Molecular aspects of human cellular zinc homeostasis: redox control of zinc potentials and zinc signals
Molecular aspects of human cellular zinc homeostasis: redox control of zinc potentials and zinc signals
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DOI：
10.1007/s10534-008-9186-z
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发表时间：
2009-02-01
期刊：
影响因子：
3.5
通讯作者：
Maret, Wolfgang
中科院分区：
文献类型：
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作者：
Maret, Wolfgang
锌(II) 离子对于所有生命形式都是必需的。在人类中，估计有 3,000 种锌蛋白具有催化和结构功能。此外，当它们调节蛋白质或当蛋白质调节细胞锌重新分布时，它们会与蛋白质短暂相互作用。迄今为止，对这些类型的锌蛋白的探索还很有限。因此，锌/蛋白质相互作用的数量可能大于上述估计给出的数量。面对如此广泛的功能，几乎影响细胞生理学的各个方面，研究人员已经开始阐明锌的细胞稳态控制的分子机制，特别是转运蛋白、传感器和运输蛋白（如金属硫蛋白）的功能，为锌金属蛋白的合成提供正确数量的锌离子。蛋白质中的含硫氨基酸半胱氨酸对于锌离子的细胞迁移具有重要作用。硫配位环境提供了与锌离子足够强的相互作用；它们可以进行快速的配体交换；它们可以作为锌结合和释放的分子氧化还原开关。对于锌的细胞功能，游离锌离子浓度（锌电位，pZn = -log[Zn2+]）和锌缓冲能力是需要定量定义的至关重要的参数。在细胞质中，游离锌离子保持在皮摩尔浓度，仅占细胞总锌浓度的数百微摩尔浓度的一小部分。然而，锌离子浓度在各种条件下可能会波动。从金属硫蛋白的锌/硫醇盐簇在细胞内释放或从专门的细胞器分泌的锌离子是蛋白质的有效效应物，被认为是锌信号。细胞锌缓冲能力决定了锌离子的生理作用和病理生理作用之间的阈值。当药物、毒素、其他过渡金属离子或反应性化合物损害锌缓冲时，锌离子的大幅波动可能会通过影响氧化还原生物学以及锌离子与通常非目标蛋白质的相互作用来伤害细胞。
Zinc(II) ions are essential for all forms of life. In humans, they have catalytic and structural functions in an estimated 3,000 zinc proteins. In addition, they interact with proteins transiently when they regulate proteins or when proteins regulate cellular zinc re-distribution. As yet, these types of zinc proteins have been explored poorly. Therefore the number of zinc/protein interactions is potentially larger than that given by the above estimate. Confronted with such a wide range of functions, which affect virtually all aspects of cellular physiology, investigators have begun to elucidate the molecular mechanisms of cellular homeostatic control of zinc, especially the functions of transporter, sensor, and trafficking proteins, such as metallothioneins, in providing the correct amounts of zinc ions for the synthesis of zinc metalloproteins. The sulfur-containing amino acid cysteine in proteins has an important role in the cellular mobility of zinc ions. Sulfur-coordination environments provide sufficiently strong interactions with zinc ions; they can undergo fast ligand-exchange; and they can serve as molecular redox switches for zinc binding and release. For the cellular functions of zinc, the free zinc ion concentrations (zinc potentials, pZn = -log[Zn2+]) and the zinc buffering capacity are critically important parameters that need to be defined quantitatively. In the cytoplasm, free zinc ions are kept at picomolar concentrations as a minute fraction of the few hundred micromolar concentrations of total cellular zinc. However, zinc ion concentrations can fluctuate under various conditions. Zinc ions released intracellularly from the zinc/thiolate clusters of metallothioneins or secreted from specialized organelles are potent effectors of proteins and are considered zinc signals. The cellular zinc buffering capacity determines the threshold between physiological and pathophysiological actions of zinc ions. When drugs, toxins, other transition metal ions or reactive compounds compromise zinc buffering, large zinc ion fluctuations can injure cells through effects on redox biology and interactions of zinc ions with proteins that are normally not targeted.