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量子力学/分子力学计算反应性网络揭示了细胞染色体P450cam及其T252A突变物如何选择其氧化途径

Binju Wang¹, Chunsen Li^2,3, Kshatresh Dutta Dubey¹

¹†Institute of Chemistry and The Lise Meitner-Minerva Center for Computational Quantum Chemistry, The Hebrew University of Jerusalem, 91904 Jerusalem, Israel.

Journal of the American Chemical Society

|May 27, 2015

概括

量子力学/分子力学计算揭示了P450酶的新催化途径,排除了"第二氧化剂",并解释了T252A突变体对基质的特定环氧化.

科学领域:

生物化学和酶学生物化学和酶学
计算化学的计算化学
结构生物学结构生物学

背景情况:

细胞P450酶催化了关键的氧化反应.
450催化机制,特别是化合物I (Cpd I) 的作用,已被广泛研究.
研究了P450cam中的一个突变 (Threonine-252-to-Alanine,T252A),以了解质子穿的作用.

研究的目的:

为了调查长期存在的关于P450酶中的"第二氧化剂"的问题.
为了阐明P450cam T252A突变的催化机制.
为了确定由T252A突变体对5-甲基甲氧化过程负责的途径.

主要方法:

使用量子力学/分子力学 (QM/MM) 计算.
通过研究氧化剂候选物:Cpd I,铁氧化物和铁过氧化物 (Fe (III) (O2H2)) 的反应性网络.
分析了基质和蛋白质相互作用在稳定中间体中的作用.

主要成果:

确定了一个"第二合路径",由Fe (III) (O2H2) 介质启动.
这一途径涉及O-O同解和H-抽象,导致Cpd I的形成.
基质 (5-甲基) 和蛋白质的相互作用决定了Fe (III) (O2H2) 的持久性和反应性,影响了环氧化,并阻止了的氧化.

结论:

该研究排除了"第二氧化剂",并确定了P450cam.cam中的额外合途径.
在T252A突变使一个新的途径涉及Fe (III) (O2H2) 进行基质环氧化.
结果导致了对cytochrome P450cam的修订后的催化循环,突出了基质-蛋白相互作用.

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