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Chemical Research in Chinese Universities ›› 2010, Vol. 26 ›› Issue (5): 833-837.

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Insight into Reaction Mechanism of Sirtuins via Molecular Simulation and Density Functional Theory Study

ZHAO Yong-shan1,3, HOU Rui-zhe2, ZHANG Hong-xing1, ZHENG Qing-chuan1* and SUN Chia-chung1   

  1. 1. State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry,
    2. Norman Bethune College of Medicine, Jilin University, Changchun 130021, P. R. China;
    3. School of Life Sciences & Biopharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang 110016, P. R. China
  • Received:2010-01-12 Revised:2010-03-31 Online:2010-09-25 Published:2010-11-26
  • Contact: ZHENG Qing-chuan. E-mail: zhengqc@jlu.edu.cn
  • Supported by:

    Supported by the National Natural Science Foundation of China(No.20573042, 20903045), Specialized Research Fund for the Doctoral Program of Higher Education of China(No.20070183046) and Specialized Fund for the Basic Research of Jilin University, China(No.200810018).

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Abstract: With density functional theory(DFT) and molecular mechanics method, the catalytic mechanism of silent information regulator(sirtuins) has been investigated. The calculations support the SN2-like reaction of the initial step of the catalysis, and are consistent with experiment results. We further explored the second step of the catalysis and proposed that this step took place in a concerted reaction. In addition, the side chain of Phenylalanine33 may help to shield the glycosidic bond from water and be in a position to protect the developing oxacabenium transition state from hydrolysis. Our results of the calculations support this hypothesis that the phenylalanine33 plays a critical role in the sirtuins biology function.

Key words: Sirtuin, NAD+, p53, Model, Density functional theory