From structure to redox: The diverse functional roles of disulfides and implications in disease.
From structure to redox: The diverse functional roles of disulfides and implications in disease.
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DOI：
10.1002/pmic.201600391
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发表时间：
2017-03
期刊：
影响因子：
3.4
通讯作者：
Weerapana E
中科院分区：
文献类型：
--
作者：
Bechtel TJ;Weerapana E
本文综述了二硫键的功能作用及其与人类疾病的相关性。讨论了二硫键在蛋白质结构稳定和蛋白质活性氧化还原调控中的关键作用。二硫键对分泌途径中许多蛋白质的结构稳定性至关重要，可以作为分子内或结构域间的二硫键存在。这些键的正确形成通常依赖于折叠伴侣和氧化酶，如蛋白质二硫异构酶（PDI）家族的成员。许多PDI家族成员通过氧化还原活性二硫化物催化二硫化物键的形成、还原和异构化，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起催化作用外，氧化还原活性二硫化物也存在于多种细胞蛋白质中，并在局部环境中响应氧化变化，调节蛋白质活性和定位。这些具有氧化还原活性的二硫化物要么是动态的分子内蛋白质二硫化物，要么是与小分子硫醇混合的二硫化物，产生谷胱甘肽化和半胱氨酸化加合物。氧化还原活性二硫化物的氧化和还原是由细胞活性氧和还原酶（如glutaredoxin和thioredoxin）的活性介导的。细胞氧化还原条件的失调和由此导致的混合二硫化物形成的变化与心血管疾病和帕金森病等疾病直接相关。
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.