title: Glycogen synthase kinase-3 is required for optimal de novo synthesis of inositol.
abstract: 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-3Delta 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-3Delta 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-3Delta. Activity of myo-inositol-3 phosphate synthase, the rate-limiting enzyme in inositol de novo biosynthesis, was decreased in gsk-3Delta. 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.
authors.affiliation: Department of Biological Sciences, Wayne State University, Detroit, MI 48202, USA.
authors.forename: Abed N
authors.initials: AN
authors.lastname: Azab
authors.forename: Quan
authors.initials: Q
authors.lastname: He
authors.forename: Shulin
authors.initials: S
authors.lastname: Ju
authors.forename: Guiling
authors.initials: G
authors.lastname: Li
authors.forename: Miriam L
authors.initials: ML
authors.lastname: Greenberg
mesh_terms: D004791:Enzyme Inhibitors / Q000494:pharmacology; D015966:Gene Expression Regulation, Fungal; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007294:Inositol / Q000378:metabolism* / Q000494:pharmacology; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D009004:Monosaccharide Transport Proteins; D009154:Mutation; D007296:Myo-Inositol-1-Phosphate Synthase / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D013696:Temperature; D013830:Thiadiazoles / Q000494:pharmacology
chemical_list: C494356:4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione; D004791:Enzyme Inhibitors; C069143:ITR1 protein, S cerevisiae; D026901:Membrane Transport Proteins; D009004:Monosaccharide Transport Proteins; D029701:Saccharomyces cerevisiae Proteins; D013830:Thiadiazoles; D007294:Inositol; D038362:Glycogen Synthase Kinase 3; D007296:Myo-Inositol-1-Phosphate Synthase