人类谷胱甘肽S-转移酶M1a-1a催化的亲核芳香取代反应的理论研究

Theoretical study of nucleophilic aromatic substitution reaction catalyzed by human glutathione S-transferase M1a-1a

利用分子力学和量子力学方法研究人类谷胱甘肽S-转移酶M1a-1a催化谷胱甘肽对1-氯-2,4二硝基苯(CDNB)的亲核芳香取代反应的细节.所获得的反应路径显示反应仅经历一个过渡态且能垒很低.电荷布居分析证明电子从谷胱甘肽基团流向二硝基苯,验证了反应的发生.计算结果表明活性位点3个残基(Tyr6,His107和Tyr115)参与了催化反应,尤其是His107,它在反应后期通过与产物形成氢键从而加速了Cl的释放.结果支持了Patskovsky等人提出的机理,并有助于其他谷胱甘肽S-转移酶的研究.

Human glutathione S-transferase Mla-la （hGSTMla-la） catalyzes the nucleophilic aromatic substitution reaction of glutathione （GSH） to 1-chloro-2,4-dinitrobenzene （CDNB）. In the present study, molecular mechanics （MM） and quantum mechanics （QM） were carried out to explore the details of the catalysis reaction.The obtained pathway reveals that the reaction only proceeds via one transition state （TS） and its energy barrier is very low. The charge population analysis shows that the electrons flow from the GSH group and CDNB to the chlorine, indicating the microcosmic process of the nucleophilic reaction. The computational models distinctly show the catalysis role of the three residues （Tyr6,Hisl07 and Tyrll5） in the active site. Especially Hisl07 accelerates the chlorine release by the hydrogen bond interaction in the final stage of the catalysis reaction. Our results support the proposed mecha- nism by Patskovsky et al. and may be helpful for the investigation of other glutathione S-transferases.