Genetic perturbation of glycolysis results in inhibition of de novo inositol biosynthesis.
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.
Shi
Yihui
Y
Department of Biological Sciences, Wayne State University, Detroit, Michigan 48202, USA.
Vaden
Deirdre L
DL
Ju
Shulin
S
Ding
Daobin
D
Geiger
James H
JH
Greenberg
Miriam L
ML
D000595:Amino Acid Sequence; D001483:Base Sequence; D017931:DNA Primers; D006019:Glycolysis; D007294:Inositol / Q000096:biosynthesis*; D008094:Lithium / Q000494:pharmacology; D008969:Molecular Sequence Data; D009154:Mutation; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D014305:Triose-Phosphate Isomerase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology
D017931:DNA Primers; D007294:Inositol; D014635:Valproic Acid; D008094:Lithium; D014305:Triose-Phosphate Isomerase