Partial transition-state inhibitors of glyoxalase I from human erythrocytes, yeast and rat liver.
Glyoxalase I (lactoylglutathione lyase, EC 4.4.1.5) converts the hemithiolacetal of glutathione and an alpha-ketoaldehyde to S-D-lactoylglutathione which is hydrolysed under the catalytic influence of glyoxalase II to produce D-lactate and regenerate glutathione. There is much evidence that glyoxalase I operates via an enediol intermediate, and in this study a number of inhibitors are described which were designed based on the enediol moiety of this reactive intermediate. These enediol and paene-enediol moieties were combined with groups designed to make use of an adjacent hydrophobic site and can be described as partial transition-state analogues. Derivatives of lapachol and kojic acid were good competitive inhibitors of glyoxalase I from various sources unless the free hydroxy group was blocked or replaced. Flavones with strong inhibitors of glyoxalase I and gallocyanine (a dye) showed spectral changes on binding to glyoxalase I indicative of binding to a metal-ion site (probably Zn2+ or Mg2+). The use of the enediol-binding determinant to produce glyoxalase I inhibitors is discussed as a route to potential antitumour derivatives.
D000818:Animals; D001665:Binding Sites; D004912:Erythrocytes / Q000201:enzymology; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D007791:Lactoylglutathione Lyase / Q000037:antagonists & inhibitors*; D008099:Liver / Q000201:enzymology; D008190:Lyases / Q000037:antagonists & inhibitors*; D009285:Naphthoquinones / Q000494:pharmacology; D011753:Pyrones / Q000494:pharmacology; D011794:Quercetin / Q000494:pharmacology; D051381:Rats; D012441:Saccharomyces cerevisiae / Q000201:enzymology
D009285:Naphthoquinones; D011753:Pyrones; C008316:maltol; D011794:Quercetin; C008252:lapachol; D008190:Lyases; D007791:Lactoylglutathione Lyase