Structural elucidation of a novel DNA-DNA cross-link of 1,2,3,4-diepoxybutane.
Structural elucidation of a novel DNA-DNA cross-link of 1,2,3,4-diepoxybutane.
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1,2,3,4-二环氧丁烷新型 DNA-DNA 交联的结构阐明。
DOI：
10.1021/tx060204e
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发表时间：
2007
影响因子：
4.1
通讯作者：
Goggin,Melissa
中科院分区：
文献类型：
--
作者：
Tretyakova,Natalia;Livshits,Alina;Park,Soobong;Bisht,Bimi;Goggin,Melissa
1，2，3，4-二环氧丁烷（DEB）引起的DNA-DNA交联被认为是其强效细胞毒性和遗传毒性作用的分子基础。DEB与DNA的反应首先产生N7-（2 ′-羟基-3 ′，4 ′-环氧丁-1 ′-基）-鸟嘌呤单加合物，然后它可以烷基化邻近的DNA碱基，形成双功能损伤。我们最近报道了DEB的四种区域异构鸟嘌呤-腺嘌呤加合物的结构，涉及鸟嘌呤的N7位置和腺嘌呤的N1、N3、N6和N7位置（Park，S.，等（2004）毒理学化学研究17，1638 - 1651）。在本工作中，DEB的一个新的双功能DNA损伤被鉴定为1-（次黄嘌呤-1-基）-4-（关-7-基）-2，3-丁二醇（N1 HX-N7 G-BD）。制备了N1 HX-N7 G-BD的真实标准品，并通过质子NMR、UV和质谱进行了结构表征。DEB处理的小牛胸腺DNA酸水解产物的HPLC-ESI-MS/MS分析显示，一个峰的保留时间、MS/MS碎片和UV光谱与N1 HX-N7 G-BD的真实标准品相同。我们提出N1 HX-N7 G-BD是由先前报道的1-（亚丁-1-基）-4-（关-7-基）-2，3-丁二醇水解脱氨基形成的。虽然N1 HX-N7 G-BD加合物在DEB处理的DNA中的丰度低于相应的鸟嘌呤-鸟嘌呤交联，但它们可能在AT和GC碱基对突变的诱导中起作用。
DNA−DNA cross-linking by 1,2,3,4-diepoxybutane (DEB) is considered the molecular basis for its potent cytotoxic and genotoxic effects. DEB reactions with DNA initially lead toN7-(2‘-hydroxy-3‘,4‘-epoxybut-1‘-yl)-guanine monoadducts, which can then alkylate neighboring DNA bases to form bifunctional lesions. We recently reported the structures of four regioisomeric guanine−adenine adducts of DEB involving the N7 position of guanine and the N1, N3, N6, and N7 positions of adenine (Park, S., et al. (2004)Chemical Research in Toxicology17, 1638−1651). In the present work, a novel bifunctional DNA lesion of DEB was identified as 1-(hypoxanth-1-yl)-4-(guan-7-yl)-2,3-butanediol (N1HX-N7G-BD). An authentic standard of N1HX-N7G-BD was prepared and structurally characterized by proton NMR, UV, and mass spectrometry. HPLC-ESI-MS/MS analyses of acid hydrolysates of DEB-treated calf thymus DNA revealed a peak that had the same retention time, MS/MS fragmentation, and UV spectrum as the authentic standard of N1HX-N7G-BD. We propose that N1HX-N7G-BD is formed by the hydrolytic deamination of previously reported 1-(aden-1-yl)-4-(guan-7-yl)-2,3-butanediol. Although N1HX-N7G-BD adducts are less abundant in DEB-treated DNA than the corresponding guanine−guanine cross-links, they may play a role in the induction of both AT and GC base pair mutations.