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Oxidative damage to guanine in DNA caused by reactive oxygen species.

机译:活性氧对DNA中鸟嘌呤的氧化损伤。

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摘要

Oxidative damage to DNA, a factor in cancer, mutation, and aging, is attributed to reactive oxygen species (ROS). The less well characterized ROS, organic peroxyl radicals and peracid are present during lipid peroxidation and also produced by peroxidases from organic hydroperoxides. Peracetic acid is also formed in mitochondria. Guanine (Gua) is the nucleobases most susceptible to oxidation due to its lowest electron potential. The study described here focuses on Gua oxidation by epoxidizing reagents including peroxyl radicals and organic peracids. Dimethyldioxirane (DMDO), peracetic acid and m-chloroperbenzoic acid selectively oxidizes the guanine moiety of dGuo, dGMP and dGTP to 5-carboxamido-5-formamido-2-iminohydantoin (2-Ih). Structures were established on mass spectrometry and NMR studies. Labeling studies support a mechanism involving initial epoxidation of the guanine 4-5 bond and contraction of the pyrimidine ring by a 1,2-migration of the guanine carbonyl C6 to form a transient dehydrodeoxyspiroiminodihydantoin followed by hydrolytic ring opening of the imidazolone ring. The 2-Ih is shown to be a major transformation in the oxidation of the single-stranded DNA 5-mer d(TTGTT) and the 5-base pair duplex d[( TTGTT)˙(AACAA)]. 2-Ih has not previously been reported as an oxidative lesion in DNA. Consistent with the proposed mechanism, no 8-oxoguanine was detected as a product of the oxidations of the oligonucleotides or monomeric species mediated by the monooxygen donors. The 2-Ih base thus appears to be a pathway-specific lesion and holds promise as a potential biomarker.;N9-(beta-D-2-deoxyribofuranosyl)-N 2,3-ethenoguanine is a highly mutagenic DNA adduct arising from exposure to known occupational and environmental carcinogens and lipid peroxidation products in vivo. Chemical synthesis has proven to be challenging because of the reported lability of the glycosidic bond under conditions generally applicable to chemical synthesis. Enzymatic and chemical glycosylations of N2,3-ethenoguanine were attempted as approaches to obtain this nucleoside under mild conditions. Both glycosylations led to nucleosides with ribosylation at positions corresponding to N7- and N2 of the Gua framework. A minor product of the enzymatic ribosylation has tentatively been assigned as the alpha-anomer of the desired N3 riboside, and rigorous confirmation of this structure would demonstrate an unusual stereochemistry for the trans ribosylation.
机译:DNA的氧化损伤是癌症,突变和衰老的一个因素,归因于活性氧(ROS)。脂质过氧化过程中存在表征欠佳的ROS,有机过氧自由基和过酸,并且过氧化酶也来自有机氢过氧化物。过氧乙酸也在线粒体中形成。鸟嘌呤(Gua)由于具有最低的电子势能,因此最容易被氧化。这里描述的研究集中在通过环氧化试剂(包括过氧自由基和有机过酸)的Gua氧化上。二甲基二环氧乙烷(DMDO),过氧乙酸和间氯过苯甲酸将dGuo,dGMP和dGTP的鸟嘌呤部分选择性氧化为5-甲酰胺基-5-甲酰胺基-2-亚氨基乙内酰脲(2-Ih)。通过质谱和NMR研究确定结构。标记研究支持一种机制,涉及鸟嘌呤4-5键的初始环氧化和嘧啶环的收缩,这是通过鸟嘌呤羰基C6的1,2-迁移形成瞬态脱氢脱氧螺亚胺二乙内酰脲,然后水解咪唑啉酮环的开环。显示2-Ih是单链DNA 5聚体d(TTGTT)和5碱基对双链体d [(TTGAT)·(AACAA)]的氧化中的主要转化。以前尚未报道2-Ih是DNA中的氧化损伤。与提出的机制一致,没有检测到8-氧鸟嘌呤是由单氧供体介导的寡核苷酸或单体物种氧化的产物。因此2-Ih碱基似乎是一种通路特异性病变,并有望作为潜在的生物标记物。; N9-(β-D-2-deoxyribofuranosyl)-N 2,3-ethenoguanine是一种高度致突变的DNA加合物,其暴露导致体内已知的职业和环境致癌物及脂质过氧化产物。由于据报道在通常适用于化学合成的条件下糖苷键的不稳定性,化学合成已具有挑战性。尝试将N2,3-乙鸟嘌呤的酶和化学糖基化作为在温和条件下获得该核苷的方法。两种糖基化导致在对应于Gua框架的N7-和N2的位置具有核糖基化的核苷。暂时将酶促核糖基化的次要产物指定为所需N3核糖苷的α-端基异构体,并且对该结构的严格确认将证明反式核糖基化具有不同寻常的立体化学。

著录项

  • 作者

    Ye, Wenjie.;

  • 作者单位

    The University of North Carolina at Chapel Hill.;

  • 授予单位 The University of North Carolina at Chapel Hill.;
  • 学科 Health Sciences Toxicology.;Environmental Sciences.;Chemistry Biochemistry.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 173 p.
  • 总页数 173
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 毒物学(毒理学);生物化学;环境科学基础理论;
  • 关键词

  • 入库时间 2022-08-17 11:37:37

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