Center for Structural Biology, Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
Antioxid Redox Signal. 2011 Jul 1;15(1):99-109. doi: 10.1089/ars.2010.3564. Epub 2010 Dec 17.
The eukaryotic, typical 2-Cys peroxiredoxins (Prxs) are inactivated by hyperoxidation of one of their active-site cysteine residues to cysteine sulfinic acid. This covalent modification is thought to enable hydrogen peroxide-mediated cell signaling and to act as a functional switch between a peroxidase and a high-molecular-weight chaperone. Moreover, hyperoxidation has been implicated in a variety of disease states associated with oxidative stress, including cancer and aging-associated pathologies. A repair enzyme, sulfiredoxin (Srx), reduces the sulfinic acid moiety by using an unusual ATP-dependent mechanism. In this process, the Prx molecule undergoes dramatic structural rearrangements to facilitate repair. Structural, kinetic, mutational, and mass spectrometry-based approaches have been used to dissect the molecular basis for Srx catalysis. The available data support the direct formation of Cys sulfinic acid phosphoryl ester and protein-based thiosulfinate intermediates. This review discusses the role of Srx in the reversal of Prx hyperoxidation, the questions raised concerning the reductant required for human Srx regeneration, and the deglutathionylating activity of Srx. The complex interplay between Prx hyperoxidation, other forms of Prx covalent modification, and the oligomeric state also are discussed.
真核生物典型的 2-Cys 过氧化物酶（Prx）通过其活性位点半胱氨酸残基之一的过氧化而失活，形成半胱氨酸亚磺酸。这种共价修饰被认为能够介导过氧化氢介导的细胞信号转导，并在过氧化物酶和高分子量伴侣之间充当功能开关。此外，过氧化已被牵连到与氧化应激相关的各种疾病状态中，包括癌症和与衰老相关的病变。修复酶，硫氧还蛋白（Srx）通过一种不寻常的 ATP 依赖性机制还原亚磺酸部分。在这个过程中，Prx 分子经历剧烈的结构重排以促进修复。结构、动力学、突变和基于质谱的方法已被用于剖析 Srx 催化的分子基础。现有数据支持 Cys 亚磺酸磷酸酯和基于蛋白质的亚硫酸氢盐中间物的直接形成。这篇综述讨论了 Srx 在逆转 Prx 过氧化中的作用、关于人 Srx 再生所需还原剂的问题以及 Srx 的去谷胱甘肽活性。还讨论了 Prx 过氧化、其他形式的 Prx 共价修饰和寡聚状态之间的复杂相互作用。
