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Journal of Bacteriology, July 2000, p. 3619-3625, Vol. 182, No. 13
0021-9193/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Tol1, a Fission Yeast Phosphomonoesterase, Is an In Vivo Target of Lithium, and Its Deletion Leads to Sulfite Auxotrophy

Rumi Miyamoto,1 Reiko Sugiura,1 Shinya Kamitani,1 Tomoko Yada,1 Yabin Lu,1 Susie O. Sio,1,dagger Masahiro Asakura,2 Akio Matsuhisa,2 Hisato Shuntoh,3 and Takayoshi Kuno1,*

Department of Pharmacology, Kobe University School of Medicine, Kobe 650-0017,1 Research and Development Center, Fuso Pharmaceutical Industries, Osaka 536-0025,2 and Faculty of Health Science, Kobe University School of Medicine, Kobe 654-0142,3 Japan

Received 24 January 2000/Accepted 4 April 2000

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.


* Corresponding author. Mailing address: Department of Pharmacology, Kobe University School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. Phone: 81-78-382-5441. Fax: 81-78-382-5459. E-mail: tkuno{at}kobe-u.ac.jp.

dagger Present address: Department of Pharmacology, College of Medicine, University of the Philippines Manila, Manila 1000, Philippines.


Journal of Bacteriology, July 2000, p. 3619-3625, Vol. 182, No. 13
0021-9193/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.



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