Department of Molecular Medicine, University of Padova, Italy; Departamento de Bioquímica, Universidad de la República, Montevideo, Uruguay.
Department of Molecular Medicine, University of Padova, Italy.
Free Radic Biol Med. 2022 Jul;187:113-122. doi: 10.1016/j.freeradbiomed.2022.05.003. Epub 2022 May 14.
The discoveries leading to our present understanding of the glutathione peroxidases (GPxs) are recalled. The cytosolic GPx, now GPx1, was first described by Mills in 1957 and claimed to depend on selenium by Rotruck et al., in 1972. With the determination of a stoichiometry of one selenium per subunit, GPx1 was established as the first selenoenzyme of vertebrates. In the meantime, the GPxs have grown up to a huge family of enzymes that prevent free radical formation from hydroperoxides and, thus, are antioxidant enzymes, but they are also involved in regulatory processes or synthetic functions. The kinetic mechanism of the selenium-containing GPxs is unusual in neither showing a defined K nor any substrate saturation. More recently, the reaction mechanism has been investigated by the density functional theory and nuclear magnetic resonance of model compounds mimicking the reaction cycle. The resulting concept sees a selenolate oxidized to a selenenic acid. This very fast reaction results from a concerted dual attack on the hydroperoxide bond, a nucleophilic one by the selenolate and an electrophilic one by a proton that is unstably bound in the reaction center. Postulated intermediates have been identified either in the native enzymes or in model compounds.
现将导致我们目前对谷胱甘肽过氧化物酶（GPx）理解的发现进行回顾。细胞溶质 GPx，现在称为 GPx1，于 1957 年由 Mills 首次描述，并于 1972 年由 Rotruck 等人声称依赖硒。随着亚基每单位一个硒的化学计量的确定，GPx1 被确立为脊椎动物的第一个硒酶。与此同时，GPx 已经发展成为一个庞大的酶家族，这些酶可以防止过氧化物形成自由基，因此是抗氧化酶，但它们也参与调节过程或合成功能。含硒 GPx 的动力学机制并不罕见，既没有确定的 K 值，也没有任何底物饱和。最近，通过模拟反应循环的模型化合物的密度泛函理论和核磁共振研究了反应机制。由此产生的概念是将硒代物氧化为硒代酸。这个非常快速的反应是由于过氧化物键的协同双重攻击，硒代物的亲核攻击和反应中心中不稳定结合的质子的亲电攻击。无论是在天然酶还是模型化合物中，都已经确定了假定的中间体。
