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J. Biol. Chem., Vol. 276, Issue 41, 37794-37801, October 12, 2001
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From the Lithium is a drug frequently used in the
treatment of manic depressive disorder. We have observed that
the yeast Saccharomyces cerevisiae is very sensitive to
lithium when growing in galactose medium. In this work we show that
lithium inhibits with high affinity yeast (IC50 ~ 0.2 mM) and human (IC50 ~ 1.5 mM)
phosphoglucomutase, the enzyme that catalyzes the reversible conversion
of glucose 1-phosphate to glucose 6-phosphate. Lithium inhibits the
rate of fermentation when yeast are grown in galactose and induces accumulation of glucose 1-phosphate and galactose 1-phosphate. Accumulation of these metabolites was also observed when a strain deleted of the two isoforms of phosphoglucomutase was incubated in
galactose medium. In glucose-grown cells lithium reduces the steady
state levels of UDP-glucose, resulting in a defect on trehalose and
glycogen biosynthesis. Lithium acts as a competitive inhibitor of yeast
phosphoglucomutase activity by competing with magnesium, a cofactor of
the enzyme. High magnesium concentrations revert lithium inhibition of
growth and phosphoglucomutase activity. Lithium stress causes an
increase of the phosphoglucomutase activity due to an induction of
transcription of the PGM2 gene, and its overexpression
confers lithium tolerance in galactose medium. These results show that
phosphoglucomutase is an important in vivo lithium target.
Phosphoglucomutase Is an in Vivo Lithium
Target in Yeast*
,,
,, and¶
Departamento de Bioquímica
Médica, Instituto de Ciências Biomédicas,
Universidade Federal do Rio de Janeiro, C. P. 68041, Rio de
Janeiro, RJ, 21941-590, Brazil and § Laboratório de
Glicobiologia, Instituto de Biofísica Carlos Chagas Filho,
Universidade Federal do Rio de Janeiro,
Rio de Janeiro, RJ, 21949-900, Brazil
*
This work was supported by grants from Fundação
Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de
Janeiro (FAPERJ) (to M. M.-L. and A. G.); fellowships
from Conselho Nacional de Desenvolvimento Cientifico e
Tecnológico (CNPq); and grants (to Dr. L. de Meis, UFRJ, Brazil)
from Financiadora de Estudos e Projetos/Pronex, CNPq, and FAPERJ.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
A Ph.D. student from Instituto de Microbiologia, UFRJ.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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