Li Chunsen, Wu Wei, Cho Kyung-Bin, Shaik Sason
State Key Laboratory of Physical Chemistry of Solid Surfaces and Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005 (China), Fax: (+86) 592-2184708.
Department of Organic Chemistry and The Lise Meitner-Minerva Center for Computational Quantum Chemistry, The Hebrew University, Jerusalem, 91904 (Israel), Fax: (+972) 2-658-4680.
Chemistry. 2009 Aug 24;15(34):8492-8503. doi: 10.1002/chem.200802215.
Two types of tertiary amine oxidation processes, namely, N-dealkylation and N-oxygenation, by compound I (Cpd I) of cytochrome P450 are studied theoretically using hybrid DFT calculations. All the calculations show that both N-dealkylation and N-oxygenation of trimethylamine (TMA) proceed preferentially from the low-spin (LS) state of Cpd I. Indeed, the computed kinetic isotope effects (KIEs) for the rate-controlling hydrogen abstraction step of dealkylation show that only the KIE(LS) fits the experimental datum, whereas the corresponding value for the high-spin (HS) process is much higher. These results second those published before for N,N-dimethylaniline (DMA), and as such, they further confirm the conclusion drawn then that KIEs can be a sensitive probe of spin state reactivity. The ferric-carbinolamine of TMA decomposes most likely in a non-enzymatic reaction since the Fe-O bond dissociation energy (BDE) is negative. The computational results reveal that in the reverse reaction of N-oxygenation, the N-oxide of aromatic amine can serve as a better oxygen donor than that of aliphatic amine to generate Cpd I. This capability of the N-oxo derivatives of aromatic amines to transfer oxygen to the heme, and thereby generate Cpd I, is in good accord with experimental data previously reported.
利用杂化密度泛函理论（DFT）计算方法对细胞色素P450的化合物I（Cpd I）介导的两种叔胺氧化过程，即N-脱烷基化和N-氧化反应进行了理论研究。所有计算结果表明，三甲胺（TMA）的N-脱烷基化和N-氧化反应均优先从Cpd I的低自旋（LS）态开始。实际上，计算得到的脱烷基化反应速率控制步骤中氢原子提取的动力学同位素效应（KIEs）表明，只有KIE(LS)符合实验数据，而高自旋（HS）过程的相应值则高得多。这些结果与之前发表的关于N,N-二甲基苯胺（DMA）的结果一致，因此，它们进一步证实了当时得出的结论，即KIEs可以作为自旋态反应性的灵敏探针。由于铁-氧键离解能（BDE）为负，TMA的铁-甲醇胺最有可能在非酶反应中分解。计算结果表明，在N-氧化反应的逆反应中，芳香胺的N-氧化物比脂肪胺的N-氧化物能更好地作为氧供体来生成Cpd I。芳香胺的N-氧代衍生物将氧转移至血红素从而生成Cpd I的这种能力与先前报道的实验数据高度吻合。
