• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文学位 >The examination of hydrogen peroxide as a general signaling agent of dithiolethione cancer chemopreventives and its effects on human Keap1.
【24h】

The examination of hydrogen peroxide as a general signaling agent of dithiolethione cancer chemopreventives and its effects on human Keap1.

机译：过氧化氢作为二硫代lethione癌症化学预防剂的一般信号传导剂的检查及其对人Keap1的影响。

获取原文
获取原文并翻译 | 示例
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Dithiolethiones are a class of cancer chemopreventives which manifest some of their biological activity through the activation of transcription factor Nrf2, resulting in the stimulation of ARE dependant transcription of a large family of cytoprotective enzymes. In determining the mechanism by which these compounds activate Nrf2 it was observed that all dithiolethiones undergo reductive metabolism. These reductive metabolites can reduce molecular oxygen forming superoxide anion. Subsequent dismutation of superoxide anion results in the formation of hydrogen peroxide which has been shown to be a second messenger for enzyme induction of dithiolethiones. Oxidants such as hydrogen peroxide have been hypothesized to encumber Keap1, a negative regulator of Nrf2, thus enhancing Nrf2 activity. Low levels of hydrogen peroxide can react directly with Keap1 forming three Type 2 disulfides, Cys23-Cys38, Cys257-Cys297 and Cys319-Cys319, all of which lie in functional domains of Keap1. Higher levels of hydrogen peroxide which lead to a perturbation of the GSH/GSSG redox couple also cause multiple modifications to Keap1. Some of the modifications, Type 1 disulfides at Cys77, Cys297, Cys319, Cys368 and Cys434, and Type 2 disulfides involving Cys23-Cys38, Cys257-Cys297 and Cys319-Cys319, form in a physiologically relevant range of redox potentials, and again lie in functional domains of Keap1. Through mathematical modeling Type 1 disulfides Cys368 and Cys434 have been shown to alter the structure of the kelch domain, the Nrf2 binding domain, of Keap1. These modifications may cause the observed activation of Nrf2 and subsequent induction of cytoprotective enzymes, which give dithiolethiones their cancer chemopreventive characteristics.
机译：二硫代噻吩酮是一类癌症化学预防剂，其通过转录因子Nrf2的激活而表现出某些生物学活性，从而刺激了一大批细胞保护酶的ARE依赖性转录。在确定这些化合物激活Nrf2的机理时，观察到所有二硫代硫酮都经历还原代谢。这些还原性代谢物可以还原分子氧，形成超氧阴离子。随后超氧化物阴离子的歧化导致形成过氧化氢，该过氧化氢已被证明是用于酶诱导二硫代硫酮的第二信使。假设过氧化氢等氧化剂会阻碍Keap1（Nrf2的负调节剂），从而增强Nrf2的活性。少量的过氧化氢可直接与Keap1反应，形成三个2型二硫键，即Cys23-Cys38，Cys257-Cys297和Cys319-Cys319，它们均位于Keap1的功能域中。较高水平的过氧化氢会引起GSH / GSSG氧化还原对的干扰，也会引起Keap1的多种修饰。一些修饰，即在Cys77，Cys297，Cys319，Cys368和Cys434上的1型二硫键，以及涉及Cys23-Cys38，Cys257-Cys297和Cys319-Cys319的2型二硫键，在生理相关的氧化还原电位范围内形成，并再次位于Keap1的功能域。通过数学建模，已显示1型二硫键Cys368和Cys434会改变Keap1的海藻结构域（Nrf2结合结构域）的结构。这些修饰可能会导致观察到的Nrf2激活和随后的细胞保护酶诱导作用，从而赋予二硫代硫酮类药物化学预防癌症的特性。

著录项

  • 作者

    Holland, Ryan John.;

  • 作者单位

    University of Maryland, Baltimore County.;

  • 授予单位 University of Maryland, Baltimore County.;
  • 学科 Chemistry Biochemistry.;Chemistry Organic.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 182 p.
  • 总页数 182
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生物化学;有机化学;
  • 关键词

  • 入库时间 2022-08-17 11:38:28

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号