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 prs1Δ and prs3Δ 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 prs1Δ prs3Δ 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.
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October 2009
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Conference Article|
September 21 2009
Valproic acid- and lithium-sensitivity in prs mutants of Saccharomyces cerevisiae
Anna Kleineidam;
Anna Kleineidam
*Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol BS1 3NY, U.K.
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Stefano Vavassori;
Stefano Vavassori
†School of Life Sciences, Heriot-Watt University, Edinburgh EH14 4AS, U.K.
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Ke Wang;
Ke Wang
†School of Life Sciences, Heriot-Watt University, Edinburgh EH14 4AS, U.K.
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Lilian M. Schweizer;
Lilian M. Schweizer
†School of Life Sciences, Heriot-Watt University, Edinburgh EH14 4AS, U.K.
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Peter Griac;
Peter Griac
‡Institute of Animal Biochemistry and Genetics, Slovak Academy of Sciences, Bratislava, Slovak Republic
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Michael Schweizer
Michael Schweizer
1
†School of Life Sciences, Heriot-Watt University, Edinburgh EH14 4AS, U.K.
1To whom correspondence should be addressed (email M.Schweizer@hw.ac.uk).
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Publisher: Portland Press Ltd
Received:
April 29 2009
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2009 Biochemical Society
2009
Biochem Soc Trans (2009) 37 (5): 1115–1120.
Article history
Received:
April 29 2009
Citation
Anna Kleineidam, Stefano Vavassori, Ke Wang, Lilian M. Schweizer, Peter Griac, Michael Schweizer; Valproic acid- and lithium-sensitivity in prs mutants of Saccharomyces cerevisiae. Biochem Soc Trans 1 October 2009; 37 (5): 1115–1120. doi: https://doi.org/10.1042/BST0371115
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