Moya-García Aurelio A, Ruiz-Pernía Javier, Martí Sergio, Sánchez-Jiménez Francisca, Tuñón Iñaki
Procel Laboratory, Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, Universidad de Málaga, Campus Teatinos, 29071 Málaga, Spain.
J Biol Chem. 2008 May 2;283(18):12393-401. doi: 10.1074/jbc.M707434200. Epub 2008 Feb 29.
We report a hybrid quantum mechanics/molecular mechanics theoretical study on the reaction mechanism of mammalian histidine decarboxylase that allows us to obtain valuable insights on the structure of the cofactor-substrate adduct (external aldimine) in the active site of rat histidine decarboxylase. By means of molecular dynamics simulations, we traced the potential of mean force corresponding to the decarboxylation reaction of the adduct both in the active site of the enzyme and in aqueous solution. By comparing this process in both media, we have identified the key electrostatic interactions that explain the lowering of the free energy barrier in the enzyme. Our analysis also offers a validation of Dunathan's hypothesis (Dunathan, H. (1966) Proc. Natl. Acad. Sci. U. S. A. 55, 712-716) regarding the role of stereoelectronic effects in the enzymatic decarboxylation process.
我们报道了一项关于哺乳动物组氨酸脱羧酶反应机制的量子力学/分子力学混合理论研究，该研究使我们能够获得关于大鼠组氨酸脱羧酶活性位点中辅因子 - 底物加合物（外部醛亚胺）结构的有价值见解。通过分子动力学模拟，我们追踪了该加合物在酶活性位点和水溶液中脱羧反应对应的平均力势能。通过比较这两种介质中的这一过程，我们确定了解释酶中自由能垒降低的关键静电相互作用。我们的分析还验证了杜纳森假说（Dunathan, H. (1966) Proc. Natl. Acad. Sci. U. S. A. 55, 712 - 716）中关于立体电子效应在酶促脱羧过程中作用的观点。
