Methylglyoxal as a Signal Initiator for Activation of the Stress-activated Protein Kinase Cascade in the Fission Yeast Schizosaccharomyces pombe

Abstract

Methylglyoxal (MG) is Methylglyoxal (MG,2 CH 3 COCHO) is a typical 2-oxoaldehyde derived from glycolysis, a ubiquitous energy-generating system present in all types of organism; nevertheless, MG inhibits the growth of cells (1). For example, MG induces apoptosis in some mammalian cells by provoking production of reactive oxygen species (2). Actually, cells exhibiting MG-induced apoptosis, such as Jurkat cells and HL60 cells, are sensitive to reactive oxygen species (3, 4). On the other hand, MG induces necrosis in the budding yeast Saccharomyces cerevisiae (5). In this case, MG does not enhance production of reactive oxygen species, and therefore, mutants lacking antioxidant enzymes (for example sod1⌬, sod2⌬, and gpx3⌬) do not show increased sensitivity to MG (5).Because the major source of MG is glycolysis, and an overaccumulation of MG adversely affects cellular function, cells of all types possess a ubiquitous enzymatic pathway, the glyoxalase system, for detoxification of MG. The glyoxalase system consists of glyoxalase I and glyoxalase II. The former catalyzes the conversion of MG to S-D-lactoylglutathione in the presence of glutathione. The latter hydrolyzes the resultant glutathione thiolester to D-lactic acid and glutathione (see Fig. 1). Previously, we have reported that the disruption of GLO1, the structural gene for glyoxalase I, enhances susceptibility to MG in S. cerevisiae (6). A mutant defective in glyoxalase II was also sensitive to MG (7). On the other hand, S. cerevisiae has another enzymatic route by which to convert MG to lactic acid, i.e. MG is reduced to L-lactaldehyde by the action of an NADPH-dependent methylglyoxal reductase, and L-lactaldehyde is further oxidized to L-lactic acid by an NAD ϩ -dependent lactaldehyde dehydrogenase (8, 9). Chen et al. (10) have reported that GRE2 encodes methylglyoxal reductase, although, as far as we could determine, gre2⌬ cells were not sensitive to MG. 3 Aguilera and Prieto (11) have reported that GRE3 encodes aldose reductase that is involved in the metabolism of MG; however, a gre3⌬ mutant did not exhibit an MG-sensitive phenotype. Consequently, the glyoxalase system is the major pathway to detoxify MG in S. cerevisiae (12). We have confirmed that a glyoxalase I-deficient mutant of the fission yeast Schizosaccharomyces pombe was also sensitive to MG (13).Aberrant metabolism of MG has been implicated in diseases such as colon cancer, diabetes, Alzheimer disease, and autism (14 -17). For example, in type 2 diabetes, the basal activity of the mitogen-activated protein (MAP) kinase family is increased, and the up-regulation of p38, one of the MAP kinases, is associated with a loss of expression of the GLUT4 glucose transporter that results in a lowering of glucose uptake, which may exacerbate hyperglycemia (18). Therefore, it is implied that there is a correlation between high MG levels and increased basal activation of p38 in type 2 diabetes. However, it remains to be clarified whether a high MG level is a consequence of diabetes, or diabetes induces abe...

Methylglyoxal Activates the Target of Rapamycin Complex 2-Protein Kinase C Signaling Pathway in Saccharomyces cerevisiae

“…We previously reported that MG causes acute cellular responses in yeasts (10,11). For example, the exogenous addition of MG activated yeast AP-1-like transcription factors (Yap1 in Saccharomyces cerevisiae and Pap1 in Schizosaccharomyces pombe) through the reversible modification of their critical Cys residues within 45 min (10,11). MG was also found to enhance the influx of extracellular Ca 2ϩ into the cell, thereby activating the Ca 2ϩ /calcineurin system in S. cerevisiae (12).…”

“…The harmful effects of MG on cellular functions have been attributed to MG-derived AGEs (4)(5)(6)(7)(8)(9). We previously reported that MG causes acute cellular responses in yeasts (10,11). For example, the exogenous addition of MG activated yeast AP-1-like transcription factors (Yap1 in Saccharomyces cerevisiae and Pap1 in Schizosaccharomyces pombe) through the reversible modification of their critical Cys residues within 45 min (10,11).…”

MaHog1, a Hog1-type mitogen-activated protein kinase gene, contributes to stress tolerance and virulence of the entomopathogenic fungus Metarhizium acridum

“…In Sc. pombe, the Sty1 pathway is activated in response to diverse stresses, such as osmotic stress, heat shock, oxidative stress, nitrogen limitation, carbon starvation, UV light, methylglyoxal, cold stress, arsenite and pressure (Degols et al, 1996;Degols & Russell, 1997;George et al, 2007;Millar et al, 1995;Rodríguez-Gabriel & Russell, 2005;Soto et al, 2002;Takatsume et al, 2006). In Candida (Ca.)…”

Glyoxalase System and Reactive Oxygen Species Detoxification System in Plant Abiotic Stress Response and Tolerance: An Intimate Relationship

“…MG activates transcription factors such as Yap1 and Msn2, and triggers a Hog1 mitogen-activated protein (MAP) kinase cascade in Saccharomyces cerevisiae. Regarding the activation of Hog1 by MG, Sln1, an osmosensor possessing histidine kinase activity, functions as a sensor of MG (Maeta et al, 2005;Takatsume et al, 2006). Our understanding of the signaling role of MG in higher plants is at a rudimentary stage.…”

“…However, a major gap exists in our understanding about how plants sense MG and oxidative stress in different subcellular compartments and how this stress signal is transduced, thus activating largescale and coordinated expression of different enzymes and metabolites of their detoxification pathways. A complete understanding of the interaction between ROS, MG and plant hormones and transcription factors (Sasaki-Sekimoto et al, 2005;Takatsume et al, 2006) and components of ROS and MG detoxification pathways in different subcellular www.intechopen.com Glyoxalase System and Reactive Oxygen Species Detoxification System in Plant Abiotic Stress Response and Tolerance: An Intimate Relationship 257 compartments will reveal more subtle regulatory roles of both detoxification systems in abiotic stress tolerance. In addition, identification of master regulators that control stress response activation will accelerate the process to improve and strengthen plant fitness to changing climates.…”