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Glycogen synthase kinase‐3 is required for optimal de novo synthesis of inositol
Author(s) -
Azab Abed N.,
He Quan,
Ju Shulin,
Li Guiling,
Greenberg Miriam L.
Publication year - 2007
Publication title -
molecular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.857
H-Index - 247
eISSN - 1365-2958
pISSN - 0950-382X
DOI - 10.1111/j.1365-2958.2007.05591.x
Subject(s) - inositol , gsk 3 , biology , glycogen synthase , inositol phosphate , biochemistry , biosynthesis , de novo synthesis , mutant , kinase , gsk3b , phosphatidylinositol , enzyme , atp synthase , gene , receptor
Summary Studies have shown that the inositol biosynthetic pathway and the enzyme glycogen synthase kinase‐3 (GSK‐3) are targets of the mood‐stabilizing drugs lithium and valproate. However, a relationship between these targets has not been previously described. We hypothesized that GSK‐3 may play a role in inositol synthesis, and that loss of GSK‐3 may lead to inositol depletion, thus providing a mechanistic link between the two drug targets. Utilizing a yeast Saccharomyces cerevisiae gsk‐3 Δ quadruple‐null mutant, in which all four genes encoding homologues of mammalian GSK‐3 are disrupted, we tested the hypothesis that GSK‐3 is required for de novo inositol biosynthesis. The gsk‐3 Δ mutant exhibited multiple features of inositol depletion, including defective growth in inositol‐lacking medium, decreased intracellular inositol, increased INO1 and ITR1 expression, and decreased levels of phosphatidylinositol. Treatment of wild‐type cells with a highly specific GSK‐3 inhibitor led to a significant increase in INO1 expression. Supplementation with inositol alleviated the temperature sensitivity of gsk‐3 Δ. Activity of myo ‐inositol‐3 phosphate synthase, the rate‐limiting enzyme in inositol de novo biosynthesis, was decreased in gsk‐3 Δ. These results demonstrate for the first time that GSK‐3 is required for optimal myo ‐inositol‐3 phosphate synthase activity and de novo inositol biosynthesis, and that loss of GSK‐3 activity causes inositol depletion.