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 p hosphate by the action of methylglyoxal synthase. The toxicity of meth ylglyoxal is believed to be due to its ability to interact with the nu cleophilic centres of macromolecules such as DNA. Bacteria possess an array of detoxification pathways for methylglyoxal. In E. coli, glutat hione-based detoxification is central to survival of exposure to methy lglyoxal. The glutathione-dependent glyoxalase I-II pathway is the pri mary route of methylglyoxal detoxification, and the glutathione conjug ates formed can activate the KefB and KefC potassium channels. The act ivation of these channels leads to a lowering of the intracellular pH of the bacterial cell, which protects against the toxic effects of ele ctrophiles. In addition to the KefB and KefC systems, E. coli cells ar e equipped with a number of independent protective mechanisms whose pu rpose appears to be directed at ensuring the integrity of the DNA. A m odel of how these protective mechanisms function will be presented. Th e production of methylglyoxal by cells is a paradox that can be resolv ed by assigning an important role in adaptation to conditions of nutri ent imbalance. Analysis of a methylglyoxal synthase-deficient mutant p rovides evidence that methylglyoxal production is required to allow gr owth under certain environmental conditions. The production of methylg lyoxal may represent a high-risk strategy that facilitates adaptation, but which on failure leads to cell death. New strategies for antibact erial therapy may be based on undermining the detoxification and defen ce mechanisms coupled with deregulation of methylglyoxal synthesis.