催化机制和产品特异性 基素甲基转移酶SET7/9的催化机制和产品特异性:一个ab initio QM/MM-FE研究与多个初始结构
1Department of Chemistry, New York University, New York 10003, USA.
Journal of the American Chemical Society
|January 26, 2006
概括
素基因甲基化调节了基因活动. 酶SET7/9通过S(N) 2反应催化这种反应,通过防止二甲基化接近攻击形状来实现特异性.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 计算化学计算化学
背景情况:
- 希斯 lysine甲基化是一个关键的表观遗传机制,调节色素结构和基因表达.
- 了解希斯甲基转移酶的反应机制和特异性对于破译基因调节至关重要.
研究的目的:
- 为了研究素甲基转移酶SET7/9.9的反应机制和产品特异性.
- 用计算方法提供对催化过程的理论理解.
主要方法:
- 一开始的量子力学/分子力学自由能量 (QM/MM-FE) 计算.
- 用分子动力学模拟来研究SET7/9酶.
- 免费能源障碍是在MP2 ((6-31+G) QM/MM级别计算的.
主要成果:
- 由SET7/9催化的甲基转移反应遵循一个线性S(N) 2核替代机制.
- 确定了一个过渡状态,70%具有离散性质.
- 计算的自由能量障碍 (20.4 +/- 1.1 kcal/mol) 与实验估计 (20.9 kcal/mol) 非常接近.
- 屏障波动与核友攻击距离和角度相关.
- SET7/9的单甲基转移酶特异性源于二甲基化中被破坏的近攻击形态.
结论:
- 该研究阐明了SET7/9的详细反应机制,证实了其S(N) 2性质.
- 计算发现支持了关于酶的催化屏障的实验观测.
- 作为一种单甲基转移酶,SET7/9的产品特异性的机制通过结构控制来解释.
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