Inhibition by alloxan of mitochondrial aconitase and other enzymes associated with the citric acid cycle

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Abstract
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, α-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 K i values for the purified enzyme in the presence of 5 μM alloxan were 0.22 μM with citrate, 4.0 μM with cis-aconitate and 0.62 μM with isocitrate as substrate. The high sensitivity of aconitase for inhibition by alloxan probably plays a prominent role for the toxic effects of alloxan.