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J. Biol. Chem., Vol. 280, Issue 51, 41805-41810, December 23, 2005

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Genetic Perturbation of Glycolysis Results in Inhibition of de Novo Inositol Biosynthesis^*

Yihui Shi1, Deirdre L. Vaden1, Shulin Ju, Daobin Ding, James H. Geiger, and Miriam L. Greenberg2

From the Department of Biological Sciences, Wayne State University, Detroit, Michigan 48202 and Department of Chemistry, Michigan State University, East Lansing, Michigan 48824

In a genetic screen for Saccharomyces cerevisiae mutants hypersensitive to the inositol-depleting drugs lithium and valproate, a loss of function allele of TPI1 was identified. The TPI1 gene encodes triose phosphate isomerase, which catalyzes the interconversion of dihydroxyacetone phosphate (DHAP) and glyceraldehyde 3-phosphate. A single mutation (N65K) in tpi1 completely abolished Tpi1p enzyme activity and led to a 30-fold increase in the intracellular DHAP concentration. The tpi1 mutant was unable to grow in the absence of inositol and exhibited the "inositol-less death" phenotype. Similarly, the pgk1 mutant, which accumulates DHAP as a result of defective conversion of 3-phosphoglyceroyl phosphate to 3-phosphoglycerate, exhibited inositol auxotrophy. DHAP as well as glyceraldehyde 3-phosphate and oxaloacetate inhibited activity of both yeast and human myo-inositol-3 phosphate synthase, the rate-limiting enzyme in de novo inositol biosynthesis. Implications for the pathology associated with TPI deficiency and responsiveness to inositol-depleting anti-bipolar drugs are discussed. This study is the first to establish a connection between perturbation of glycolysis and inhibition of de novo inositol biosynthesis.

Received for publication, May 11, 2005 , and in revised form, October 3, 2005.

^* This work was supported by National Institutes of Health Grant MH56220 (to M. L. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These two authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 313-577-5202; Fax: 313-577-6891; E-mail: MLGREEN{at}sun.science.wayne.edu.

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