Maret Wolfgang
Department of Preventive Medicine & Community Health, The University of Texas Medical Branch, Galveston, TX 77555-1109, USA.
Exp Gerontol. 2008 May;43(5):363-9. doi: 10.1016/j.exger.2007.11.005. Epub 2007 Nov 28.
A critical aspect of cellular zinc metabolism is the tight control of the picomolar concentrations of free zinc ions and their fluctuations to balance folding and misfolding of proteins, supply of thousands of zinc-requiring proteins with zinc, and dual functions of zinc as either a pro-oxidant or a pro-antioxidant. Zinc/sulfur (cysteine) bonds in proteins have a key role in this control because they generate redox-active coordination environments. Metallothionein (MT) is such a redox-active zinc protein, which couples biochemically to the cellular redox state. The coordination dynamics and redox state of its zinc/thiolate clusters determine cellular zinc availability. A fraction of MT in tissues and cells contains free thiols and disulfides. Thus, MT with seven zinc ions and twenty reduced thiols as characterized by high-resolution 3D structures does not represent its biologically active form. Redox stress affects the zinc and redox buffering capacity of MT and elicits fluctuations of zinc ions that are potent effectors of multiple metabolic and signaling pathways. We are beginning to appreciate the sensitivity of cellular zinc homeostasis to perturbations, the clinical importance of linked zinc and redox imbalances for aging and the development of chronic diseases, and the tangible benefits of preventive and therapeutic nutritional interventions.
细胞锌代谢的一个关键方面是对皮摩尔浓度的游离锌离子及其波动进行严格控制，以平衡蛋白质的折叠与错误折叠、为数千种需要锌的蛋白质供应锌，以及锌作为促氧化剂或促抗氧化剂的双重功能。蛋白质中的锌/硫（半胱氨酸）键在这种控制中起关键作用，因为它们产生具有氧化还原活性的配位环境。金属硫蛋白（MT）就是这样一种具有氧化还原活性的锌蛋白，它在生物化学上与细胞氧化还原状态相关联。其锌/硫醇盐簇的配位动力学和氧化还原状态决定了细胞锌的可用性。组织和细胞中的一部分MT含有游离硫醇和二硫键。因此，以高分辨率三维结构表征的含有七个锌离子和二十个还原硫醇的MT并不代表其生物活性形式。氧化还原应激会影响MT的锌和氧化还原缓冲能力，并引发锌离子的波动，而锌离子是多种代谢和信号通路的有效效应器。我们开始认识到细胞锌稳态对扰动的敏感性、锌和氧化还原失衡与衰老及慢性疾病发展的临床相关性，以及预防性和治疗性营养干预的切实益处。
