Inhibition by alloxan of mitochondrial aconitase and other enzymes associated with the citric acid cycle.
Considerable variations were found in the in vitro effect of alloxan on mouse liver enzymes associated with the citric acid cycle. The following approximative alloxan concentrations induced 50% inhibition of enzyme activity: 10(-6)M for aconitase, 10(-4)M for NAD-linked isocitrate dehydrogenase, glutamate dehydrogenase, alpha-ketoglutarate dehydrogenase, succinyl-CoA synthetase and fumarase, and 10(-3)M for citrate synthase and NADP-linked isocitrate dehydrogenase. Pyruvate dehydrogenase, succinate dehydrogenase and malate dehydrogenase were not inhibited by 10(-3)M alloxan. The inhibition of aconitase was competitive both when using mouse liver and purified porcine heart enzyme. The Ki values for the purified enzyme in the presence of 5 microM alloxan were 0.22 microM with citrate, 4.0 microM with cis-aconitate and 0.62 microM with isocitrate as substrate. The high sensitivity of aconitase for inhibition by alloxan probably plays a prominent role for the toxic effects of alloxan.
D000154:Aconitate Hydratase / Q000037:antagonists & inhibitors*; D000496:Alloxan / Q000494:pharmacology*; D000818:Animals; D002950:Citrate (si)-Synthase / Q000037:antagonists & inhibitors; D002952:Citric Acid Cycle; D004305:Dose-Response Relationship, Drug; D005260:Female; D005969:Glutamate Dehydrogenase / Q000037:antagonists & inhibitors; D007521:Isocitrate Dehydrogenase / Q000037:antagonists & inhibitors; D007655:Ketoglutarate Dehydrogenase Complex / Q000037:antagonists & inhibitors; D008291:Malate Dehydrogenase / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology*; D013389:Succinate-CoA Ligases / Q000037:antagonists & inhibitors
D000496:Alloxan; D008291:Malate Dehydrogenase; D007521:Isocitrate Dehydrogenase; D007655:Ketoglutarate Dehydrogenase Complex; D005969:Glutamate Dehydrogenase; D002950:Citrate (si)-Synthase; D000154:Aconitate Hydratase; D013389:Succinate-CoA Ligases