Redox regulation of copper-metallothionein
Redox regulation of copper-metallothionein
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DOI：
10.1006/abbi.1998.1077
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发表时间：
1999-03-01
影响因子：
3.9
通讯作者：
Kagan, VE
中科院分区：
文献类型：
--
作者：
Fabisiak, JP;Tyurin, VA;Kagan, VE
铜（Cu）是一种必需元素，必须仔细控制其在细胞内的定位，以避免铜依赖性氧化还原循环。金属硫蛋白（MT）是富含半胱氨酸的金属结合蛋白，在金属暴露和氧化应激过程中发挥细胞保护作用。然而，MT在调节Cu依赖性氧化还原循环中的具体作用仍未得到解决。我们的研究利用了化学定义的模型系统，研究MT调制铜依赖的氧化还原循环还原（铜/抗坏血酸）和温和的氧化（铜/抗坏血酸+H2 O2）条件下。在铜和抗坏血酸盐的存在下，MT阻断铜依赖性脂质氧化和抗坏血酸自由基的形成与化学计量对应的Cu/MT比小于或等于12。在H2 O2的存在下，MT的保护程度较小，生物氧化和自由基形成仅在Cu/MT比为6时才被抑制。利用溶液中游离Cu ~（2+）的低温电子顺磁共振（EPR）研究了MT与Cu的物理相互作用。EPR沉默铜1+（大概是在与MT复合）的最大量对应于12摩尔当量的Cu/MT在还原条件下，但只有9在H2 O2的存在下。H2 O2调制MT的能力，以保护HL-60细胞从铜诱导的细胞死亡的方式，与MT的能力，以减轻铜的氧化还原循环在无细胞系统。因此，在还原条件下实现Cu与MT的最佳结合;然而，该Cu的一部分在氧化条件下出现可释放。在氧化应激过程中，MT释放游离铜可促进活性氧自由基的形成，加重细胞损伤。(C)北京：科学出版社.
Copper (Cu) is an essential element whose localization within cells must be carefully controlled to avoid Cu-dependent redox cycling. Metallothioneins (MTs) are cysteine-rich metal-binding proteins that exert cytoprotective effects during metal exposure and oxidative stress. The specific role of MTs, however, in modulating Cu-dependent redox cycling remains unresolved. Our studies utilized a chemically defined model system to study MT modulation of Cu-dependent redox cycling under reducing (Cu/ascorbate) and mild oxidizing (Cu/ascorbate + H2O2) conditions. In the presence of Cu and ascorbate, MT blocked Cu-dependent lipid oxidation and ascorbyl radical formation with a stoichiometry corresponding to Cu/MT ratios less than or equal to 12. In the presence of H2O2 the degree of protection by MT was less and biological oxidations and radical formation were inhibited only up to Cu/MT ratios of 6. Physical interaction of MT and Cu was measured by using low-temperature EPR of free Cu2+ in solution. The maximal amount of EPR-silent Cu1+ (presumably in complex with MT) corresponded to 12 molar equivalents of Cu/MT under reducing conditions, but only 9 in the presence of H2O2. H2O2 modulated the ability of MT to protect HL-60 cells from Cu-induced cell death in a manner that correlated with the ability of MT to mitigate Cu-redox cycling in cell-free systems. Thus, optimal binding of Cu to MT is achieved under reducing conditions; however, a portion of this Cu appears releasable under oxidizing conditions. Release of free Cu from MT during oxidative stress could enhance the formation of reactive oxygen species and potentiate cellular damage. (C) 1999 Academic Press.