Common and Divergent Features of Galactose-1-phosphate and Fructose-1-phosphate Toxicity in Yeast.

TitleCommon and Divergent Features of Galactose-1-phosphate and Fructose-1-phosphate Toxicity in Yeast.
Publication TypeJournal Article
Year of Publication2018
AuthorsGibney, PA, Schieler, A, Chen, JC, Bacha-Hummel, JM, Botstein, M, Volpe, M, Silverman, SJ, Xu, Y, Bennett, BD, Rabinowitz, JD, Botstein, D
JournalMol Biol Cell
Date Published2018 Feb 14
ISSN1939-4586
Abstract

Toxicity resulting from accumulation of sugar-phosphate molecules is an evolutionarily conserved phenomenon, observed in multiple bacterial and eukaryotic systems, including a number of human diseases. However, the molecular mechanisms involved in sugar-phosphate toxicity remain unclear. Using the model eukaryote, we developed two systems to accumulate human disease-associated sugar-phosphate species. One system utilizes constitutive expression of galactose permease and galactose kinase to accumulate galactose-1-phosphate, while the other system utilizes constitutive expression of a mammalian ketohexokinase gene to accumulate fructose-1-phosphate. These systems advantageously dissociate sugar phosphate toxicity from metabolic demand for downstream enzymatic products. Using them, we characterized the pathophysiological effects of sugar-phosphate accumulation, in addition to identifying a number of genetic suppressors that repair sugar-phosphate toxicity. By comparing the effects of different sugar-phosphates, and examining the specificity of genetic suppressors, we observed a number of striking similarities and significant differences. These results suggest that sugar-phosphates exert toxic effects, at least in part, through isomer-specific mechanisms rather than through a single general mechanism common to accumulation of any sugar-phosphate.

DOI10.1091/mbc.E17-11-0666
Alternate JournalMol. Biol. Cell
PubMed ID29444955