Dixon Monica, Woodrick Jordan, Gupta Suhani, Karmahapatra Soumendra Krishna, Devito Stephen, Vasudevan Sona, Dakshanamurthy Sivanesan, Adhikari Sanjay, Yenugonda Venkata M, Roy Rabindra
Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, United States.
Department of Biochemistry, Georgetown University Medical School, Washington, DC 20057, United States.
Bioorg Med Chem. 2015 Mar 1;23(5):1102-11. doi: 10.1016/j.bmc.2014.12.067. Epub 2015 Jan 17.
Interest in the mechanisms of DNA repair pathways, including the base excision repair (BER) pathway specifically, has heightened since these pathways have been shown to modulate important aspects of human disease. Modulation of the expression or activity of a particular BER enzyme, N-methylpurine DNA glycosylase (MPG), has been demonstrated to play a role in carcinogenesis and resistance to chemotherapy as well as neurodegenerative diseases, which has intensified the focus on studying MPG-related mechanisms of repair. A specific small molecule inhibitor for MPG activity would be a valuable biochemical tool for understanding these repair mechanisms. By screening several small molecule chemical libraries, we identified a natural polyphenolic compound, morin hydrate, which inhibits MPG activity specifically (IC50=2.6μM). Detailed mechanism analysis showed that morin hydrate inhibited substrate DNA binding of MPG, and eventually the enzymatic activity of MPG. Computational docking studies with an x-ray derived MPG structure as well as comparison studies with other structurally-related flavonoids offer a rationale for the inhibitory activity of morin hydrate observed. The results of this study suggest that the morin hydrate could be an effective tool for studying MPG function and it is possible that morin hydrate and its derivatives could be utilized in future studies focused on the role of MPG in human disease.
自从DNA修复途径，特别是碱基切除修复（BER）途径被证明可调节人类疾病的重要方面以来，人们对这些途径的机制的兴趣日益浓厚。已证明，调节特定BER酶N-甲基嘌呤DNA糖基化酶（MPG）的表达或活性在致癌作用、化疗耐药性以及神经退行性疾病中发挥作用，这进一步强化了对研究MPG相关修复机制的关注。一种针对MPG活性的特异性小分子抑制剂将是理解这些修复机制的有价值的生化工具。通过筛选几个小分子化学文库，我们鉴定出一种天然多酚化合物——水合桑色素，它能特异性抑制MPG活性（IC50 = 2.6μM）。详细的机制分析表明，水合桑色素抑制MPG与底物DNA的结合，并最终抑制MPG的酶活性。利用X射线衍生的MPG结构进行的计算对接研究以及与其他结构相关黄酮类化合物的比较研究，为观察到的水合桑色素的抑制活性提供了理论依据。本研究结果表明，水合桑色素可能是研究MPG功能的有效工具，并且水合桑色素及其衍生物有可能用于未来关注MPG在人类疾病中作用的研究。
