Redox reactions of copper complexes formed with different β-amyloid peptides and their neuropathalogical relevance
Redox reactions of copper complexes formed with different β-amyloid peptides and their neuropathalogical relevance
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DOI：
10.1021/bi700508n
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发表时间：
2007-08-14
期刊：
影响因子：
2.9
通讯作者：
Zhou, Feimeng
中科院分区：
文献类型：
--
作者：
Jiang, Dianlu;Men, Lijie;Zhou, Feimeng
通过电喷雾电离-傅立叶变换离子回旋共振质谱(ESI-FTICR-MS)和循环伏安法测定Cu(II)和全长β-淀粉样蛋白Aβ(1 -42)之间的结合化学计量以及所得复合物中铜的氧化态。将相同的方法扩展到 A beta(1-16) 和 A beta(1-28) 的铜配合物。直接观察到1:1的化学计量比，并且推断所有配合物中铜的氧化态均为2+，且Aβ(1-42)-Cu(II)配合物中残基酪氨酸-10和蛋氨酸-35未被氧化。当 Cu(II) 过量 10 倍以上时，化学计量比保持不变。唯一的酪氨酸残基和 Cu(II) 中心的氧化还原电位被确定为约。相对于 Ag/AgCl 分别为 0.75 和 0.08 V [或相对于普通氢电极 (NHE) 分别为 0.95 和 0.28 V]。更重要的是，首次通过电化学方法生成了 A beta-Cu(I) 络合物，并发现该络合物可以催化氧还原产生过氧化氢。三个 Aβ 片段的伏安行为表明，氧向金属中心的扩散可能受到 Aβ 肽的长度和疏水性的影响。氧化还原电位的测定和分配澄清了涉及 Aβ 的氧化还原反应中的一些误解，并为氧化还原金属离子在阿尔茨海默病 (AD) 发病机制中的可能作用提供了新的见解。在细胞环境中，Aβ-Cu(II) 复合物的还原电位足够高，足以与抗氧化剂（例如抗坏血酸）和细胞氧化还原缓冲液（例如谷胱甘肽）发生反应，并且产生的 Aβ-Cu(I) 复合物随后可以通过催化循环还原氧气形成过氧化氢。使用伏安法，发现溶液中形成的 A beta-Cu(II) 络合物很容易被抗坏血酸还原。产生的过氧化氢除了破坏 DNA、蛋白质和脂质分子外，还可能参与抗氧化剂的进一步消耗，导致神经元中抗氧化剂的消耗，最终破坏神经元防御系统。另一种可能性是，A beta-Cu(II) 可能与参与线粒体电子传递事件级联的物种发生反应，并可能偏离呼吸链中的电子传递过程，导致线粒体功能障碍。
The binding stoichiometry between Cu(II) and the full-length beta-amyloid A beta(l -42) and the oxidation state of copper in the resultant complex were determined by electrospray ionization-Fourier transform ion cyclotron resonance mass spectrometry (ESI-FTICR-MS) and cyclic voltammetry. The same approach was extended to the copper complexes of A beta(1-16) and A beta(1-28). A stoichiometric ratio of 1:1 was directly observed, and the oxidation state of copper was deduced to be 2+ for all of the complexes, and residues tyrosine-10 and methionine-35 are not oxidized in the A beta(1-42)-Cu(II) complex. The stoichiometric ratio remains the same in the presence of more than a 10-fold excess of Cu(II). Redox potentials of the sole tyrosine residue and the Cu(II) center were determined to be ca. 0.75 and 0.08 V vs Ag/AgCl [or 0.95 and 0.28 V vs normal hydrogen electrode (NHE)], respectively. More importantly, for the first time, the A beta-Cu(I) complex has been generated electrochemically and was found to catalyze the reduction of oxygen to produce hydrogen peroxide. The voltammetric behaviors of the three A beta segments suggest that diffusion of oxygen to the metal center can be affected by the length and hydrophobicity of the A beta peptide. The determination and assignment of the redox potentials clarify some misconceptions in the redox reactions involving A beta and provide new insight into the possible roles of redox metal ions in the Alzheimer's disease (AD) pathogenesis. In cellular environments, the reduction potential of the A beta-Cu(II) complex is sufficiently high to react with antioxidants (e.g., ascorbic acid) and cellular redox buffers (e.g., glutathione), and the A beta-Cu(I) complex produced could subsequently reduce oxygen to form hydrogen peroxide via a catalytic cycle. Using voltammetry, the A beta-Cu(II) complex formed in solution was found to be readily reduced by ascorbic acid. Hydrogen peroxide produced, in addition to its role in damaging DNA, protein, and lipid molecules, can also be involved in the further consumption of antioxidants, causing their depletion in neurons and eventually damaging the neuronal defense system. Another possibility is that A beta-Cu(II) could react with species involved in the cascade of electron transfer events of mitochondria and might potentially sidetrack the electron transfer processes in the respiratory chain, leading to mitochondrial dysfunction.