Detoxification of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by cytochrome P450 enzymes: A theoretical investigation.
Detoxification of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by cytochrome P450 enzymes: A theoretical investigation.
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细胞色素 P450 酶对 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 的解毒：理论研究。
DOI：
10.1016/j.jinorgbio.2015.10.009
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发表时间：
2016
影响因子：
3.9
通讯作者：
Hong
中科院分区：
文献类型：
--
作者：
Xiaoxuan Li;Yong Wang;Qingchuan Zheng;Hong
两种类型的解毒途径，N-去甲基化生成4-苯基-1，2，3，6-四氢吡啶（PTP）和芳族羟基化生成4-（4′-羟基苯基）-1-甲基-1，2，3，6-四氢吡啶（MPTP-OH），用于1-甲基-4-苯基-1，2，3，6-四氢吡啶，用杂化密度泛函方法研究了化合物I（Cpd I）介导的细胞色素P450对6-四氢吡啶（MPTP）的作用.量子化学结果表明，N-去甲基化反应的初始C-H键活化是通过氢原子转移（HAT）机制完成的。这之后是随后的O-反弹，以产生甲醇胺中间体。由于周环反应的性质，生成的甲醇胺在水分子的帮助下在非酶的水性环境中分解，形成胺和水合甲醛。对于芳族羟基化，化合物I向底物的初始添加主要通过侧边方法进行，随后进行质子穿梭以形成苯酚产物。两种途径的能垒比较表明，N-去甲基化（溶剂中四重态/二重态的7.5/5.7 kcal/mol）比芳族羟基化过程（溶剂中四重态/二重态的14.9/14.8 kcal/mol）更有利。这种趋势与实验产物分布，即，N-脱甲基产物PTP多于芳香羟基化产物MPTP-OH。综上所述，这些观察不仅丰富了我们的知识theN-脱烷基化和芳香族羟基化的P450的机制细节，但也提供了一定的见解其他类似毒素的代谢。
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 theN-demethylation, the initial C–H bond activation is achievedviaa 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 theN-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., theN-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 theN-dealkylation and the aromatic hydroxylation by P450s, but also provide certain insights into the metabolism of other analogous toxins.
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影响因子：
3.8
作者：
Herraiz, Tomas;Guillen, Hugo;Gonzalez, Frank J.
通讯作者：
Gonzalez, Frank J.
细胞色素 P-450 氧化环烷基胺。
DOI：
--
发表时间：
1989
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Bondon,A;Macdonald,TL;Harris,TM;Guengerich,FP
通讯作者：
Guengerich,FP
影响因子：
15
作者：
Usharani D;Lacy DC;Borovik AS;Shaik S
通讯作者：
Shaik S
大鼠肝微粒体对 4-碘苯甲醚的氧化和非氧化代谢。
DOI：
10.3109/00498259509061840
发表时间：
1995
期刊：
Xenobiotica; the fate of foreign compounds in biological systems.
影响因子：
--
作者：
Rizk,PN;Hanzlik,RP
通讯作者：
Hanzlik,RP
细胞色素 P-450 催化黑质纹状体毒素 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 环 α-碳氧化的研究。
影响因子：
4.1
作者：
Ottoboni,S;Carlson,TJ;Trager,WF;Castagnoli,K;CastagnoliJr,N
通讯作者：
CastagnoliJr,N