Atrián-Blasco Elena, Santoro Alice, Pountney Dean L, Meloni Gabriele, Hureau Christelle, Faller Peter
LCC (Laboratoire de Chimie de Coordination), CNRS UPR 8241, 205 route de Narbonne, 31062 Toulouse Cedex 09, France.
Chem Soc Rev. 2017 Dec 11;46(24):7683-7693. doi: 10.1039/c7cs00448f.
Cu and Zn ions are essential in most living beings. Their metabolism is critical for health and mis-metabolism can be lethal. In the last two decades, a large body of evidence has reported the role of copper, zinc and iron, and oxidative stress in several neurodegenerative diseases like Alzheimer's, Parkinson's, prion diseases, etc. To what extent this mis-metabolism is causative or a consequence of these diseases is still a matter of research. In this context metallothioneins (MTs) appear to play a central gate-keeper role in controlling aberrant metal-protein interactions. MTs are small proteins that can bind high amounts of Zn(ii) and Cu(i) ions in metal-cluster arrangements via their cysteine thiolates. Moreover, MTs are well known antioxidants. The present tutorial outlines the chemistry underlying the interconnection between copper(i/ii) and zinc(ii) coordination to amyloidogenic proteins and MTs, and their redox properties in generation and/or silencing reactive oxygen species (overproduced in oxidative stress) and other reactants. These studies have revealed the coordination chemistry involved in neurodegenerative diseases and the interactions between MTs and amyloidogenic protein metal-complexes (like amyloid-β, α-synuclein and prion-protein). Overall, the protective role of MTs in neurodegenerative processes is emerging, serving as a foundation for exploring MT chemistry as inspiration for therapeutic approaches.
铜离子和锌离子对大多数生物来说都是必不可少的。它们的新陈代谢对健康至关重要，而新陈代谢异常可能是致命的。在过去二十年中，大量证据表明铜、锌、铁以及氧化应激在阿尔茨海默病、帕金森病、朊病毒病等多种神经退行性疾病中所起的作用。这种新陈代谢异常在多大程度上是这些疾病的病因或结果仍是一个研究课题。在这种背景下，金属硫蛋白（MTs）似乎在控制异常的金属 - 蛋白质相互作用中发挥着核心守门人的作用。金属硫蛋白是一种小蛋白，它可以通过其半胱氨酸硫醇盐以金属簇排列的方式结合大量的锌（ii）和铜（i）离子。此外，金属硫蛋白是众所周知的抗氧化剂。本教程概述了铜（i/ii）和锌（ii）与淀粉样蛋白生成蛋白及金属硫蛋白配位之间相互联系的化学原理，以及它们在产生活性氧物种（在氧化应激中过量产生）和其他反应物以及使这些物质失活过程中的氧化还原特性。这些研究揭示了神经退行性疾病中涉及的配位化学以及金属硫蛋白与淀粉样蛋白生成蛋白金属复合物（如淀粉样β蛋白、α - 突触核蛋白和朊病毒蛋白）之间的相互作用。总体而言，金属硫蛋白在神经退行性过程中的保护作用正在显现，这为探索金属硫蛋白化学以启发治疗方法奠定了基础。
