Inhibitors of DNA polymerase β:: Activity and mechanism
Inhibitors of DNA polymerase β:: Activity and mechanism
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DOI：
10.1016/j.bmc.2008.02.071
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发表时间：
2008-04-15
影响因子：
3.5
通讯作者：
Hecht, Sidney M.
中科院分区：
文献类型：
--
作者：
Gao, Zhijie;Maloney, David J.;Hecht, Sidney M.
用生物测定法对苦参和栀子花提取物进行分离，分离出DNA聚合酶β (pol β)抑制剂齐墩果酸(1)、苦参苷(2)、白桦酸(3)和豆甾醇(4)。对这些pol b抑制剂的研究表明，其中3种抑制剂对DNA聚合酶β的裂解酶和聚合酶活性都有抑制作用，而豆甾醇仅对裂解酶活性有抑制作用。进一步的研究表明，这四种抑制剂对DNA-pol β二元复合物的影响有很大的不同，而DNA-pol β二元复合物被认为是裂解酶反应的必需中间体。结果发现，这些抑制剂在培养的A549细胞中增强了抗癌药物博来霉素的抑制作用，而不影响细胞中pol β的表达。计划外DNA合成试验的结果支持了DNA pol β抑制剂增强博来霉素细胞毒性是抑制DNA修复合成的结果。(C) 2008 Elsevier Ltd版权所有。
Bioassay-guided fractionation of extracts prepared from Couepia polyandra and Edgeworthia gardneri resulted in the isolation of the DNA polymerase beta (pol beta) inhibitors oleanolic acid (1), edgeworin (2), betulinic acid (3), and stigmasterol (4). Study of these pol b inhibitors revealed that three of them inhibited both the lyase and polymerase activities of DNA polymerase beta, while stigmasterol inhibited only the lyase activity. Further investigation indicated that the four inhibitors had substantially different effects on the DNA-pol beta binary complex that is believed to be an obligatory intermediate in the lyase reaction. It was found that the inhibitors potentiated the inhibitory action of the anticancer drug bleomycin in cultured A549 cells, without any influence on the expression of pol beta in the cells. The results of the unscheduled DNA synthesis assay support the thesis that the potentiation of bleomycin cytotoxicity by DNA pol beta inhibitors was a result of an inhibition of DNA repair synthesis. (C) 2008 Elsevier Ltd. All rights reserved.