Genetic perturbation of glycolysis results in inhibition of de novo inositol biosynthesis

doi:10.1074/jbc.M505181200

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Papers In Press, published online ahead of print October 12, 2005
J. Biol. Chem, 10.1074/jbc.M505181200
Submitted on May 11, 2005
Accepted on October 12, 2005

Genetic perturbation of glycolysis results in inhibition of de novo inositol biosynthesis

Yihui Shi, Deirdre L. Vaden, Shulin Ju, Daobin Ding, James H. Geiger, and Miriam L. Greenberg

Biological Sciences, Wayne State University, Detroit, MI 48202

Corresponding Author: mlgreen{at}sun.science.wayne.edu

In a genetic screen for Saccharomyces cerevisiae mutants hypersensitive to the inositol-depleting drugs lithium (Li) and valproate (VPA), 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 (G-3-P). 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-phosphoglyceroylphosphate to 3-phosphoglycerate, exhibited inositol auxotrophy. DHAP as well as G-3-P and oxaloacetate (OAA) inhibited activity of both yeast and human myo-inositol-3 phosphate (MIP) 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.

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