A theoretical examination of the factors controlling the catalytic efficiency of a transmethylation enzyme: Catechol O-methyltransferase
A theoretical examination of the factors controlling the catalytic efficiency of a transmethylation enzyme: Catechol O-methyltransferase
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DOI：
10.1021/ja971019d
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发表时间：
1997-09-03
影响因子：
15
通讯作者：
Bruice, TC
中科院分区：
文献类型：
--
作者：
Zheng, YJ;Bruice, TC
用从头算和半经验量子力学方法研究了S-腺苷甲基硫代磷酸酯（S-adenosylmethithiophenol，S-Met）对邻苯二酚的非酶促甲基转移反应机理。邻苯二酚盐和锍之间的气相反应非常快，不涉及整体屏障。反应曲线在某种程度上类似于典型的气相S（N）2反应。然而，在水溶液中，该反应非常缓慢，预测势垒为37.3 kcal/mol。计算的（k（H）/k（D））（alpha）、k（12）/k（13）、k（16）/k（18）和k（32）/k（34）分别为0.80、1.06、1.003和1.010。此前，Schowen及其同事测量了儿茶酚O-甲基转移酶（COMT）催化的3，4-二羟基苯乙酮甲基化的（k（H）/k（D））（α）和k（12）/k（13）分别为0.83 +/- 0.05和1.09 +/- 0.05。计算的动力学同位素效应的模型反应和测得的动力学同位素效应的酶促反应之间的这种良好的协议似乎表明，酶促过渡态的结构是非常相似的非酶促反应。本文结合邻苯二酚O-甲基转移酶非酶催化反应的研究现状和最近获得的晶体结构，讨论了影响邻苯二酚O-甲基转移酶催化效率的因素。
The reaction mechanism of the nonenzymatic transmethylation of catechol by S-adenosylnethionine (AdoMet, as modeled by sulfonium ion) has been elucidated using ab initio and semiempirical quantum mechanical methods. The gas phase reaction between catecholate and sulfonium is extremely fast, involving no overall barrier. The reaction profile to some extent resembles a typical gas phase S(N)2 reaction. However, in aqueous solution, this reaction is very slow with a predicted barrier of 37.3 kcal/mol. The calculated (k(H)/k(D))(alpha), k(12)/k(13), k(16)/k(18), and k(32)/k(34) are 0.80, 1.06, 1.003, and 1.010, respectively. Previously, Schowen and co-workers measured (k(H)/k(D))(alpha) and k(12)/k(13) to be 0.83 +/- 0.05 and 1.09 +/- 0.05 for the catechol O-methyltransferase (COMT)-catalyzed methylation of 3,4-dihydroxyacetophenone by AdoMet. This good agreement between the calculated kinetic isotope effects for the model reaction and the measured kinetic isotope effects for the enzymatic reaction seems to suggest that the structure of the enzymatic transition state is very similar to that of the nonenzymatic reaction. Factors that modulate the catalytic efficacy of catechol O-methyltransferase were discussed in light of the present study on the nonenzymatic reaction and the recently solved X-ray crystal structure.