ArticleScientific reports2023
Valproate regulates inositol synthesis by reducing expression of myo-inositol-3-phosphate synthase.
Article in Scientific reports, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed, 5 citations in OpenAlex.
- Valproic acid remodels phosphatidylglycerol homeostasis and epithelial-macrophage crosstalk in inflammatory signaling.iScience · 2026Article
- Inositol biosynthesis is inversely regulated by glycolytic activity.Biochimica et biophysica acta. Molecular and cell biology of lipids · 2026Article
- Valproate independently activates Snf1, inhibits TORC1, and induces repression of INO1 transcription by increasing nuclear localization of Opi1.Scientific reports · 2025Article
- Inositol Phosphates and Synthesizing Enzymes: Implications in Neurodegenerative Disorders.Biomolecules · 2025Review
- Kinase-catalyzed crosslinking: A comparison of ATP-crosslinker analogs.Bioorganic & medicinal chemistry letters · 2024Article
- Disorder-to-order active site capping regulates the rate-limiting step of the inositol pathway.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Inositol depletion is a hypothesized mechanism of action of mood stabilization drugs used in the treatment of bipolar disorder. It was previously reported that the mood stabilizer valproate (VPA) increased phosphorylation of myo-inositol-3-phosphate synthases (MIPS), the rate limiting enzyme of inositol synthesis. Phosphosites were identified and examination of site-directed mutants suggested that phosphorylation leads to decreased enzymatic activity. In this study, we examined the extent of MIPS phosphorylation in response to VPA and used two interaction screens to identify protein kinases that interact with MIPS. Using an epitope tagged MIPS construct, we determined the fraction of phosphorylated MIPS to be very low (less than 2% of total), and we could not detect phosphorylation of untagged MIPS in response to VPA. In vitro analyses of phosphorylation revealed that putative protein kinases, PKC and CKII, have low specificity toward MIPS. These findings suggest that VPA likely depletes inositol via a mechanism other than MIPS phosphorylation. Consistent with this, mRNA levels of the MIPS-encoding gene INO1 and MIPS protein levels were significantly reduced during the mid-log growth phase in response to VPA treatment. These findings suggest that the mechanism whereby VPA causes inositol depletion is by reducing expression of the rate-limiting enzyme MIPS.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.