Brussels Center for Redox Biology, de Duve Institute, Université catholique de Louvain, Brussels 1200, Belgium.
Antioxid Redox Signal. 2013 Jul 1;19(1):63-71. doi: 10.1089/ars.2012.4864. Epub 2012 Oct 2.
The discovery of the oxidoreductase disulfide bond protein A (DsbA) in 1991 opened the way to the unraveling of the pathways of disulfide bond formation in the periplasm of Escherichia coli and other Gram-negative bacteria. Correct oxidative protein folding in the E. coli envelope depends on both the DsbA/DsbB pathway, which catalyzes disulfide bond formation, and the DsbC/DsbD pathway, which catalyzes disulfide bond isomerization.
Recent data have revealed an unsuspected link between the oxidative protein-folding pathways and the defense mechanisms against oxidative stress. Moreover, bacterial disulfide-bond-forming systems that differ from those at play in E. coli have been discovered.
In this review, we discuss fundamental questions that remain unsolved, such as what is the mechanism employed by DsbD to catalyze the transfer of reducing equivalents across the membrane and how do the oxidative protein-folding catalysts DsbA and DsbC cooperate with the periplasmic chaperones in the folding of secreted proteins.
Understanding the mechanism of DsbD will require solving the structure of the membranous domain of this protein. Another challenge of the coming years will be to put the knowledge of the disulfide formation machineries into the global cellular context to unravel the interplay between protein-folding catalysts and chaperones. Also, a thorough characterization of the disulfide bond formation machineries at work in pathogenic bacteria is necessary to design antimicrobial drugs targeting the folding pathway of virulence factors stabilized by disulfide bonds.
1991 年发现氧化还原酶二硫键蛋白 A（DsbA），为揭示大肠杆菌和其他革兰氏阴性菌周质中二硫键形成途径开辟了道路。大肠杆菌包膜中正确的氧化蛋白折叠既依赖于催化二硫键形成的 DsbA/DsbB 途径，也依赖于催化二硫键异构化的 DsbC/DsbD 途径。
最近的数据揭示了氧化蛋白折叠途径与抗氧化应激防御机制之间出人意料的联系。此外，还发现了不同于大肠杆菌中发挥作用的细菌二硫键形成系统。
在这篇综述中，我们讨论了一些悬而未决的基本问题，例如 DsbD 如何利用其机制来催化还原当量穿过膜的转移，以及氧化蛋白折叠催化剂 DsbA 和 DsbC 如何与周质伴侣蛋白合作折叠分泌蛋白。
理解 DsbD 的机制需要解决该蛋白膜结构域的结构问题。未来几年的另一个挑战将是将二硫键形成机制的知识置于全局细胞环境中，以揭示折叠催化剂和伴侣蛋白之间的相互作用。此外，还需要对工作在致病细菌中二硫键形成机制进行彻底的特征描述，以便设计针对稳定性依赖二硫键的毒力因子折叠途径的抗菌药物。
