Cells have developed a highly conserved enzymatic detoxification system to neutralize the reactive and cytotoxic metabolite methylglyoxal (pyruvaldehyde). The glyoxalase system which had initially been reported in 1913 is composed of two enzymes working in tandem. Glyoxalase I (E.C. 184.108.40.206) converts the non-enzymatically formed hemithioacetal of methylglyoxal and glutathione to the thioester S-lactoylglutathione. This product serves as the substrate for glyoxalase II (E.C. 220.127.116.11) which hydrolyzes the thioester to D-lactate and regenerates the glutathione co-substrate. Although extensive investigation of the glyoxalase I enzyme suggested a system that was Zn2+-activated, recent findings on the Escherichia coli GlxI indicate the presence of a second class of GlxI that is not activated by Zn2+, but is instead maximally activated in the presence of Ni2+. Sequence comparisons have been used to identify putative GlxI enzymes from bacterial species. Several other Ni2+-activated GlxI enzymes have been isolated and characterized from Pseudomonas aeruginosa, Neisseria meningitidis and Yersinia pestis. Crystallographic studies of the E. coli GlxI have indicated structural similarity to the Zn2+-activated GlxI from human. Given the substantial level of structural and sequence conservation between the two enzymes, it is surprising to observe a divergence in metal selectivity. This chapter reviews the critical aspects of the Ni2+-activated class of GlxI enzymes from an enzymological and biophysical perspective.
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