Insights into the Role of Magnesium Triad in myo-Inositol Monophosphatase: Metal Mechanism, Substrate Binding, and Lithium Therapy

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• 作者：Shaoyong Lu ; Wenkang Huang ; Xiaobai Li ; Zhimin Huang ; Xinyi Liu ; Yingyi Chen ; Ting Shi ; Jian Zhang
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2012
• 出版时间：September 24, 2012
• 年：2012
• 卷：52
• 期：9
• 页码：2398-2409
• 全文大小：561K
• 年卷期：v.52,no.9(September 24, 2012)
• ISSN：1549-960X

文摘

myo-Inositol monophosphatase (IMPase) plays a pivotal role in the intracellular phosphatidylinositol cell signaling pathway. It has attracted considerable attention as a putative therapeutic target for lithium therapy in the treatment of bipolar disorder. A trio of activated cofactor Mg<sup>2+sup> ions is required for inositol monophosphate hydrolysis by IMPase. In the present study, computational studies, including two-layered ONIOM-based quantum mechanics/mechanical mechanics (QM/MM) calculations, molecular modeling, and molecular dynamics (MD) simulations, were performed to ascertain the role of the Mg<sup>2+sup> triad in the IMPase active site. The QM/MM calculations show that the structural identity of the nucleophilic water molecule W1 shared by Mg<sup>2+sup>-1 and Mg<sup>2+sup>-3, activated by Thr95/Asp47 dyad, is a hydroxide ion. Moreover, Mg<sup>2+sup>-3 needs to be conjugated with Mg<sup>2+sup>-1 in the binding site to create the activated nucleophilic hydroxide ion in accordance with the three-metal ion catalytic mechanism. The MD simulation of the IMPase鈥搒ubstrate鈥揗g<sup>2+sup> complex shows that the three Mg<sup>2+sup> ions promote substrate binding and help fix the phosphate moiety of the substrate for nucleophilic attack by the hydroxide ion. When Mg<sup>2+sup>-2 is displaced with Li<sup>+sup>, the MD simulations of the postreaction complex indicate that the conformation of the catalytic loop (residues 33 to 44) is disrupted and water molecule W2 does not coordinate with Li<sup>+sup>. This disruption traps the inorganic phosphate and inositolate in the active site, which lead to IMPase inhibition. By contrast, in the native Mg<sup>2+sup> system, the W2 ligated by Mg<sup>2+sup>-2 and Asp200 aids in protonation of the leaving inositolate moiety.