Methylglyoxal production in bacteria: suicide or survival?
Methylglyoxal is a toxic electrophile. In Escherichia coli cells, the principal route of methylglyoxal production is from dihydroxyacetone phosphate by the action of methylglyoxal synthase. The toxicity of methylglyoxal is believed to be due to its ability to interact with the nucleophilic centres of macromolecules such as DNA. Bacteria possess an array of detoxification pathways for methylglyoxal. In E. coli, glutathione-based detoxification is central to survival of exposure to methylglyoxal. The glutathione-dependent glyoxalase I-II pathway is the primary route of methylglyoxal detoxification, and the glutathione conjugates formed can activate the KefB and KefC potassium channels. The activation of these channels leads to a lowering of the intracellular pH of the bacterial cell, which protects against the toxic effects of electrophiles. In addition to the KefB and KefC systems, E. coli cells are equipped with a number of independent protective mechanisms whose purpose appears to be directed at ensuring the integrity of the DNA. A model of how these protective mechanisms function will be presented. The production of methylglyoxal by cells is a paradox that can be resolved by assigning an important role in adaptation to conditions of nutrient imbalance. Analysis of a methylglyoxal synthase-deficient mutant provides evidence that methylglyoxal production is required to allow growth under certain environmental conditions. The production of methylglyoxal may represent a high-risk strategy that facilitates adaptation, but which on failure leads to cell death. New strategies for antibacterial therapy may be based on undermining the detoxification and defence mechanisms coupled with deregulation of methylglyoxal synthesis.
Ferguson
G P
GP
Department of Molecular and Cell Biology, Institute of Medical Sciences, Foresterhill, University of Aberdeen, Aberdeen, Scotland AB25 2ZD.
Tötemeyer
S
S
MacLean
M J
MJ
Booth
I R
IR
D017920:Antiporters / Q000378:metabolism; D001419:Bacteria / Q000201:enzymology / Q000378:metabolism*; D001426:Bacterial Proteins / Q000378:metabolism; D004269:DNA, Bacterial / Q000378:metabolism; D004926:Escherichia coli / Q000737:chemistry / Q000201:enzymology / Q000502:physiology; D029968:Escherichia coli Proteins; D005978:Glutathione / Q000378:metabolism; D006019:Glycolysis / Q000502:physiology; D015221:Potassium Channels / Q000378:metabolism; D027961:Potassium-Hydrogen Antiporters; D011765:Pyruvaldehyde / Q000378:metabolism*; D012808:Sigma Factor / Q000378:metabolism
D017920:Antiporters; D001426:Bacterial Proteins; D004269:DNA, Bacterial; D029968:Escherichia coli Proteins; D015221:Potassium Channels; D027961:Potassium-Hydrogen Antiporters; D012808:Sigma Factor; C069567:sigma factor KatF protein, Bacteria; C069287:KefC protein, E coli; D011765:Pyruvaldehyde; D005978:Glutathione