Reaction rates and mechanism of the ascorbic acid oxidation by molecular oxygen facilitated by Cu(II)-containing amyloid-beta complexes and aggregates.
Reaction rates and mechanism of the ascorbic acid oxidation by molecular oxygen facilitated by Cu(II)-containing amyloid-beta complexes and aggregates.
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DOI：
10.1021/jp9095375
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发表时间：
2010-04-15
期刊：
影响因子：
--
通讯作者：
Zhou F
中科院分区：
文献类型：
--
作者：
Jiang D;Li X;Liu L;Yagnik GB;Zhou F
阿尔茨海默病 (AD) 研究的前沿是β淀粉样蛋白 (Aβ) 肽与氧化还原金属离子（例如 Cu(II)、Fe(III) 和 Fe(II)）的相互作用，以及 Aβ-金属复合物与神经元细胞损失以及必需金属和其他细胞物种稳态的生物学相关性。这项工作涉及分子氧抗坏血酸氧化反应的动力学和机理研究，该反应由 Cu(II) 与 Aβ(1–16)、Aβ(1–42) 和 Aβ(1–42) 聚集体的络合物促进。发现反应速率随着 Aβ-Cu(II) 和溶解氧的浓度线性增加，并且随着高抗坏血酸浓度不变。在低 (<100 µM) 和高 AA 浓度下，测得速率常数分别为 117.2 ± 15.4 和 15.8 ± 2.8 M−1s−1。与游离 Cu(II) 不同，在 AA 存在下，Aβ-Cu(II) 络合物通过产生 H2O2 作为主要产物来促进氧的还原。这一结论是基于当Aβ浓度保持在远大于Cu(II)浓度的值时，AA和O2之间的反应化学计量为1:1而得出的。提出了一种 AA 氧化机制，其中 Aβ 复合物中铜中心的氧化态在 2+ 和 1+ 之间交替。 Cu(II)对O2还原的催化活性按以下顺序降低：游离Cu(II) > Aβ(1–16)-Cu(II) > Aβ(1–42)-Cu(II) > Aβ低聚物/原纤维混合物络合的Cu(II) > Aβ原纤维中的Cu(II)。低聚和纤维状 Aβ 聚集体中的 Cu(II) 对 H2O2 生成具有相当大的活性这一发现尤其重要，因为在 AD 患者的老年斑中，共存的铜和 Aβ 聚集体被认为通过产生活性氧 (ROS) 来造成氧化应激。尽管与寡聚体和纤维状 Aβ 聚集体结合的 Cu(II) 在产生 ROS 方面不如游离 Cu(II) 和单体 Aβ-Cu(II) 复合物有效，但在体内，含 Cu(II) 的 Aβ 寡聚体和原纤维可能更具生物学相关性，因为它们与细胞膜的结合更强，并且 ROS 更接近细胞膜。
A forefront of the research on Alzheimer’s disease (AD) is the interaction of amyloid beta (Aβ) peptides with redox metal ions (e.g., Cu(II), Fe(III) and Fe(II)) and the biological relevance of the Aβ-metal complexes to neuronal cell loss and homeostasis of essential metals and other cellular species. This work is concerned with the kinetic and mechanistic studies of the ascorbic acid oxidation reaction by molecular oxygen that is facilitated by Cu(II) complexes with Aβ(1–16), Aβ(1–42), and aggregates of Aβ(1–42). The reaction rate was found to linearly increase with the concentrations of Aβ-Cu(II) and dissolved oxygen, and be invariant with high ascorbic acid concentrations. The rate constants were measured to be 117.2 ± 15.4 and 15.8 ± 2.8 M−1s−1 at low (<100 µM) and high AA concentrations, respectively. Unlike free Cu(II), in the presence of AA, Aβ-Cu(II) complexes facilitate the reduction of oxygen by producing H2O2 as a major product. Such a conclusion is drawn on the basis that the reaction stoichiometry between AA and O2 is 1:1 when Aβ concentration is kept at a much greater value than that of Cu(II). A mechanism is proposed for the AA oxidation in which the oxidation states of the copper center in the Aβ complex alternates between 2+ and 1+. The catalytic activity of Cu(II) towards O2 reduction was found to decrease in the order of free Cu(II) > Aβ(1–16)-Cu(II) > Aβ(1–42)-Cu(II) > Cu(II) complexed by the Aβ oligomer/fibril mixture > Cu(II) in Aβ fibrils. The finding that Cu(II) in oligomeric and fibrous Aβ aggregates possesses considerable activity towards H2O2 generation is particularly significant, since in senile plaques of AD patients the co-existing copper and Aβ aggregates have been suggested to inflict oxidative stress through the production of reactive oxygen species (ROS). Although Cu(II) bound to oligomeric and fibrous Aβ aggregates is less effective than free Cu(II) and the monomeric Aβ-Cu(II) complex in producing ROS, in vivo the Cu(II)-containing Aβ oligomers and fibrils might be more biologically relevant given their stronger association with cell membranes and the closer proximity of ROS to cell membranes.
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