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Molecular Dynamics Analysis Reveals Structural Insights into Mechanism of Nicotine N-Demethylation Catalyzed by Tobacco Cytochrome P450 Mono-Oxygenase

文献类型： 外文期刊

作者： Wang, Shan 1 ; Yang, Shuo 1 ; An, Baiyi 1 ; Wang, Shichen 2 ; Yin, Yuejia 2 ; Lu, Yang 1 ; Xu, Ying 3 ; Hao, Dongyun 1 ;

作者机构： 1.Jilin Univ, Key Lab Mol Enzymol & Engn, Minist Educ, Changchun 130023, Peoples R China

2.Jilin Acad Agr Sci, Biotechnol Res Ctr, Changchun, Peoples R China

3.Univ Georgia, Computat Syst Biol Lab, Dept Biochem & Mol Biol, Athens, GA 30602 USA

4.Univ Georgia, Inst Bioinformat, Athens, GA 30602 USA

5.Jilin Univ, Coll Comp Sci & Technol, Changchun 130023, Peoples R China

期刊名称：PLOS ONE （ 影响因子：3.24； 五年影响因子：3.788 ）

ISSN： 1932-6203

年卷期： 2011 年 6 卷 8 期

页码：

收录情况： SCI

摘要： CYP82E4, a cytochrome P450 monooxygenase, has nicotine N-demethylase (NND) activity, which mediates the bioconversion of nicotine into nornicotine in senescing tobacco leaves. Nornicotine is a precursor of the carcinogen, tobacco-specific nitrosamine. CYP82E3 is an ortholog of CYP82E4 with 95% sequence identity, but it lacks NND activity. A recent site-directed mutagenesis study revealed that a single amino acid substitution, i.e., cysteine to tryptophan at the 330 position in the middle of protein, restores the NND activity of CYP82E3 entirely. However, the same amino acid change caused the loss of the NND activity of CYP82E4. To determine the mechanism of the functional turnover of the two molecules, four 3D structures, i.e., the two molecules and their corresponding cys-trp mutants were modeled. The resulting structures exhibited that the mutation site is far from the active site, which suggests that no direct interaction occurs between the two sites. Simulation studies in different biological scenarios revealed that the mutation introduces a conformation drift with the largest change at the F-G loop. The dynamics trajectories analysis using principal component analysis and covariance analysis suggests that the single amino acid change causes the opening and closing of the transfer channels of the substrates, products, and water by altering the motion of the F-G and B-C loops. The motion of helix I is also correlated with the motion of both the F-G loop and the B-C loop and; the single amino acid mutation resulted in the curvature of helix I. These results suggest that the single amino acid mutation outside the active site region may have indirectly mediated the flexibility of the F-G and B-C loops through helix I, causing a functional turnover of the P450 monooxygenase.

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