...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Biochimica et Biophysica Acta. Protein Structure and Molecular Enzymology >Theoretical evidence of the existence of a diazafulvene intermediate in the reaction pathway of imidazoleglycerol phosphate dehydratase: design of a novel and potent heterocycle structure for the inhibitor on the basis of the electronic structure-act
【24h】

Theoretical evidence of the existence of a diazafulvene intermediate in the reaction pathway of imidazoleglycerol phosphate dehydratase: design of a novel and potent heterocycle structure for the inhibitor on the basis of the electronic structure-act

机译：咪唑甘油磷酸脱水酶反应途径中存在重氮富烯中间体的理论证据：基于电子结构作用设计抑制剂的新型有效杂环结构

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

The reaction mechanism of imidazoleglycerol phosphate dehydratase has not yet been clearly revealed. Structural comparison between inhibitors and the substrate IGP implicates that the reaction involves a diazafulvene intermediate. Here, we present evidence to support this hypothesis by investigating the electronic structure-enzyme inhibitory activity relationship on inhibitors with different heterocycles using 6-31G * * level theory of the ab initio molecular orbital method. The calculation results showed that potent inhibitors can be distinguished from weak ones by the atomic charge density and by the energy levels of the highest occupied lone-pair orbital on the nitrogen atoms in the heterocycles. Furthermore, very good correlations (r~2 = 0.8 - 0.9) were found between the charge density on the nitrogen atom and the inhibitory activity. It was also revealed that the diazafulvene is electronically similar to the potent inhibitors. Thus, these results strongly suggest the existence of the diazafulvene as an intermediate possessing tight-binding affinity to the enzyme. Based on the electronic structural similarity between the potent inhibitors and the proposed intermediate, a novel heterocycle was designed and predicted its inhibitory activity prior to the synthesis. Then, activity of synthesized inhibitors showed excellent agreement with this prediction. Hence, from the theoretical studies and experimental results, we conclude to obtain evidence of the hypothesis that the enzyme reaction proceeds via the diazafulvene intermediate.
机译：咪唑甘油磷酸脱水酶的反应机理尚未明确。抑制剂和底物IGP之间的结构比较表明该反应涉及二氮烯富烯中间体。在这里，我们通过使用从头算分子轨道方法的6-31G * *水平理论研究具有不同杂环的抑制剂的电子结构-酶抑制活性关系，来提供支持这一假设的证据。计算结果表明，强抑制剂可通过原子电荷密度和杂环中氮原子上最高占据的孤对轨道的能级与弱抑制剂区分开。此外，在氮原子上的电荷密度与抑制活性之间发现了很好的相关性（r〜2 = 0.8-0.9）。还揭示了二氮烯富烯在电子学上与有效抑制剂相似。因此，这些结果强烈暗示了二氮杂富烯的存在，该中间体具有对该酶的紧密结合亲和力。基于强效抑制剂与拟议的中间体之间的电子结构相似性，设计了新型杂环并预测了其在合成之前的抑制活性。然后，合成抑制剂的活性与该预测显示出极好的一致性。因此，从理论研究和实验结果中，我们得出结论，以得出有关酶反应通过二氮杂富烯中间体进行的假说的证据。

著录项

相似文献

  • 外文文献
  • 中文文献
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