...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Biochemistry >Mechanistic Studies on Transcriptional Coactivator Protein Arginine Methyltransferase 1
【24h】

Mechanistic Studies on Transcriptional Coactivator Protein Arginine Methyltransferase 1

机译：转录共激活蛋白精氨酸甲基转移酶1的机制研究。

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

Protein arginine methyltransferases (PRMTs) catalyze the transfer of methyl groups from S-adenosylmethionine (SAM) to the guanidinium group of arginine residues in a number of important cell signaling proteins. PRMT1 is the founding member of this family, and its activity appears to be dysregulated in heart disease and cancer. To begin to characterize the catalytic mechanism of this isozyme, we assessed the effects of mutating a number of highly conserved active site residues (i.e., Y39, R54, E100, E144, E153, M155, and H293), which are believed to play key roles in SAM recognition, substrate binding, and catalysis. The results of these studies, as well as pH-rate studies, and the determination of solvent isotope effects (SIEs) indicate that M155 plays a critical role in both SAM binding and the processivity of the reaction but is not responsible for the regiospecific formation of asymmetrically dimethylated arginine (ADMA). Additionally, mutagenesis studies on H293, combined with pH studies and the lack of a normal SIE, do not support a role for this residue as a general base. Furthermore, the lack of a normal SIE with either the wild type or catalytically impaired mutants suggests that general acid/base catalysis is not important for promoting methyl transfer. This result, combined with the fact that the E144A/E153A double mutant retains considerably more activity then the single mutants alone, suggests that the PRMT1-catalyzed reaction is primarily driven by bringing the substrate guanidinium into the proximity of the S-methyl group of SAM and that the prior deprotonation of the substrate guanidinium is not required for methyl transfer.
机译：蛋白质精氨酸甲基转移酶（PRMT）催化甲基从S-腺苷甲硫氨酸（SAM）转移到许多重要细胞信号蛋白中的精氨酸残基的胍基上。 PRMT1是该家族的创始成员，其活性在心脏病和癌症中似乎失调。为了开始表征这种同工酶的催化机制，我们评估了突变许多高度保守的活性位点残基（即Y39，R54，E100，E144，E153，M155和H293）的影响，这些作用被认为是关键在SAM识别，底物结合和催化中的作用。这些研究以及pH值研究的结果以及溶剂同位素效应（SIEs）的确定表明，M155在SAM结合和反应的过程中均起着关键作用，但不负责甲基的区域特异性形成。不对称二甲基化精氨酸（ADMA）。此外，对H293的诱变研究与pH研究以及缺乏正常SIE的结合，不支持该残基作为一般碱基的作用。此外，缺乏野生型或催化受损突变体的正常SIE，表明一般的酸/碱催化对于促进甲基转移并不重要。这一结果，加上E144A / E153A双突变体比单独的单个突变体保留更多活性的事实，表明PRMT1催化的反应主要是通过将底物胍带到SAM的S-甲基附近来驱动的并且甲基转移不需要底物胍的预先去质子化。

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