|Title||Common and Divergent Features of Galactose-1-phosphate and Fructose-1-phosphate Toxicity in Yeast.|
|Publication Type||Journal Article|
|Year of Publication||2018|
|Authors||Gibney, PA, Schieler, A, Chen, JC, Bacha-Hummel, JM, Botstein, M, Volpe, M, Silverman, SJ, Xu, Y, Bennett, BD, Rabinowitz, JD, Botstein, D|
|Journal||Mol Biol Cell|
|Date Published||2018 Feb 14|
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.
|Alternate Journal||Mol. Biol. Cell|