Biochimica et Biophysica Acta (BBA) - General Subjects ( IF 2.8 ) Pub Date : 2019-10-31 , DOI: 10.1016/j.bbagen.2019.129456 A Haimovich 1 , A Goldbourt 1
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Background
Lithium, in the form of a salt, is a mood stabilizer and a leading drug for the treatment of bipolar disorder. It has a very narrow therapeutic range and a variety of side effects. Lithium can replace magnesium and other cations in enzymes and small molecules, among them ATP, thereby affecting and inhibiting many biochemical pathways. The form of binding of lithium ions to ATP is not known.
Methods
Here we extract the binding environment of lithium in solid ATP using a multi-nuclear multi-dimensional solid-state NMR approach.
Results
We determine that the coordination sphere of lithium includes, at a distance of 3.0(±0.4) Å, three phosphates; the two phosphates closest to the ribose ring from one ATP molecule, and the middle phosphate from another ATP molecule. A water molecule most probably completes the fourth coordination. Despite the use of excess lithium in the preparations, sodium ions still remain bound to the sample, at distances of 4.3–5.5 Å from Li, and coordinate the first phosphate and two terminal phosphates.
Conclusions
Solid-state NMR enables to unravel the exact coordination of lithium in ATP showing binding to three phosphates from two molecules, none of which are the terminal gamma phosphate.
General significance
The methods we use are applicable to study lithium bound to a variety of ATP-bound enzymes, or to other cellular targets of lithium, consequently suggesting a molecular basis for its mode of action.
中文翻译：
情绪稳定剂锂如何与ATP（细胞的能量货币）结合：固态NMR的见解。
背景
盐形式的锂是一种情绪稳定剂，是治疗躁郁症的主要药物。它具有非常狭窄的治疗范围和多种副作用。锂可以代替酶和小分子中的镁和其他阳离子，其中包括ATP，从而影响和抑制许多生化途径。锂离子与ATP结合的形式尚不清楚。
方法
在这里，我们使用多核多维固态NMR方法提取锂在固体ATP中的结合环境。
结果
我们确定锂的配位球在3.0（±0.4）Å的距离内包含三种磷酸盐；一个ATP分子中最靠近核糖环的两个磷酸根，另一个ATP分子中的中间磷酸根。水分子很可能完成第四次配位。尽管制备中使用了过量的锂，但钠离子仍与样品结合，与锂之间的距离为4.3-5.5Å，并与第一磷酸盐和两个末端磷酸盐配位。
结论
固态NMR能够解开ATP中锂的精确配位，从而显示与两个分子中的三个磷酸酯的结合，而这三个磷酸酯都不是末端的γ磷酸酯。
一般意义
我们使用的方法适用于研究与多种ATP结合酶结合的锂，或与锂的其他细胞靶结合的锂，因此提示了其作用方式的分子基础。
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