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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >The mechanism of M.HhaI DNA C5 cytosine methyltransferase enzyme: A quantum mechanics/molecular mechanics approach
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The mechanism of M.HhaI DNA C5 cytosine methyltransferase enzyme: A quantum mechanics/molecular mechanics approach

机译：M.HhaI DNA C5胞嘧啶甲基转移酶的机制：量子力学/分子力学方法

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摘要

The mechanism of DNA cytosine-5-methylation catalyzed by the bacterial M.Hhal enzyme has been considered as a stepwise nucleophilic addition of Cys-81-S- to cytosine C6 followed by C5 nucleophilic replacement of the methyl of S-adenosyl-L-methionine to produce 5-methyl-6-Cys-81-S-5,6-dihydrocytosine. In this study, we show that the reaction is concerted from a series of energy calculations by using the quantum mechanical/molecular mechanical hybrid method. Deprotonation of 5-methyl-6-Cys-81-S-5,6-dihydrocytosine and expulsion of Cys-81-S- provides the product DNA 5-methylcytosine. A required base catalyst for this deprotonation is not available as a member of the active site structure. A water channel between the active site and bulk water allows entrance of solvent to the active site. Hydroxide at 10(-7) mole fraction (pH = 7) is shown to be sufficient for the required catalysis. We also show that Glu-119-CO2H can divert the reaction by protonating cytosine N3 when Cys-81-S- attacks cytosine, to form the 6-Cys-81-S-3-hydrocytosine. The reactants and 6-Cys-81-S-3-hydrocytosine product are in rapid equilibrium, and this explains the observed hydrogen exchange of cytosine with solvent.
机译：细菌M.Hhal酶催化DNA胞嘧啶5甲基化的机理被认为是将Cys-81-S-逐步亲核加到胞嘧啶C6中，然后C5亲核取代S-腺苷-L-的甲基甲硫氨酸生产5-甲基-6-Cys-81-S-5,6-二氢胞嘧啶。在这项研究中，我们表明该反应是通过使用量子力学/分子机械混合方法从一系列能量计算中协调而来的。 5-甲基-6-Cys-81-S-5,6-二氢胞嘧啶去质子化和Cys-81-S-的排出将提供产物DNA 5-甲基胞嘧啶。这种去质子化所需的碱催化剂不能作为活性位点结构的成员。活性部位和大量水之间的水通道允许溶剂进入活性部位。已显示摩尔分数为10（-7）（pH = 7）的氢氧化物足以满足所需的催化作用。我们还显示，当Cys-81-S-攻击胞嘧啶形成6-Cys-81-S-3-hydrocytosine时，Glu-119-CO2H可以通过质子化胞嘧啶N3转移反应。反应物和6-Cys-81-S-3-氢胞嘧啶产物处于快速平衡状态，这解释了观察到的胞嘧啶与溶剂的氢交换。

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