1/2 catalytic activity.
