Shi Y, et al. (2005) Genetic perturbation of glycolysis results in inhibition of de novo inositol biosynthesis. J Biol Chem 280(51):41805-10
Abstract: 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.
|Status: Published||Type: Journal Article||PubMed ID: 16221686|
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