Yeast Mutants of Glucose Metabolism with Defects in the Coordinate Regulation of Carbon Assimilation

The enzymes of the glyoxylate cycle and gluconeogenesis are tightly regulated by transcriptional, posttranscriptional, and posttranslational mechanisms inSaccharomyces cerevisiae.We have previously identified four genes,ACN8, ACN9, ACN17,andACN18,whose mutant phenotype includes two- to fourfold elevated levels of enzymes of the glyoxylate cycle, gluconeogenesis, and acetyl-CoA metabolism. The affected enzymes are elevated on nonfermentable carbon sources but are still fully repressed by glucose. Catabolite inactivation of the cytosolic malate dehydrogenase is not affected in the mutants. Instead, the phenotype appeared to be manifested primarily at the level of transcription. TheACN8, ACN17,andACN18genes were isolated by functional complementation of the respective mutantʹs inability to utilize acetate as a carbon and energy source, and these genes were shown to encode subunits of metabolic enzymes.ACN8was identical toFBP1,which encodes the gluconeogenic enzyme, fructose 1,6-bisphosphatase, whileACN17andACN18were identical to theSDH2andSDH4genes, respectively, that encode subunits of the respiratory chain and tricarboxylic acid cycle enzyme, succinate dehydrogenase. Mutants defective in other glyoxylate cycle and gluconeogenic enzymes also display the elevated enzyme phenotype, indicating that the enzyme superinduction is a general property of gluconeogenic dysfunction. Glucose 6-phosphate levels were diminished in the mutants, suggesting that endogenous glucose synthesis can regulate the expression of gluconeogenic enzymes.