Regulation of inositol monophosphatase in Saccharomyces cerevisiae

Abstract

SummaryInositol monophosphatase is a key enzyme in the de novo biosynthesis of inositol and in the phosphoinositide second-messenger signalling pathway. Inhibition of this enzyme is a proposed mechanism for lithium's pharmacological action in bipolar illness (manic depression). Very little is known about how expression of this enzyme is regulated. Because the yeast Saccharomyces cerevisiae has been shown to be an excellent model system in which to understand the regulation of inositol metabolism, we characterized inositol monophosphatase in this yeast. Lithium inhibited monophosphatase activity in vitro. Growth in the presence of inositol resulted in increased expression of the enzyme in vivo, although inositol had no effect on enzyme activity in vitro. The inositol effect was apparent when cells were grown in glucose but not in glycerol/ethanol. Monophosphatase activity was derepressed as cells entered stationary phase. This effect was apparent only during growth in glucose plus inositol. The results demonstrate that S. cerevisiae monophosphatase is inhibited by lithium and regulated by factors affecting phospholipid biosynthesis.

Lithium and Valproate Decrease Inositol Mass and Increase Expression of the Yeast INO1 and INO2Genes for Inositol Biosynthesis

“…Both drugs, in therapeutically relevant concentrations, cause a decrease in intracellular inositol mass and an increase in expression of a structural (INO1) and a regulatory (INO2) gene required for inositol synthesis. The mechanism of inositol depletion by lithium is most likely by inhibition of inositol monophosphatase, as previous studies have shown that lithium inhibits yeast inositol monophosphatase activity and reduces expression of the INM1 gene (17,31). We propose that the mechanism of inositol depletion by valproate is most likely via inhibition of Ins-1-P synthase.…”

“…A likely mechanism for the lithium-induced decrease is via inhibition of inositol monophosphatase activity (17,31,34). We propose that valproate leads to decreased inositol by inhibition of the Ins-1-P synthase reaction.…”

Decreased Anterior Cingulate Myo-inositol/Creatine Spectroscopy Resonance with Lithium Treatment in Children with Bipolar Disorder

“…It is apparent that lithium exerts an effect on intracellular second-messenger systems in which activated receptorligand complexes stimulate the turnover of inositolcontaining phospholipids (del Rio et al 1998;Feldman et al 1997;Murray and Greenberg 1997;Soares et al 1999). Lithium's inhibitory action on receptor-mediated signal-transduction pathways has been demonstrated in vitro (Atack et al 1995) showing that it reduces myoinositol levels by non-competitively inhibiting the enzyme inositol monophosphate, a catalyst for converting inositol monophosphate hydroxyls to myo-inositol (Manji et al 1996).…”

“…Lithium's inhibitory action on receptor-mediated signal-transduction pathways has been demonstrated in vitro (Atack et al 1995) showing that it reduces myoinositol levels by non-competitively inhibiting the enzyme inositol monophosphate, a catalyst for converting inositol monophosphate hydroxyls to myo-inositol (Manji et al 1996). Since the phosphoinositide cycle (PI) regulates a wide variety of neuronal functions, including intracellular calcium mobilization and protein kinase C (PKC) activity (Feldman et al 1997), lithiuminduced modification of the PI cycle has been proposed as a potential therapeutic mechanism underlying its mood-stabilizing effect (Berridge et al 1982;del Rio et al 1998;Murray and Greenberg 1997;Soares et al 1999). Although brain tissue can synthesize myo-inositol de novo , the ability of neurons to maintain a steady-state supply of cytosolic myo-inositol appears to be crucial to the resynthesis of phosphoinositides, and, conceivably, to the membrane receptor response to stimulation and neuronal homeostasis.…”

Epi-inositol regulates expression of the yeast INO1 gene encoding inositol-1-P synthase

“…To prepare overnight cultures, yeast cells were inoculated from colonies on YPD plates (yeast extract (1% w/v), bacto-peptone (2% w/v), glucose (2% w/v), agar (2% w/v)) into minimal synthetic medium (glucose (2% w/v), the essential amino acids and nucleotides (histidine (10 mg l −1 ), leucine (60 mg l −1 ), methionine (10 mg l −1 ), tryptophan (10 mg l −1 ) and uracil (10 mg l −1 )), vitamin free yeast base (0.069% w/v), ammonium sulfate (0.201%), vitamins 29 and myo-inositol (75 M)) and grown overnight at 30°C with aeration. Cells were harvested by centrifugation (10°C, 5000 rpm, 5 min), washed twice with 50 ml inositol-free minimal medium, and resuspended in 25 ml of this medium.…”