人类5'-甲基氨酸酸化酶的过渡状态结构
Vipender Singh1, Vern L Schramm
1Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Journal of the American Chemical Society
|November 9, 2006
概括
这项研究使用了动态同位素效应和计算机建模来揭示人类5'-甲基氨酸酸化酶 (MTAP) 的过渡状态. 结果表明S(N) 1过渡状态较晚,含有显著的酸核参与.
科学领域:
- 生物化学 生物化学
- 酶动力学 酶动力学
- 计算化学是一种计算化学.
背景情况:
- 人类5-甲基氨酸酸化酶 (MTAP) 是 purin代谢中的关键酶.
- 了解MTAP的催化机制和过渡状态对于药物开发至关重要.
研究的目的:
- 用动态同位素效应 (KIEs) 和密度函数理论 (DFT) 建模阐明人类MTAP的过渡状态结构.
- 确定反应机制并确定过渡状态的关键相互作用.
主要方法:
- 在由MTAP催化的化过程中测量各种同位素标记的5-甲基氨酸 (MTA) 基质的KIEs.
- 为获得内在的KIEs,对KIEs进行修正,以对催化物的期货承诺进行修正.
- 使用DFT进行计算建模,以近似过渡状态,并与实验KIEs进行比较.
主要成果:
- 主要的内在KIEs (1' - 14C和9 - 15N) 暗示了一个解离性的S-N1过渡状态,在异构碳和离离子腺离开组的阴离子中心.
- 计算分析表明,在过渡状态下,酸盐组具有显著的核友性参与,氧核友与异构碳相距2.0安格斯特罗姆.
- 过渡状态表现出一个zwitterionic特征与一个阴离子异构碳和一个阴离子3'-OH氧,采用一个3'-endo形状.
结论:
- 人类MTAP通过晚期S(N) 1过渡状态机制运行.
- 酸盐组的显著核友性参与是MTAP催化机制的一个关键特征.
- 该研究为MTAP催化提供了详细的结构和机制洞察力,对抑制剂设计有价值.
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