A novel target of lithium therapy.
Phosphatases converting 3'-phosphoadenosine 5'-phosphate (PAP) into adenosine 5'-phosphate are of fundamental importance in living cells as the accumulation of PAP is toxic to several cellular systems. These enzymes are lithium-sensitive and we have characterized a human PAP phosphatase as a potential target of lithium therapy. A cDNA encoding a human enzyme was identified by data base screening, expressed in Escherichia coli and the 33 kDa protein purified to homogeneity. The enzyme exhibits high affinity for PAP (K(m)<1 microM) and is sensitive to subtherapeutic concentrations of lithium (IC(50)=0.3 mM). The human enzyme also hydrolyzes inositol-1, 4-bisphosphate with high affinity (K(m)=0.4 microM), therefore it can be considered as a dual specificity enzyme with high affinity (microM range) for both PAP and inositol-1,4-bisphosphate. Hydrolysis of inositol-1,4-bisphosphate was also inhibited by lithium (IC(50)=0.6 mM). Thus, we present experimental evidence for a novel target of lithium therapy, which could explain some of the side effects of this therapy.
Yenush
L
L
Instituto de Biología Molecular y Celular de Plantas, Universidad Politécnica de Valencia-Consejo Superior de Investigaciones Científicas, Camino de Vera s/n, E-46022, Valencia, Spain.
Bellés
J M
JM
López-Coronado
J M
JM
Gil-Mascarell
R
R
Serrano
R
R
Rodríguez
P L
PL
D000244:Adenosine Diphosphate / Q000378:metabolism; D000249:Adenosine Monophosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D001483:Base Sequence; D002851:Chromatography, High Pressure Liquid; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000737:chemistry; D004926:Escherichia coli; D020224:Expressed Sequence Tags; D006801:Humans; D008094:Lithium / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D008969:Molecular Sequence Data; D009708:Nucleotidases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D012441:Saccharomyces cerevisiae
D018076:DNA, Complementary; D000249:Adenosine Monophosphate; D000244:Adenosine Diphosphate; D008094:Lithium; C010840:adenosine 3'-phosphate-5'-phosphate; D009708:Nucleotidases; D010744:Phosphoric Monoester Hydrolases; C053087:inositol-1,4-bisphosphate 1-phosphatase; C053354:bisphosphoadenylate 3'-nucleotidase