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首页> 外文期刊>Chemistry: A European journal >Formation of the active species of cytochrome P450 by using iodosylbenzene: A case for spin-selective reactivity
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Formation of the active species of cytochrome P450 by using iodosylbenzene: A case for spin-selective reactivity

机译：利用碘基苯形成细胞色素P450活性物种：自旋选择反应性的案例

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The generation of the active species for the enzyme cytochrome P450 by using the highly versatile oxygen surrogate iodosylbenzene (PhIO) often produces different results compared with the native route, in which the active species is generated through O-2 uptake and reduction by NADPH. One of these differences that is addressed here is the deuterium kinetic isotope effect (KIE) jump observed during N-dealkylation of N,N-dimethylaniline (DMA) by P450, when the reaction conditions change from the native to the PhIO route. The paper presents a theoretical analysis targeted to elucidate the mechanism of the reaction of PhIO with heme, to form the high-valent iron-oxo species Compound I (CpdI), and define the origins of the KIE jump in the reaction of CpdI with DMA. It is concluded that the likely origin of the KIE jump is the spin-selective chemistry of the enzyme cytochrome P450 under different preparation procedures. In the native route, the reaction proceeds via the doublet spin state of CpdI and leads to a low KIE value. PhIO, however, diverts the reaction to the quartet spin state of CpdI, which leads to the observed high KIE values. The KIE jump is reproduced here experimentally for the dealkylation of N,N-dimethyl-4-(methylthio)aniline, by using intramolecular KIE measurements that avoid kinetic complexities. The effect of PhIO is compared with N,N-dimethylaniline-N-oxide (DMAO), which acts both as the oxygen donor and the substrate and leads to the same KIE values as the native route.
机译：与天然途径相比，使用高度通用的氧替代碘代碘苯（PhIO）生成细胞色素P450酶的活性物种通常会产生不同的结果，在天然途径中，活性物种是通过O-2的吸收和NADPH的还原而产生的。此处要解决的这些差异之一是，当反应条件从天然转变为PhIO时，P450对N，N-二甲基苯胺（DMA）进行N-脱烷基化时，氘动力学同位素效应（KIE）跃升。本文提出了一种理论分析，旨在阐明PhIO与血红素反应的机理，以形成高价铁-氧代化合物I（CpdI），并定义CpdI与DMA反应中KIE跃迁的起源。 。结论是，在不同的制备程序下，KIE跳跃的可能原因是酶细胞色素P450的自旋选择化学。在天然路线中，反应通过CpdI的双峰自旋状态进行，并导致低KIE值。然而，PhIO将反应转移到CpdI的四重旋态，这导致观察到的高KIE值。通过使用避免动力学复杂性的分子内KIE测量，此处通过实验复制了KIE跃迁，用于N，N-二甲基-4-（甲硫基）苯胺的脱烷基化。将PhIO的作用与N，N-二甲基苯胺-N-氧化物（DMAO）进行了比较，后者既充当氧气供体，又充当底物，并产生与天然途径相同的KIE值。

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