Metabolism of the 2-oxoaldehyde methylglyoxal by aldose reductase and by glyoxalase-I: roles for glutathione in both enzymes and implications for diabetic complications

Numerous physiological aldehydes besides glucose are substrates of aldose r eductase, the first enzyme of the polyol pathway which has been implicated in the etiology of diabetic complications. The 2-oxoaldehyde methylglyoxal is a preferred substrate of aldose reductase but is also the main physiolog ical substrate of the glutathione-dependent glyoxalase system. Aldose reduc tase catalyzes the reduction of methylglyoxal efficiently (k(cat) = 142 min (-1) and k(cat)/K-m = 1.8 x 10(7) M-1 min(-1)). In the presence of physiolo gical concentrations of glutathione, methylglyoxal is significantly convert ed into the hemithioacetal. which is the actual substrate of glyoxalase-I. However, in the presence of glutathione, the efficiency of reduction of met hylglyoxal, catalyzed by aldose reductase, also increases. In addition, the site of reduction switches from the aldehyde to the ketone carbonyl. Thus, glutathione converts aldose reductase from an aldehyde reductase to a keto ne reductase with methylglyoxal as substrate. The relative importance of al dose reductase and gryoxalase-I in the metabolic disposal of methylglyoxal is highly dependent upon the concentration of glutathione, owing to the non -catalytic pre-enzymatic reaction between methylglyoxal and glutathione. (C ) 2001 Elsevier Science Ireland Ltd. All rights reserved.