Seal Manas, Dey Somdatta Ghosh
Department of Inorganic Chemistry, Indian Association for the Cultivation of Science , Jadavpur, Kolkata 700032, India.
Inorg Chem. 2018 Jan 2;57(1):129-138. doi: 10.1021/acs.inorgchem.7b02266. Epub 2017 Dec 18.
Type 2 diabetes mellitus (T2Dm) is characterized by reduced β cell mass and amyloid deposits of human islet amyloid polypeptide (hIAPP) or amylin, a 37 amino acid containing peptide around pancreatic β cells. The interaction of copper (Cu) with amylin and its mutants has been studied in detail using absorption, circular dichroism, electron paramagnetic resonance spectroscopy, and cyclic voltammetry. Cu binds amylin in a 1:1 ratio, and the binding domain lies within the first 19 amino acid residues of the peptide. Depending on the pH of the medium, Cu-amylin shows the formation of five pH-dependent components (component IV at pH 4.0, component III at pH 5.0, component II at pH 6.0, component I at pH 8.0, and another higher pH component above pH 9.0). The terminal amine, His18, and amidates are established as key residues in the peptide that coordinate the Cu center. The physiologically relevant components I and II can generate HO, which can possibly account for the enhanced toxicity of amylin in the presence of Cu, causing damage of the β cells of the pancreas via oxidative stress.
2型糖尿病（T2Dm）的特征是β细胞数量减少以及人胰岛淀粉样多肽（hIAPP）或胰淀素（一种含37个氨基酸的肽，存在于胰腺β细胞周围）的淀粉样沉积物。已经使用吸收光谱、圆二色光谱、电子顺磁共振光谱和循环伏安法详细研究了铜（Cu）与胰淀素及其突变体的相互作用。铜以1:1的比例结合胰淀素，结合域位于该肽的前19个氨基酸残基内。根据介质的pH值，铜-胰淀素显示出形成五种pH依赖性组分（pH 4.0时为组分IV，pH 5.0时为组分III，pH 6.0时为组分II，pH 8.0时为组分I，pH 9.0以上时为另一种更高pH值的组分）。末端胺、His18和酰胺化基团被确定为该肽中与铜中心配位的关键残基。生理相关的组分I和II可以产生羟基自由基（HO），这可能解释了在有铜存在的情况下胰淀素毒性增强的原因，即通过氧化应激导致胰腺β细胞受损。
