人类MAT2A在1.07 Å分辨率下的三酸盐水解机制
Agnidipta Ghosh1, Courtney N Niland1, Sean M Cahill1
1Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, United States.
Journal of the American Chemical Society
|October 20, 2021
概括
甲氨基转移酶2A (MAT2A) 使用过渡状态模仿物来揭示酸盐水解的机制. 这说明了MAT2A如何促进发育和癌症中的基本表观基因甲基化反应.
科学领域:
- 生物化学
- 酵素学
- 结构生物学
背景情况:
- 氨基基转移酶2A (MAT2A) 对于合成S-氨基-l-氨基 (AdoMet),一种通用甲基供体至关重要.
- 在细胞过程,发育和癌症中,AdoMet依赖的表观基因甲基化起着重要作用.
- 了解MAT2A的催化机制,特别是酸盐水解,是其功能的关键.
研究的目的:
- 通过人类MAT2A阐明酸盐水解的催化机制.
- 使用结构和光谱方法来描述水解反应的过渡状态.
- 提供有关酶在调节表观遗传修饰中的作用的见解.
主要方法:
- 过渡状态分析和MAT2A的运动研究.
- 用MgF3,AlF30和malonate复合的MAT2A的X射线结晶学
- 核磁共振 (NMR) 光谱以确认化物复合物的结合.
主要成果:
- 晶体结构显示MgF3和AlF30是离开基的稳定模仿物.
- 在过渡状态模型中观察到平面MgF3,模仿PO3离开组.
- 核磁共振检测证实了MgF3- 和AlF30作为基模仿物.
- 一种催化性氨酸残留物被确定为指导核友水攻击.
结论:
- 这项研究揭示了由MAT2A进行的松散,对称的过渡状态的催化机制.
- 结构和NMR数据提供了过渡状态的详细视图,有助于理解酶功能.
- 这些发现提高了我们对表观遗传调节和癌症潜在治疗点的理解.
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