CAS Key Laboratory of Soft Matter Chemistry, School of Chemistry and Materials Science, University of Science and Technology of China, Hefei, Anhui, China.
Metallomics. 2013 Jun;5(7):879-87. doi: 10.1039/c3mt20262c.
Platinum phenanthroline complexes have been found to inhibit Aβ aggregation and reduce Aβ caused neurotoxicity. Our previous results revealed the synergistic roles of phenanthroline ligand and Pt(ii) coordination in the inhibition of Aβ aggregation. In this work, the reactions of PtCl2(phen) with metal bound Aβ complexes were investigated. HPLC results show that the copper coordination decreases the reaction rate of PtCl2(phen) with Aβ1-16 and influences the distribution of products on HPLC profiles. EPR results reveal that Cu(2+) remains coordinated to the Aβ peptide upon the binding of Pt(phen), however, the Cu(2+) coordination sites are changed. The formation of bimetallic coordination complex [Pt(phen)+Aβ1-16+Cu(II)] was confirmed by ESI-MS. Tandem MS analysis shows that, similar to the reaction of apo-Aβ peptide, the His6/His14 chelation is also the preferred binding mode for Pt(phen) in the presence of copper ions. EPR spectra suggest that the binding of Pt(phen) alters the copper coordination from mode I to mode II in Aβ. Tandem MS analysis indicates that His13 and N-terminal amine could be involved in the Cu(2+) coordination in the bimetallic adduct. Similar results were observed in the reaction of Zn(2+) bound Aβ peptide, although the different zinc binding residues were detected in the bimetallic complex. These results indicate that the binding of platinum complex disturbs the most favorable coordination sphere of Cu(2+)/Zn(2+) and turns these metal ions to the secondary coordination site on Aβ. The release of Cu(2+)/Zn(2+) occurs at low pH. This result suggests that the binding of Pt(phen) scaffold could interfere with the binding of Zn(2+) and Cu(2+) to Aβ, thus reducing the metal-induced Aβ aggregation and toxicity.
铂菲咯啉配合物已被发现可抑制 Aβ 聚集并降低 Aβ 引起的神经毒性。我们之前的研究结果表明菲咯啉配体和 Pt(ii)配位在抑制 Aβ 聚集方面具有协同作用。在这项工作中，研究了 PtCl2(phen)与金属结合的 Aβ 配合物的反应。HPLC 结果表明，铜配位降低了 PtCl2(phen)与 Aβ1-16 的反应速率，并影响了 HPLC 图谱上产物的分布。EPR 结果表明，[Pt(phen)]2+结合后，Cu2+仍与 Aβ 肽配位，但 Cu2+的配位位置发生了变化。ESI-MS 证实了双金属配位配合物[Pt(phen)+Aβ1-16+Cu(II)]的形成。串联质谱分析表明，与apo-Aβ 肽的反应类似，在铜离子存在下，His6/His14 螯合也是[Pt(phen)]2+的首选结合模式。EPR 谱表明，[Pt(phen)]2+的结合将 Aβ 中铜的配位从模式 I 转变为模式 II。串联质谱分析表明，His13 和 N 端胺可能参与双金属加合物中 Cu2+的配位。在 Zn2+结合的 Aβ 肽的反应中也观察到了类似的结果，尽管在双金属配合物中检测到了不同的锌结合残基。这些结果表明，铂配合物的结合扰乱了 Cu2+ / Zn2+最有利的配位球，并将这些金属离子转化为 Aβ 的次级配位位。Cu2+ / Zn2+的释放发生在低 pH 值下。这一结果表明，[Pt(phen)]2+支架的结合可能会干扰 Zn2+和 Cu2+与 Aβ 的结合，从而减少金属诱导的 Aβ 聚集和毒性。
