Modulation of thiol-dependent redox system by metal ions via thioredoxin and glutaredoxin systems,Metallomics

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Modulation of thiol-dependent redox system by metal ions via thioredoxin and glutaredoxin systems
Metallomics ( IF 2.9 ) Pub Date : 2018-01-22 00:00:00 , DOI: 10.1039/c7mt00327g
Yanfang Ouyang _{1,

2,

3,

4,

5} , Yi Peng _{1,

2,

3,

4,

5} , Jing Li _{1,

2,

3,

4,

5} , Arne Holmgren _{6,

7,

8,

9,

10} , Jun Lu _{1,

2,

3,

4,

5}

Affiliation

The thioredoxin and glutaredoxin systems possess a variety of biological activities in mammalian cells, including the defense against oxidative stress, regulation of DNA synthesis, the cell cycle and the mediation of apoptosis. The thioredoxin system, comprised of NADPH, thioredoxin reductase (TrxR) and thioredoxin (Trx), exerts its activities via a disulfide–dithiol exchange reaction. Mammalian TrxRs are selenoproteins; the thiols and selenols in the active site of these enzymes confer the thioredoxin system to work as soft bases, which have a high affinity with soft acids, including numerous metal ions. In this review we focus on recent advances in the modulation of thioredoxin and glutaredoxin systems by metal ion soft acids. Numerous clinical metal-containing drugs, such as platinum- and gold-containing compounds, show inhibitory effects on the thioredoxin system, providing strategies to develop novel anti-cancer drugs. Moreover, inhibition of the Trx system by soft acids, such as mercury-, chromium- and arsenic-containing compounds cause changes in the cellular redox state and contribute to their cell toxicity. In addition, metal ions are also involved in the regulation of the glutaredoxin system. Iron ions participate in regulating Grx2 activity via iron–sulfur cluster formation. Moreover, Grx5 in mitochondria contains a 2Fe–2S cluster stabilized by GSH, which can mediate cellular iron metabolism. Collectively, these results demonstrate that metal ions are major players in regulating the Trx and Grx systems-mediated cellular redox processes and thus, provide an opportunity to understand the functions of metal ions in thiol metabolism dysfunction-related diseases.

中文翻译：

金属离子通过硫氧还蛋白和戊二醛毒素系统对硫醇依赖性氧化还原系统的调节

硫氧还蛋白和戊二醛系统在哺乳动物细胞中具有多种生物学活性，包括抗氧化应激的防御，DNA合成的调控，细胞周期和细胞凋亡的介导。由NADPH，硫氧还蛋白还原酶（TrxR）和硫氧还蛋白（Trx）组成的硫氧还蛋白系统通过二硫化物-二硫醇交换反应。哺乳动物的TrxRs是硒蛋白。这些酶的活性位点中的硫醇和硒醇赋予硫氧还蛋白系统以软碱的作用，该软碱对包括许多金属离子在内的软酸具有很高的亲和力。在这篇综述中，我们关注金属离子软酸调节硫氧还蛋白和戊二醛系统的最新进展。许多临床上的含金属药物，例如含铂和金的化合物，对硫氧还蛋白系统具有抑制作用，为开发新型抗癌药物提供了策略。此外，诸如汞，铬和砷的软酸对Trx系统的抑制作用会导致细胞氧化还原状态发生变化，并对其细胞毒性做出贡献。此外，金属离子也参与了戊二醛系统的调节。铁离子参与调节Grx2活性通过铁-硫团簇形成。此外，线粒体中的Grx5包含2Fe-2S簇，该簇由GSH稳定，可以介导细胞铁代谢。总的来说，这些结果表明金属离子是调节Trx和Grx系统介导的细胞氧化还原过程的主要参与者，因此，提供了一个了解金属离子在硫醇代谢功能障碍相关疾病中的功能的机会。

更新日期：2018-01-22

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