Raymond and Beverly Sackler Faculty of Exact Sciences, School of Chemistry, Tel Aviv University, Tel Aviv, Israel.
J Am Chem Soc. 2012 Mar 28;134(12):5647-51. doi: 10.1021/ja211794x. Epub 2012 Mar 15.
Inositol monophosphatase (IMPase) catalyzes the hydrolysis of inositol monophosphate to inorganic phosphate and inositol. For this catalytic process to occur, Mg(2+) cations must exist in the active site. According to the inositol depletion hypothesis, IMPase activity is assumed to be higher than normal in patients suffering from bipolar disorder. Treatment with Li(+), an inhibitor of IMPase, reduces its activity, but the mechanism by which lithium exerts its therapeutic effects is still at a stage of conjecture. The Escherichia coli SuhB gene product possesses IMPase activity, which is also strongly inhibited by Li(+). It has significant sequence similarity to human IMPase and has most of its key active-site residues. Here we show that by using (7)Li magic-angle-spinning solid-state NMR spectroscopy, including {(13)C}(7)Li dipolar recoupling experiments, the bound form of lithium in the active site of wild-type E. coli SuhB can be unambiguously detected, and on the basis of our data and other biochemical data, lithium binds to site II, coupled to aspartate residues 84, 87, and 212.
肌醇单磷酸酶（IMPase）催化肌醇单磷酸水解为无机磷酸和肌醇。为了发生这种催化过程，Mg(2+)阳离子必须存在于活性部位。根据肌醇耗竭假说，患有双相情感障碍的患者的 IMPase 活性被假设高于正常水平。用 Li(+)治疗，IMPase 的抑制剂，降低其活性，但锂发挥其治疗效果的机制仍处于推测阶段。大肠杆菌的 SuhB 基因产物具有 IMPase 活性，也被 Li(+)强烈抑制。它与人类 IMPase 具有显著的序列相似性，并且具有其大部分关键活性位点残基。在这里，我们通过使用（7）Li 魔角旋转固态 NMR 光谱学，包括{(13)C}(7)Li 偶极重聚实验，明确检测到野生型大肠杆菌 SuhB 活性部位中结合形式的锂，并且基于我们的数据和其他生化数据，锂结合到位点 II，与天冬氨酸残基 84、87 和 212 相连。
