Electronic Thesis/Dissertation


The cytotoxic effect of methylglyoxal on yeast cell growth Open Access

Abstract of ThesisThe Cytotoxic Effect of Methylglyoxal on Yeast Cell GrowthMethylglyoxal (MG) is a highly reactive, cytotoxic dicarbonyl compound, mainly formed as a by-product of glycolysis. It is one of the most potent glycating agents and readily reacts with proteins, lipids and nucleic acids to form advanced glycation end products (AGEs). However, the molecular targets of MG are largely unknown. Glucose is the preferred carbon source of yeast Saccharomyces cerevisiae which it can sense and utilize efficiently over a broad range of concentrations. It prefers to ferment rather than oxidize glucose, even when oxygen is abundant. The yeast cell-surface glucose sensors Rgt2 and Snf3 function as glucose receptors that sense extracellular glucose and generate a signal for induction of genes encoding glucose transporters (Hxts). Using molecular and cell biology approaches, including Western blotting, qRT-PCR analysis and fluorescence microscopy, I have provided evidence that MG inhibits expression of the Hxts (Hxt1 and Hxt3) by inactivating the low-affinity yeast glucose sensor Rgt2. MG inhibits the growth of glucose-fermenting yeast cells by inducing endocytosis and degradation of the glucose sensor. However, the glucose sensor with mutations at their putative ubiquitin-acceptor lysine residues is resistant to MG-induced degradation. The results of this study suggest that the low-affinity glucose sensor Rgt2 is inactivated through ubiquitin-mediated endocytosis and degraded in the presence of MG. Under physiological conditions, MG is detoxified by the glyoxalase system into D-lactate, with glyoxalase 1 (Glo1) as the key enzyme in the anti-glycation defense. This study further indicates that the inhibitory effect of MG on the glucose sensor is greatly enhanced in the cells lacking Glo1. Thus, the stability of this glucose sensor seems to be critically regulated by intracellular MG levels. Taken together, these findings suggest that MG attenuates glycolysis by promoting degradation of the cell surface glucose sensor and thus identify MG as a potential glycolytic inhibitor.

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