naphthoquinones and maltol

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.

Topics: Animals; Binding Sites; Erythrocytes; Humans; In Vitro Techniques; Kinetics; Lactoylglutathione Lyase; Liver; Lyases; Naphthoquinones; Pyrones; Quercetin; Rats; Saccharomyces cerevisiae