Stabilization of a Transition-State Analogue at the Active Site of Yeast Cytosine Deaminase: Importance of Proton Transfers

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• 作者：Qin Xu ; Haobo Guo ; Andrey Gorin ; Hong Guo
• 刊名：Journal of Physical Chemistry B
• 出版年：2007
• 出版时间：June 14, 2007
• 年：2007
• 卷：111
• 期：23
• 页码：6501 - 6506
• 全文大小：290K
• 年卷期：v.111,no.23(June 14, 2007)
• ISSN：1520-5207

文摘

It is believed that the binding of pyrimidin-2-one to cytosine deaminase (CD) leads to the formation of 4-[R]-hydroxyl-3,4-dihydropyrimidine (DHP). Here the formation of transition-state analogue (TSA) at the activesite of yeast cytosine deaminase (yCD) is investigated by quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) and free energy simulations. It is shown that DHP may in fact be unstablein the active site and a proton transfer from the Zn hydroxide group to Glu-64 may occur during the nucleophilicattack, leading to an alkoxide-like TSA complex instead. The free energy simulations for the nucleophilicattack process show that the proton transfer from the Zn hydroxide to Glu-64 may play an important role instabilizing the TSA complex.