Detoxification of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by cytochrome P450 enzymes: A theoretical investigation | |
Li, Xiao-Xi2,3; Wang, Yong2; Zheng, Qing-Chuan1,3; Zhang, Hong-Xing3 | |
刊名 | Journal of Inorganic Biochemistry |
2016 | |
卷号 | 154页码:21-28 |
关键词 | Cytochrome P450 enzyme Density functional calculations N-demethylation Aromatic hydroxylation |
ISSN号 | 0162-0134 |
通讯作者 | Zheng, Qing-Chuan |
英文摘要 | Two types of detoxification routes, N-demethylation to form 4-phenyl-1,2,3,6-tetrahydropyridine (PTP) and aromatic hydroxylation to generate 4-(4′-hydroxyphenyl)-1-methyl-1,2,3,6-tetrahydropyridine (MPTP-OH), for 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mediated by Compound I (Cpd I) of cytochrome P450 are investigated theoretically using hybrid density functional calculations. Quantum chemical results reveal that for the N-demethylation, the initial C–H bond activation is achieved via a hydrogen atom transfer (HAT) mechanism. This is followed by a subsequent O-rebound to yield the carbinolamine intermediate. Due to the nature of pericyclic reaction, the generated carbinolamine decomposes in a non-enzymatic aqueous environment with the assistance of water molecules, forming amine and hydrated formaldehyde. For the aromatic hydroxylation, an initial addition of Cpd I to the substrate occurs mainly through a side-on approach with a subsequent proton shuttle to form the phenol product. A comparison of the energy barriers for both routes indicates that the N-demethylation (7.5/5.7 kcal/mol for the quartet/doublet state in solvent) is thermodynamically more favorable than the aromatic hydroxylation process (14.9/14.8 kcal/mol for the quartet/doublet state in solvent). This trend is in good agreement with the experimental product distribution, viz., the N-demethylation product PTP is more than the aromatic hydroxylation product MPTP-OH. Taken together, these observations not only enrich our knowledge on the mechanistic details of the N-dealkylation and the aromatic hydroxylation by P450s, but also provide certain insights into the metabolism of other analogous toxins. |
学科主题 | 物理化学与绿色催化 |
收录类别 | SCI |
资助信息 | the Natural Science Foundation of China (Grant No. 21273095) |
语种 | 英语 |
WOS记录号 | WOS:000367213400003 |
内容类型 | 期刊论文 |
源URL | [http://210.77.64.217/handle/362003/19198] |
专题 | 兰州化学物理研究所_OSSO国家重点实验室 |
作者单位 | 1.Jilin Univ, Minist Educ, Key Lab Mol Enzymol & Engn, Changchun 130023, Peoples R China 2.Chinese Acad Sci, Lanzhou Inst Chem Phys, State Key Lab Oxo Synth & Select Oxidat, Lanzhou 730000, Peoples R China 3.Jilin Univ, Inst Theoret Chem, State Key Lab Theoret & Computat Chem, Changchun 130023, Peoples R China |
推荐引用方式 GB/T 7714 | Li, Xiao-Xi,Wang, Yong,Zheng, Qing-Chuan,et al. Detoxification of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by cytochrome P450 enzymes: A theoretical investigation[J]. Journal of Inorganic Biochemistry,2016,154:21-28. |
APA | Li, Xiao-Xi,Wang, Yong,Zheng, Qing-Chuan,&Zhang, Hong-Xing.(2016).Detoxification of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by cytochrome P450 enzymes: A theoretical investigation.Journal of Inorganic Biochemistry,154,21-28. |
MLA | Li, Xiao-Xi,et al."Detoxification of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by cytochrome P450 enzymes: A theoretical investigation".Journal of Inorganic Biochemistry 154(2016):21-28. |
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