P450/NADPH/O2- and P450/PhIO-catalyzed N-dealkylations are mechanistically distinct
P450/NADPH/O2- and P450/PhIO-catalyzed N-dealkylations are mechanistically distinct
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DOI：
10.1021/ja0436143
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发表时间：
2005-02-09
影响因子：
15
通讯作者：
Wimalasena, K
中科院分区：
文献类型：
--
作者：
Bhakta, MN;Hollenberg, PF;Wimalasena, K
与过氧化物酶的化合物I类似的高价铁氧物种被认为是P450催化反应中的活性氧物种。光谱表征的催化活性的铁氧物种在碘代苯（PhIO）支持的模型反应和这些模型反应之间的平行和PhIO和NADPH/O2支持的P450反应已被视为这一建议的有力证据。为了支持这一提议，在区域和化学选择性、同位素效应和氧源等方面观察到的细微差异，NADPH/O2-和PhIO-支持的P450反应之间的差异通常归因于两个系统之间的机制差异以外的原因。在本研究中，我们使用了一系列敏感的机制探针，4-氯-N-环丙基-N-烷基苯胺，比较和对比的NADPH/O2-和PhIO支持的纯化CYP 2B 1 N-脱烷基化反应的化学。在此，我们提出了第一个实验证据，证明NADPH/O2-和PhIO-支持的P450 N-脱烷基化是不同的机制，因此，P450/PhIO系统可能不是一个很好的机制模型P450/NADPH/O2-催化的N-脱烷基化。
A high-valent iron-oxo species analogous to the compound I of peroxidases has been thought to be the activated oxygen species in P450-catalyzed reactions. Spectroscopic characterization of the catalytically competent iron-oxo species in iodosobenzene (PhIO)-supported model reactions and parallels between these model reactions and PhIO- and NADPH/O2-supported P450reactions have been taken as strong evidence for this proposal. To support this proposal, subtle differences observed in regio- and chemoselectivities, isotope effects, and source of oxygen, etc., between NADPH/O2- and PhIO-supported P450reactions have been generally attributed to reasons other than the mechanistic differences between the two systems. In the present study, we have used a series of sensitive mechanistic probes, 4-chloro-N-cyclopropyl-N-alkylanilines, to compare and contrast the chemistries of the NADPH/O2- and PhIO-supported purified CYP2B1 N-dealkylation reactions. Herein we present the first experimental evidence to demonstrate that the NADPH/O2- and PhIO-supported P450N-dealkylations are mechanistically distinct and, thus, the P450/PhIO system may not be a good mechanistic model for P450/NADPH/O2-catalyzed N-dealkylations.