Glyoxalase I is inactivated by nitration of its tyrosine residues

Glyoxalase I, an anti-cancer target enzyme, catalyses the detoxification of the cytotoxic hemithiolacetal formed between methylglyoxal and glutathione (GSH) by rearrangement to S-D-lactoylglutathione, which, in a reaction catalysed glyoxalase II, is hydrolysed to free GSH and D-lactate. The enzymic activity of glyoxalase I is completely and rapidly destroyed by nitration of its tyrosine residues by tetranitromethane (TNM), the reaction being 90% complete within 30 minutes. Efficient protection against this irreversible modification was afforded by the presence of the competitive inhibitor S-p-bromobenzylglutathione. Amino-acid analysis and spectral evidence showed a progressive loss of tyrosine titre and concurrent appearance of 3-nitrotyrosine with the time of reaction of the enzyme with TNM. The nitration of tyrosine residue(s) in or near the active site is probably responsible for the loss of glyoxalase I activity, though the precise role of this tyrosine(s) is not yet clear.