Glutathione-dependent detoxification of alpha-oxoaldehydes by the glyoxalase system: involvement in disease mechanisms and antiproliferative activity of glyoxalase I inhibitors.

The glyoxalase system is a metabolic pathway that catalyses the detoxification of alpha-oxoaldehydes RCOCHO to corresponding aldonic acids RCH(OH)CO2H. It thereby protects cells from alpha-oxoaldehyde-mediated formation of advanced glycation endproducts (AGEs). It is comprised of two enzymes, glyoxalase I and glyoxalase II, and a catalytic amount of reduced glutathione (GSH) as cofactor. It is present in the cytosol of cells of mammals and most micro-organisms. Physiological substrates of the glyoxalase system are: glyoxal--formed from lipid peroxidation and glycation reactions, methylglyoxal--formed from triosephosphates, ketone body metabolism and threonine catabolism, and 4,5-dioxovalerate--formed from 5-aminolevulinate and alpha-ketoglutarate. alpha-Oxoaldehydes react with guanyl residues in DNA and RNA, and with cysteine, lysine and arginine residues in proteins. The modification of DNA induces mutagenesis and apoptosis. The modification of proteins leads to protein degradation and activation of a cytokine-mediated immune response.