How does the mood stabilizer lithium bind ATP, the energy currency of the cell

Abstract

Lithium is a leading drug for the treatment of bipolar disorder and affects many biochemical pathways via inhibition of phosphatases and kinases. Lithium can replace magnesium cations in enzymes and small molecules, among them ATP. Here we extract the binding environment of lithium in LiATP. Using a multi-nuclear solidstate NMR approach, we determine that lithium coordinates with the first (Pa) and second (Pb) phosphates of one ATP molecule, and with the second (Pb') phosphate of a second ATP molecule in the unit cell. The Li-P distance is 3 Å. The fourth coordination is probably to water. We suggest that the phosphate chains are non-linear and that Pg of one ATP molecule resides in between Pa' and Pg' of a second ATP molecule. 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 Pg, Pg ' , and Pa.