Competition between Li+ and Mg2+ in Metalloproteins. Implications for Lithium Therapy
Competition between Li+ and Mg2+ in Metalloproteins. Implications for Lithium Therapy
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DOI：
10.1021/ja201985s
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发表时间：
2011-06-22
影响因子：
15
通讯作者：
Lim, Carmay
中科院分区：
文献类型：
--
作者：
Dudev, Todor;Lim, Carmay
锂（以可溶性盐的形式）用于治疗双相情感障碍，并且被认为是治疗慢性神经退行性疾病如阿尔茨海默病、帕金森病和亨廷顿病的可能药物。提出的Li+作用机制之一涉及外来Li+和天然Mg 2+之间对金属结合位点的竞争，以及随后对参与特定神经传递途径的关键酶的抑制，但不是细胞中重要的Mg 2+蛋白。这引发了以下有趣的问题：为什么Li+只在双相情感障碍相关的酶中取代Mg 2+，而不是在细胞必需的Mg 2+蛋白中？一般来说，是什么因素使单价Li+取代蛋白质中的二价Mg 2+？具体来说，如何做的组成，总电荷，和溶剂暴露的金属结合位点以及金属结合的磷酸盐影响的选择性Li+超过Mg 2+？在许多可能的因素中，我们表明，Mg 2+和Li+之间的竞争取决于金属络合物的净电荷，这是由金属阳离子和带负电荷的配体的数量，以及金属腔的相对溶剂暴露。发现蛋白质本身通过提供由带负电荷的Asp/Glu内衬的溶剂不可接近的Mg 2+结合位点而选择Mg 2+超过单价Li+，而发现细胞机器通过在各种生物隔室中保持Mg 2+与其生物竞争物的高浓度比而在细胞液中的其他竞争性二价阳离子（如Ca 2+和Zn 2+）中选择Mg 2+。计算揭示了为什么Li+仅在Li+治疗的已知靶点酶中取代Mg 2+，而不是在细胞必需的Mg 2+酶中，并且还揭示了前者与后者蛋白质不同的共同特征。
Lithium is used (in the form of soluble salts) to treat bipolar disorder and has been considered as a possible drug in treating chronic neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's diseases. One of the proposed mechanisms of Li+ action involves a competition between the alien Li+ and native Mg2+ for metal-binding sites and subsequent inhibition of key enzymes involved in specific neurotransmission pathways, but not vital Mg2+ proteins in the cell. This raises the following intriguing questions: Why does Li+ replace Mg2+ only in enzymes involved in bipolar disorder, but not in Mg2+ proteins essential to cells? In general, what factors allow monovalent Li+ to displace divalent Mg2+ in proteins? Specifically, how do the composition, overall charge, and solvent exposure of the metal-binding site as well as a metal-bound phosphate affect the selectivity of Li+ over Mg2+? Among the many possible factors, we show that the competition between Mg2+ and Li+ depends on the net charge of the metal complex, which is determined by the numbers of metal cations and negatively charged ligands, as well as the relative solvent exposure of the metal cavity. The protein itself is found to select Mg2+ over the monovalent Li+ by providing a solvent-inaccessible Mg2+-binding site lined by negatively charged Asp/Glu, whereas the cell machinery was found to select Mg2+ among other competing divalent cations in the cellular fluids such as Ca2+ and Zn2+ by maintaining a high concentration ratio of Mg2+ to its biogenic competitor in various biological compartments. The calculations reveal why Li+ replaces Mg2+ only in enzymes that are known targets of Li+ therapy, but not in Mg2+ enzymes essential to cells, and also reveal features common to the former that differ from those in the latter proteins.