...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Biochemistry >Distinct binding of cholesterol and 5-cholestane-3 alpha,7 alpha,12 alpha-triol to cytochrome P450 27A1: Evidence from modeling and site-directed mutagenesis studies
【24h】

Distinct binding of cholesterol and 5-cholestane-3 alpha,7 alpha,12 alpha-triol to cytochrome P450 27A1: Evidence from modeling and site-directed mutagenesis studies

机译：胆固醇和5-胆甾烷3α，7α，12α-三醇与细胞色素P450 27A1的独特结合：来自建模和定点诱变研究的证据

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

Cytochrome P450 27A1 (P450 27A1 or CYP27A1) is an important enzyme that participates in different pathways of cholesterol degradation as well as in the activation of vitamin D-3. Several approaches were utilized to investigate how two physiological substrates, cholesterol and 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol, interact with CYP27A1. The enzyme active site was first probed spectrally by assessing binding of the two substrates and five substrate analogues followed by computer modeling and site-directed mutagenesis. The computer models suggest that the spatial positions and orientations of cholesterol and 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol are different in the enzyme active site. As a result, some of the active site residues interact with both substrates, although they are situated differently relative to each steroid, and some residues bind only one substrate. Mutation of the overlapping substrate-contact residues (W 100, H103, T110, M301C, V367, I481, and V482) affected CYP27A1 binding and enzyme activity in a substrate-dependent manner and allowed identification of several important side chains. T110 is proposed to interact with the 12 alpha-hydroxyl of 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol, whereas V367 seems to be crucial for correct positioning of the cholesterol C26 methyl group and for regioselective hydroxylation of this substrate. Distinct binding of the CYP27A1 substrates may provide insight into why phenotypic manifestations of cerebrotendinous xanthomatosis, a disease associated with CYP27A1 deficiency, are so diverse.
机译：细胞色素P450 27A1（P450 27A1或CYP27A1）是一种重要的酶，它参与胆固醇降解的不同途径以及维生素D-3的活化。几种方法被用来研究两种生理底物胆固醇和5β-胆甾烷3α，7α，12α-三醇如何与CYP27A1相互作用。首先通过评估两个底物和五个底物类似物的结合进行光谱探测，然后通过计算机建模和定点诱变。计算机模型表明胆固醇和5β-胆甾烷3α，7α，12α-三醇的空间位置和方向在酶活性位点上是不同的。结果，一些活性位点残基与两种底物相互作用，尽管它们相对于每种类固醇的位置不同，并且一些残基仅结合一种底物。重叠的底物接触残基（W 100，H103，T110，M301C，V367，I481和V482）的突变以底物依赖性方式影响CYP27A1的结合和酶活性，并允许鉴定一些重要的侧链。 T110被提议与5个β-胆甾烷3α，7α，12α-三醇的12α-羟基相互作用，而V367对于胆固醇C26甲基的正确定位以及该底物的区域选择性羟基化似乎至关重要。 CYP27A1底物的不同结合可能提供洞察力，说明为什么与CYP27A1缺乏症有关的脑性黄原体病的表型表现如此多样。

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