A novel target of lithium therapy

Phosphatases converting 3'-phosphoadenosine 5'-phosphate (PAP) into adenosi ne 5'-phosphate are of fundamental importance in living cells as the accumu lation of PAP is toxic to several cellular systems. These enzymes are lithi um-sensitive and we have characterized a human PAP phosphatase as a potenti al target of lithium therapy, A cDNA encoding a human enzyme was identified hg data base screening, expressed in Escherichia coli and the 33 kDa prote in purified to homogeneity, The enzyme exhibits high affinity for PAP (K-m <1 mu M) and is sensitive to subtherapeutic concentrations of lithium (IC50 =0.3 mM). The human enzyme also hydrolyzes inositol-1,4-bisphosphate with high affinity (K-m = 0.4 mu M), therefore it can be considered as a dual sp ecificity enzyme with high affinity (mu M range) for both PAP and inositol- 1,4-bisphosphate. Hydrolysis of inositol-1,4- bisphosphate was also inhibit ed by lithium (IC50 = 0.6 mM). Thus, we present experimental evidence for a novel target of lithium therapy, which could explain some of the side effe cts of this therapy. (C) 2000 Federation of European Biochemical Societies.