title: Valproic acid- and lithium-sensitivity in prs mutants of Saccharomyces cerevisiae.
abstract: Prs [PRPP (phosphoribosyl pyrophosphate) synthetase] catalyses the transfer of pyrophosphate from ATP to ribose 5-phosphate, thereby activating the pentose sugar for incorporation into purine and pyrimidine nucleotides. The Saccharomyces cerevisiae genome contains five genes, PRS1-PRS5, whose products display characteristic PRPP and bivalent-cation-binding sites of Prs polypeptides. Deletion of one or more of the five PRS genes has far-reaching and unexpected consequences, e.g. impaired cell integrity, temperature-sensitivity and sensitivity to VPA (valproic acid) and LiCl. CTP pools in prs1Delta and prs3Delta are reduced to 12 and 31% of the wild-type respectively, resulting in an imbalance in phospholipid metabolism which may have an impact on the intracellular inositol pool which is affected by the administration of either VPA or LiCl. Overexpression of CTP synthetase in prs1Delta prs3Delta strains partially reverses the VPA-sensitive phenotype. Yeast two-hybrid screening revealed that Prs3 and the yeast orthologue of GSK3 (glycogen synthase kinase 3), Rim11, a serine/threonine kinase involved in several signalling pathways, interact with each other. Furthermore, Prs5, an essential partner of Prs3, which also interacts with GSK3 contains three neighbouring phosphorylation sites, typical of GSK3 activation. These studies on yeast PRPP synthetases bring together and expand the current theories for the mood-stabilizing effects of VPA and LiCl in bipolar disorder.
authors.affiliation: Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Kleineidam
authors.forename: Stefano
authors.initials: S
authors.lastname: Vavassori
authors.forename: Ke
authors.initials: K
authors.lastname: Wang
authors.forename: Lilian M
authors.initials: LM
authors.lastname: Schweizer
authors.forename: Peter
authors.initials: P
authors.lastname: Griac
authors.forename: Michael
authors.initials: M
authors.lastname: Schweizer
mesh_terms: D000927:Anticonvulsants / Q000494:pharmacology*; D018692:Antimanic Agents / Q000494:pharmacology*; D001714:Bipolar Disorder / Q000188:drug therapy; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D018020:Lithium Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012268:Ribose-Phosphate Pyrophosphokinase / Q000235:genetics* / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism; D020798:Two-Hybrid System Techniques; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D000927:Anticonvulsants; D018692:Antimanic Agents; D047908:Intracellular Signaling Peptides and Proteins; D018020:Lithium Compounds; D029701:Saccharomyces cerevisiae Proteins; D014635:Valproic Acid; D017346:Protein Serine-Threonine Kinases; C090458:RIM11 protein, S cerevisiae; D012268:Ribose-Phosphate Pyrophosphokinase