title: Detoxification of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by cytochrome P450 enzymes: A theoretical investigation.
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 (7.5/5.7kcal/mol for the quartet/doublet state in solvent) is thermodynamically more favorable than the aromatic hydroxylation process (14.9/14.8kcal/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.
authors.affiliation: State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, People's Republic of China; State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University, Changchun 130023, People's Republic of China.
authors.forename: Xiao-Xi
authors.initials: XX
authors.lastname: Li
authors.affiliation: State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, People's Republic of China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, Jilin University, Changchun 130023, People's Republic of China; State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University, Changchun 130023, People's Republic of China. Electronic address: zhengqc@jlu.edu.cn.
authors.forename: Qing-Chuan
authors.initials: QC
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University, Changchun 130023, People's Republic of China.
authors.forename: Hong-Xing
authors.initials: HX
authors.lastname: Zhang
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000737:chemistry*; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry*; D006801:Humans; D006900:Hydroxylation; D008658:Inactivation, Metabolic; D008956:Models, Chemical; D008958:Models, Molecular; D010084:Oxidation-Reduction; D013816:Thermodynamics
chemical_list: D003577:Cytochrome P-450 Enzyme System; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
keywords: Aromatic hydroxylation; Cytochrome P450 enzyme; Density functional calculations; N-demethylation