Bechtel Tyler J, Weerapana Eranthie
Department of Chemistry, Boston College, Chestnut Hill, MA, USA.
Proteomics. 2017 Mar;17(6). doi: 10.1002/pmic.201600391.
This review provides a comprehensive overview of the functional roles of disulfide bonds and their relevance to human disease. The critical roles of disulfide bonds in protein structure stabilization and redox regulation of protein activity are addressed. Disulfide bonds are essential to the structural stability of many proteins within the secretory pathway and can exist as intramolecular or inter-domain disulfides. The proper formation of these bonds often relies on folding chaperones and oxidases such as members of the protein disulfide isomerase (PDI) family. Many of the PDI family members catalyze disulfide-bond formation, reduction, and isomerization through redox-active disulfides and perturbed PDI activity is characteristic of carcinomas and neurodegenerative diseases. In addition to catalytic function in oxidoreductases, redox-active disulfides are also found on a diverse array of cellular proteins and act to regulate protein activity and localization in response to oxidative changes in the local environment. These redox-active disulfides are either dynamic intramolecular protein disulfides or mixed disulfides with small-molecule thiols generating glutathionylation and cysteinylation adducts. The oxidation and reduction of redox-active disulfides are mediated by cellular reactive oxygen species and activity of reductases, such as glutaredoxin and thioredoxin. Dysregulation of cellular redox conditions and resulting changes in mixed disulfide formation are directly linked to diseases such as cardiovascular disease and Parkinson's disease.
本综述全面概述了二硫键的功能作用及其与人类疾病的相关性。文中探讨了二硫键在蛋白质结构稳定和蛋白质活性氧化还原调节中的关键作用。二硫键对于分泌途径中许多蛋白质的结构稳定性至关重要，可作为分子内或结构域间二硫键存在。这些键的正确形成通常依赖于折叠伴侣和氧化酶，如蛋白质二硫键异构酶（PDI）家族成员。许多PDI家族成员通过氧化还原活性二硫键催化二硫键的形成、还原和异构化，而PDI活性紊乱是癌症和神经退行性疾病的特征。除了在氧化还原酶中的催化功能外，氧化还原活性二硫键还存在于多种细胞蛋白质上，并根据局部环境的氧化变化调节蛋白质活性和定位。这些氧化还原活性二硫键要么是动态的分子内蛋白质二硫键，要么是与小分子硫醇形成的混合二硫键，生成谷胱甘肽化和半胱氨酸化加合物。氧化还原活性二硫键的氧化和还原由细胞活性氧和还原酶（如谷氧还蛋白和硫氧还蛋白）的活性介导。细胞氧化还原状态的失调以及由此导致的混合二硫键形成的变化与心血管疾病和帕金森病等疾病直接相关。
