...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Antimicrobial agents and chemotherapy. >Pre-steady-state kinetic analysis of the incorporation of anti-HIV nucleotide analogs catalyzed by human X- and Y-family DNA polymerases.
【24h】

Pre-steady-state kinetic analysis of the incorporation of anti-HIV nucleotide analogs catalyzed by human X- and Y-family DNA polymerases.

机译：对人X和Y家族DNA聚合酶催化的抗HIV核苷酸类似物掺入的稳态前动力学分析。

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

Nucleoside reverse transcriptase inhibitors (NRTIs) are an important class of antiviral drugs used to manage infections by human immunodeficiency virus, which causes AIDS. Unfortunately, these drugs cause unwanted side effects, and the molecular basis of NRTI toxicity is not fully understood. Putative routes of NRTI toxicity include the inhibition of human nuclear and mitochondrial DNA polymerases. A strong correlation between mitochondrial toxicity and NRTI incorporation catalyzed by human mitochondrial DNA polymerase has been established both in vitro and in vivo. However, it remains to be determined whether NRTIs are substrates for the recently discovered human X- and Y-family DNA polymerases, which participate in DNA repair and DNA lesion bypass in vivo. Using pre-steady-state kinetic techniques, we measured the substrate specificity constants for human DNA polymerases beta, lambda, eta, iota, kappa, and Rev1 incorporating the active, 5'-phosphorylated forms of tenofovir, lamivudine, emtricitabine, and zidovudine. For the six enzymes, all of the drug analogs were incorporated less efficiently (40- to >110,000-fold) than the corresponding natural nucleotides, usually due to a weaker binding affinity and a slower rate of incorporation for the incoming nucleotide analog. In general, the 5'-triphosphate forms of lamivudine and zidovudine were better substrates than emtricitabine and tenofovir for the six human enzymes, although the substrate specificity profile depended on the DNA polymerase. Our kinetic results suggest NRTI insertion catalyzed by human X- and Y-family DNA polymerases is a potential mechanism of NRTI drug toxicity, and we have established a structure-function relationship for designing improved NRTIs.
机译：核苷类逆转录酶抑制剂（NRTIs）是一类重要的抗病毒药物，用于控制人类免疫缺陷病毒（AIDS）的感染。不幸的是，这些药物会引起不良的副作用，并且尚未完全了解NRTI毒性的分子基础。 NRTI毒性的推定途径包括抑制人类核和线粒体DNA聚合酶。线粒体毒性与人线粒体DNA聚合酶催化的NRTI掺入之间存在很强的相关性。然而，仍有待确定NRTI是否是最近发现的人类X和Y家族DNA聚合酶的底物，该酶参与体内DNA修复和DNA损伤旁路。使用稳态前动力学技术，我们测量了人类DNA聚合酶β，lambda，eta，iota，kappa和Rev1的底物特异性常数，该酶结合了替诺福韦，拉米夫定，恩曲他滨和齐多夫定的活性5'-磷酸化形式。对于这六种酶，所有药物类似物的掺入效率均比相应的天然核苷酸低（40-> 110,000倍），这通常是由于较弱的结合亲和力和较慢的引入核苷酸类似物的掺入速率所致。通常，拉米夫定和齐多夫定的5'-三磷酸形式是优于恩曲他滨和替诺福韦的6种人类酶的底物，尽管底物特异性谱取决于DNA聚合酶。我们的动力学结果表明，由人X和Y家族DNA聚合酶催化的NRTI插入是NRTI药物毒性的潜在机制，并且我们已经建立了结构-功能关系，用于设计改良的NRTI。

著录项

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