Gluconeogenesis is the process whereby glucose is synthesized from non-carbohydrate precursors, which enables yeast cells to grow on non-sugar carbon sources like ethanol, glycerol, or peptone. The reactions of gluconeogenesis, shown here, mediate conversion of pyruvate to glucose, which is the opposite of glycolysis, the formation of pyruvate from glucose. While these two pathways have several reactions in common, they are not the exact reverse of each other. As the glycolytic enzymes phosphofructokinase (Pfk1p, Pfk2p) and pyruvate kinase (Cdc19p) only function in the forward direction, the gluconeogenesis pathway replaces those steps with the enzymes pyruvate carboxylase (Pyc1p, Pyc2p) and phosphoenolpyruvate carboxykinase (Pck1p)-generating oxaloacetate as an intermediate from pyruvate to phosphoenolpyruvate-and also the enzyme fructose-1,6-bisphosphatase (Fbp1p) (reviewed in 4). Overall, the gluconeogenic reactions convert two molecules of pyruvate to a molecule of glucose, with the expenditure of six high-energy phosphate bonds, four from ATP and two from GTP. Expression of genes encoding several of the gluconeogenic enzymes is subject to glucose repression (5).

MDH2 encodes cytosolic malate dehydrogenase, which generates oxaloacetate for glucose synthesis during gluconeogenesis. As such, Mdh2p is required for growth on minimal medium with ethanol or acetate as the carbon source (1). There are two other malate dehydrogenase isozymes: Mdh1p localizes to mitochondria and functions in the TCA cycle, and Mdh3p is in the peroxisome and is thought to catalyze a step in the glyoxylate pathway (reviewed in 3).

Levels of Mdh2p are regulated by glucose represssion of transcription and also by protein degradation when glucose-starved cells are replenished with glucose (6). Mdh2p is phosphorylated during the process of degradation, and both phosphorylation and degradation require a 12-residue amino-terminal extension not found in Mdh1p and Mdh3p (7, 8). There appear to be two pathways for degradation of Mdh2p: a proteasomal pathway that acts following short-term glucose starvation and a vacuolar pathway that functions following long-term glucose starvation (6). Mdh2p interacts with Pck1p and Fbp1p, which may facilitate flux through the gluconeogenic pathway, given the unfavorable equilibrium for formation of oxaloacetate from malate (3).

Last updated: 2005-06-23