Balta B, Monard G, Ruiz-López M F, Antoine M, Gand A, Boschi-Muller S, Branlant G
UMR CNRS-UHP 7565, Equipe de Chimie et Biochimie Théoriques, Université Henri Poincaré - Nancy I, BP 239, 54506 Vandoeuvre-lès-Nancy, France.
J Phys Chem A. 2006 Jun 22;110(24):7628-36. doi: 10.1021/jp0573036.
Theoretical computations have been carried out to investigate the reaction mechanism of the sulfoxide reduction by thiols in solution. This reaction is a suitable model for enzymatic processes involving methionine sulfoxide reductases (Msrs). Recent investigations on the Msr mechanism have clearly shown that a sulfenic acid intermediate is formed on the catalytic cysteine of the active site concomitantly to the methionine product. In contrast, experimental studies for the reaction of a number of thiols and sulfoxides in solution did not observe sulfenic acid formation. Only, a disulfide was identified as the final product of the process. The present study has been carried out at the MP2/6-311+G(3d2f,2df,2p)//B3LYP/6-311G(d,p) level of theory. The solvent effect in DMSO has been incorporated using a discrete-continuum model. The calculations provide a basic mechanistic framework that allows discussion on the apparent discrepancy existing between experimental data in solution and in the enzymes. They show that, in the early steps of the process in solution, a sulfurane intermediate is formed the rate of which is limiting. Then, a proton transfer from a second thiol molecule to the sulfurane leads to the formation of either a sulfenic acid or a disulfide though the latter is much more stable than the former. If a sulfenic acid is formed in solution, it should react with a thiol molecule making its experimental detection difficult or even unfeasible.
已进行理论计算以研究溶液中硫醇还原亚砜的反应机理。该反应是涉及甲硫氨酸亚砜还原酶（Msrs）的酶促过程的合适模型。最近对Msr机理的研究清楚地表明，在甲硫氨酸产物形成的同时，活性位点的催化半胱氨酸上会形成亚磺酸中间体。相比之下，对溶液中许多硫醇和亚砜反应的实验研究未观察到亚磺酸的形成。仅鉴定出二硫键为该过程的最终产物。本研究是在MP2/6-311+G(3d2f,2df,2p)//B3LYP/6-311G(d,p)理论水平上进行的。使用离散-连续介质模型纳入了二甲基亚砜中的溶剂效应。这些计算提供了一个基本的机理框架，有助于讨论溶液中和酶中实验数据之间存在的明显差异。结果表明，在溶液中该过程的早期步骤中，会形成一种硫烷中间体，其形成速率是限速的。然后，质子从第二个硫醇分子转移到硫烷上，导致形成亚磺酸或二硫键，尽管后者比前者稳定得多。如果在溶液中形成了亚磺酸，它应该会与硫醇分子反应，这使得其实验检测变得困难甚至不可行。
