Detoxification of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by cytochrome P450 enzymes: A theoretical investigation | |
Department | OSSO国家重点实验室 |
Li, Xiao-Xi2,3; Wang, Yong2; Zheng, Qing-Chuan1,3; Zhang, Hong-Xing3 | |
2016 | |
Source Publication | Journal of Inorganic Biochemistry |
ISSN | 0162-0134 |
Volume | 154Pages:21-28 |
Abstract | 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. |
Keyword | Cytochrome P450 Enzyme Density Functional Calculations N-demethylation Aromatic Hydroxylation |
Subject Area | 物理化学与绿色催化 |
DOI | 10.1016/j.jinorgbio.2015.10.009 |
Funding Organization | the Natural Science Foundation of China (Grant No. 21273095) |
Indexed By | SCI |
If | 3.348 |
Language | 英语 |
compositor | 第二作者单位 |
Citation statistics | |
Document Type | 期刊论文 |
Identifier | http://ir.licp.cn/handle/362003/19198 |
Collection | 羰基合成与选择氧化国家重点实验室(OSSO) |
Corresponding Author | Zheng, Qing-Chuan |
Affiliation | 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 |
Recommended Citation 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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