title: Tol1, a fission yeast phosphomonoesterase, is an in vivo target of lithium, and its deletion leads to sulfite auxotrophy.
abstract: Lithium is the drug of choice for the treatment of bipolar affective disorder. The identification of an in vivo target of lithium in fission yeast as a model organism may help in the understanding of lithium therapy. For this purpose, we have isolated genes whose overexpression improved cell growth under high LiCl concentrations. Overexpression of tol1(+), one of the isolated genes, increased the tolerance of wild-type yeast cells for LiCl but not for NaCl. tol1(+) encodes a member of the lithium-sensitive phosphomonoesterase protein family, and it exerts dual enzymatic activities, 3'(2'),5'-bisphosphate nucleotidase and inositol polyphosphate 1-phosphatase. tol1(+) gene-disrupted cells required high concentrations of sulfite in the medium for growth. Consistently, sulfite repressed the sulfate assimilation pathway in fission yeast. However, tol1(+) gene-disrupted cells could not fully recover from their growth defect and abnormal morphology even when the medium was supplemented with sulfite, suggesting the possible implication of inositol polyphosphate 1-phosphatase activity for cell growth and morphology. Given the remarkable functional conservation of the lithium-sensitive dual-specificity phosphomonoesterase between fission yeast and higher-eukaryotic cells during evolution, it may represent a likely in vivo target of lithium action across many species.
authors.affiliation: Department of Pharmacology, Kobe University School of Medicine, Kobe 650-0017, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Miyamoto
authors.forename: R
authors.initials: R
authors.lastname: Sugiura
authors.forename: S
authors.initials: S
authors.lastname: Kamitani
authors.forename: T
authors.initials: T
authors.lastname: Yada
authors.forename: Y
authors.initials: Y
authors.lastname: Lu
authors.forename: S O
authors.initials: SO
authors.lastname: Sio
authors.forename: M
authors.initials: M
authors.lastname: Asakura
authors.forename: A
authors.initials: A
authors.lastname: Matsuhisa
authors.forename: H
authors.initials: H
authors.lastname: Shuntoh
authors.forename: T
authors.initials: T
authors.lastname: Kuno
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D003470:Culture Media / Q000494:pharmacology; D004271:DNA, Fungal; D017353:Gene Deletion; D015870:Gene Expression; D005800:Genes, Fungal; D008094:Lithium / Q000378:metabolism*; D018021:Lithium Chloride / Q000494:pharmacology; D008969:Molecular Sequence Data; D009708:Nucleotidases / Q000235:genetics / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D012568:Schizosaccharomyces / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D029702:Schizosaccharomyces pombe Proteins; D017386:Sequence Homology, Amino Acid; D012965:Sodium Chloride / Q000494:pharmacology; D013431:Sulfates / Q000378:metabolism; D013447:Sulfites / Q000378:metabolism*
chemical_list: D003470:Culture Media; D004271:DNA, Fungal; D029702:Schizosaccharomyces pombe Proteins; D013431:Sulfates; D013447:Sulfites; D012965:Sodium Chloride; D008094:Lithium; D009708:Nucleotidases; D010744:Phosphoric Monoester Hydrolases; C053087:inositol-1,4-bisphosphate 1-phosphatase; C411969:Tol1 protein, S pombe; C053354:bisphosphoadenylate 3'-nucleotidase; D018021:Lithium Chloride