Major groove orientation of the (2S)-N(6)-(2-hydroxy-3-buten-1-yl)-2'-deoxyadenosine DNA adduct induced by 1,2-epoxy-3-butene.
Major groove orientation of the (2S)-N(6)-(2-hydroxy-3-buten-1-yl)-2'-deoxyadenosine DNA adduct induced by 1,2-epoxy-3-butene.
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1,2-环氧-3-丁烯诱导的 (2S)-N(6)-(2-羟基-3-丁烯-1-基)-2'-脱氧腺苷 DNA 加合物的主沟方向。
DOI：
10.1021/tx500159w
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发表时间：
2014-10-20
影响因子：
4.1
通讯作者：
Stone, Michael P.
中科院分区：
文献类型：
--
作者：
Kowal, Ewa A.;Wickramaratne, Susith;Kotapati, Srikanth;Turo, Michael;Tretyakova, Natalia;Stone, Michael P.
1，3-丁二醇（BD）是一种环境和职业毒物，被列为人类致癌物。它被细胞色素P450单加氧酶氧化成1，2-环氧-3-丁烯（EB），使DNA烷基化。BD暴露导致A：T碱基对的大量突变，即使鸟嘌呤的烷基化更普遍，这表明BD的一种或多种腺嘌呤加合物在BD介导的遗传毒性中发挥作用。然而，对腺嘌呤的BD介导的遗传毒性的病因学仍然知之甚少。EB将腺嘌呤的N6环外氮烷基化形成N6-（羟基-3-丁烯-1-基）-2′-dA（（2S）-N6-HB-dA）加合物（（），−）。通过NMR光谱法，在含有人N-ras原癌基因密码子61（下划线）的5′-d（C1 G2 G3 A4 C5 Y 6A 7 G8 A9 A10 G11）-3′：5′-d（C12 T13 T14 C15 T16 T17 G18 T19 C20 C21 G22）-3′双链体[Y =（2S）-N6-HB-dA]中确定了（2S）-N6-HB-dA加合物的结构。（2S）-N6-HB-dA加合物位于大沟中，使得丁二烯部分在3′方向上取向。在Cα碳上，修饰的核碱基Y 6的亚甲基质子朝向5′方向，这将Cβ碳置于3′方向。Cβ羟基朝向溶剂，Cγ和Cδ也是如此。Cβ羟基不与T16 O 4或T17 O 4形成氢键。（2S）-N6-HB-dA核苷保留了糖基键的反构象，修饰后的碱基保留了与互补碱基的Watson-Crick碱基配对（T17）。加合物干扰了碱基对C5：G18、Y 6：T17和A7：T16的堆积相互作用，使得Y 6碱基不与其5′邻居C5堆积，但与其3′邻居A7堆积。互补的胸腺嘧啶T17与5′和3′相邻的T16和G18堆叠良好。（2S）-N6-HB-dA的存在导致双链体的Tm降低5 °C，这归因于在大沟中不太有利的堆叠相互作用和加合物调节。
1,3-Butadiene (BD) is an environmental and occupational toxicant classified as a human carcinogen. It is oxidized by cytochrome P450 monooxygenases to 1,2-epoxy-3-butene (EB), which alkylates DNA. BD exposures lead to large numbers of mutations at A:T base pairs even though alkylation of guanines is more prevalent, suggesting that one or more adenine adducts of BD play a role in BD-mediated genotoxicity. However, the etiology of BD-mediated genotoxicity at adenine remains poorly understood. EB alkylates the N6 exocyclic nitrogen of adenine to form N6-(hydroxy-3-buten-1-yl)-2′-dA ((2S)-N6-HB-dA) adducts ( () , −). The structure of the (2S)-N6-HB-dA adduct has been determined in the 5′-d(C1G2G3A4C5Y6A7G8A9A10G11)-3′:5′-d(C12T13T14C15T16T17G18T19 C20C21G22)-3′ duplex [Y = (2S)-N6-HB-dA] containing codon 61 (underlined) of the human N-ras protooncogene, from NMR spectroscopy. The (2S)-N6-HB-dA adduct was positioned in the major groove, such that the butadiene moiety was oriented in the 3′ direction. At the Cα carbon, the methylene protons of the modified nucleobase Y6 faced the 5′ direction, which placed the Cβ carbon in the 3′ direction. The Cβ hydroxyl group faced toward the solvent, as did carbons Cγ and Cδ. The Cβ hydroxyl group did not form hydrogen bonds with either T16O4 or T17O4. The (2S)-N6-HB-dA nucleoside maintained the anti conformation about the glycosyl bond, and the modified base retained Watson–Crick base pairing with the complementary base (T17). The adduct perturbed stacking interactions at base pairs C5:G18, Y6:T17, and A7:T16 such that the Y6 base did not stack with its 5′ neighbor C5, but it did with its 3′ neighbor A7. The complementary thymine T17 stacked well with both 5′ and 3′ neighbors T16 and G18. The presence of the (2S)-N6-HB-dA resulted in a 5 °C reduction in the Tm of the duplex, which is attributed to less favorable stacking interactions and adduct accommodation in the major groove.
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影响因子：
14.9
作者：
Cavaluzzi, MJ;Borer, PN
通讯作者：
Borer, PN
影响因子：
4.1
作者：
FENG, BB;STONE, MP
通讯作者：
STONE, MP
影响因子：
4.7
作者：
COCHRANE, JE;SKOPEK, TR
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影响因子：
4.5
作者：
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影响因子：
4.7
作者：
COCHRANE, JE;SKOPEK, TR
通讯作者：
SKOPEK, TR