Quantum chemical study of the mechanism of action of vitamin K carboxylase (VKC). IV. Intermediates and transition states
Quantum chemical study of the mechanism of action of vitamin K carboxylase (VKC). IV. Intermediates and transition states
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DOI：
10.1021/jp068564y
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发表时间：
2007-08-09
影响因子：
2.9
通讯作者：
Pedersen, Lee G.
中科院分区：
文献类型：
--
作者：
Davis, Charles H.;Deerfield, David, II;Pedersen, Lee G.
我们用密度泛函理论(DFT)量子化学方法研究了酶促合成γ-羧基谷氨酸的步骤。我们对一个潜在可行机制的结果表明，维生素K醇盐中间体可以在伽马碳处从谷氨酸中提取质子，形成碳负离子和维生素K环氧化物。然后，水合的碳负离子可以与二氧化碳反应生成伽马-羧基谷氨酸。在B3LYP/6-311G**水平上的计算被用来确定整个过程的中间体和过渡态。气相反应的活化自由能为22kcal/mol，反应的限速步骤是碳负离子对CO2的攻击。然而，更多的溶剂化研究表明，在高介电性体系中，碳负离子步骤的形成可能与二氧化碳攻击步骤竞争。我们将这些计算与血液凝固级联中的整个维生素K循环联系起来，这对脊椎动物的生存至关重要。
We studied proposed steps for the enzymatic formation of gamma-carboxyglutamic acid by density functional theory (DFT) quantum chemistry. Our results for one potentially feasible mechanism show that a vitamin K alkoxide intermediate can abstract a proton from glutamic acid at the gamma-carbon to form a carbanion and vitamin K epoxide. The hydrated carbanion can then react with CO2 to form gamma-carboxyglutamic acid. Computations at the B3LYP/6-311G** level were used to determine the intermediates and transition states for the overall process. The activation free energy for the gas-phase path is 22 kcal/mol, with the rate-limiting step for the reaction being the attack of the carbanion on CO2. Additional solvation studies, however, indicate that the formation of the carbanion step can be competitive with the CO2 attack step in high-dielectric systems. We relate these computations to the entire vitamin K cycle in the blood coagulation cascade, which is essential for viability of vertebrates.