title: The glucose metabolite methylglyoxal inhibits expression of the glucose transporter genes by inactivating the cell surface glucose sensors Rgt2 and Snf3 in yeast.
abstract: Methylglyoxal (MG) is a cytotoxic by-product of glycolysis. MG has inhibitory effect on the growth of cells ranging from microorganisms to higher eukaryotes, but its molecular targets are largely unknown. The yeast cell-surface glucose sensors Rgt2 and Snf3 function as glucose receptors that sense extracellular glucose and generate a signal for induction of expression of genes encoding glucose transporters (HXTs). Here we provide evidence that these glucose sensors are primary targets of MG in yeast. MG inhibits the growth of glucose-fermenting yeast cells by inducing endocytosis and degradation of the glucose sensors. However, the glucose sensors with mutations at their putative ubiquitin-acceptor lysine residues are resistant to MG-induced degradation. These results suggest that the glucose sensors are inactivated through ubiquitin-mediated endocytosis and degraded in the presence of MG. In addition, the inhibitory effect of MG on the glucose sensors is greatly enhanced in cells lacking Glo1, a key component of the MG detoxification system. Thus the stability of these glucose sensors 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 sensors and thus identify MG as a potential glycolytic inhibitor.
authors.affiliation: Department of Biochemistry and Molecular Medicine, George Washington University School of Medicine and Health Science, Washington, DC 20037.
authors.forename: Adhiraj
authors.initials: A
authors.lastname: Roy
authors.affiliation: Department of Biochemistry and Molecular Medicine, George Washington University School of Medicine and Health Science, Washington, DC 20037.
authors.forename: Salman
authors.initials: S
authors.lastname: Hashmi
authors.affiliation: Department of Biochemistry and Molecular Medicine, George Washington University School of Medicine and Health Science, Washington, DC 20037.
authors.forename: Zerui
authors.initials: Z
authors.lastname: Li
authors.affiliation: Virginia Bioinformatics Institute, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061.
authors.forename: Angela D
authors.initials: AD
authors.lastname: Dement
authors.affiliation: Department of Biology, Indiana State University, Terre Haute, IN 47809.
authors.forename: Kyu Hong
authors.initials: KH
authors.lastname: Cho
authors.affiliation: Department of Biochemistry and Molecular Medicine, George Washington University School of Medicine and Health Science, Washington, DC 20037 jh_kim@gwu.edu.
authors.forename: Jeong-Ho
authors.initials: JH
authors.lastname: Kim
mesh_terms: D004705:Endocytosis / Q000502:physiology; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D005947:Glucose / Q000378:metabolism; D051246:Glucose Transport Proteins, Facilitative / Q000235:genetics* / Q000378:metabolism; D007791:Lactoylglutathione Lyase / Q000235:genetics / Q000378:metabolism; D009004:Monosaccharide Transport Proteins / Q000235:genetics / Q000378:metabolism*; D011765:Pyruvaldehyde / Q000378:metabolism* / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D043743:Ubiquitin-Protein Ligase Complexes / Q000235:genetics / Q000378:metabolism
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D051246:Glucose Transport Proteins, Facilitative; C090594:HXT1 protein, S cerevisiae; C090595:HXT3 protein, S cerevisiae; D009004:Monosaccharide Transport Proteins; C112512:RGT2 protein, S cerevisiae; C104463:SNF3 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D011765:Pyruvaldehyde; D043743:Ubiquitin-Protein Ligase Complexes; D007791:Lactoylglutathione Lyase; C469287:RSP5 protein, S cerevisiae; D005947:Glucose