INHIBITION OF PIGEON BREAST MUSCLE ALPHA-KETOGLUTARATE DEHYDROGENASE BY STRUCTURAL ANALOGS OF ALPHA-KETOGLUTARATE

Inhibition of alpha-ketoglutarate dehydrogenase (KGD) by dicarboxylate s with (oxaloacetate and ketomalonate) and without (malonate, succinat e, and glutarate) alpha-keto group was studied. Ketodicarboxylates at low concentrations inhibit KGD in competitive manner. Increase in thei r concentrations results in appearance of the noncompetitive component . The extent of KGD inhibition by ketodicarboxylates increases with st ructural similarity of the inhibitor and the substrate, irrespective o f preliminary incubation of the enzyme with the inhibitor. This is ind icative of blocking the substrate-binding site of KGD by dicarboxylate s. In contrast, inhibitory effect of dicarboxylates which contains no keto group increases as their structural similarity with the substrate decreases. Saturation of KGD with dicarboxylates of this type does no t completely suppress the enzymatic activity. Alternatively, these ana logs display competitive mode of inhibition. Analysis of the data obta ined suggests that these dicarboxylates produce catalytically active t riple complex keto substrate-KGD-dicarboxylate and that KGD which ente rs the composition of such a complex exhibits a decreased affinity for the keto substrate as a result of the inhibitor binding.