Oxidation of Tertiary Amines by Cytochrome P450-Kinetic Isotope Effect as a Spin-State Reactivity Probe
Oxidation of Tertiary Amines by Cytochrome P450-Kinetic Isotope Effect as a Spin-State Reactivity Probe
复制标题
作为自旋态反应性探针的细胞色素 P450 动力学同位素效应氧化叔胺
DOI：
10.1002/chem.200802215
复制
发表时间：
2009-01-01
影响因子：
4.3
通讯作者：
Shaik, Sason
中科院分区：
文献类型：
--
作者：
Li, Chunsen;Wu, Wei;Shaik, Sason
采用混合密度泛函理论研究了细胞色素P450化合物I（Cpd I）氧化叔胺的两类过程，即N-脱烷基化和N-加氧反应.计算结果表明，化合物Ⅰ的N-脱烷基和N-氧化反应都优先发生在低自旋态。事实上，计算动力学同位素效应（KIEs）的脱烷基化的速率控制氢提取步骤表明，只有KIELS适合的实验数据，而相应的值为高自旋（HS）的过程要高得多。这些结果是对N，N-二甲基苯胺（DMA）的补充，进一步证实了KIE可以作为自旋态反应性灵敏探针的结论。TMA的铁甲醇胺最有可能在非酶促反应中分解，因为Fe-O键离解能（BDE）为负。计算结果表明，在N-氧化逆反应中，芳香胺的N-氧化物比脂肪胺更能作为氧供体生成化合物I。芳香胺的N-氧代衍生物将氧转移到血红素上从而生成化合物I的能力与先前报道的实验数据良好地雅阁。
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 KIELS 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.