Inhibition of Pigeon Breast Muscle alpha-Ketoglutarate Dehydrogenase by Structural Analogs of alpha-Ketoglutarate

V. I. Bunik^1,2 and O. G. Pavlova¹

¹Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119899 Russia; fax: (7-095) 939-0338; E-mail: vbun@bac.genebee.msu.su

²To whom correspondence should be addressed.

Submitted March 27, 1997; revision submitted June 16, 1997.

---

Inhibition of alpha-ketoglutarate dehydrogenase (KGD) by dicarboxylates with (oxaloacetate and ketomalonate) and without (malonate, succinate, and glutarate) alpha-keto group was studied. Ketodicarboxylates at low concentrations inhibit KGD in competitive manner. Increase in their concentrations results in appearance of the noncompetitive component. The extent of KGD inhibition by ketodicarboxylates increases with structural similarity of the inhibitor and the substrate, irrespective of preliminary incubation of the enzyme with the inhibitor. This is indicative of blocking the substrate-binding site of KGD by dicarboxylates. In contrast, inhibitory effect of dicarboxylates which contain no keto group increases as their structural similarity with the substrate decreases. Saturation of KGD with dicarboxylates of this type does not completely suppress the enzymatic activity. Alternatively, these analogs display competitive mode of inhibition. Analysis of the data obtained suggests that these dicarboxylates produce catalytically active triple complex KGD--keto substrate--dicarboxylate and that KGD which enters the composition of such a complex exhibits a decreased affinity for the keto substrate as a result of the inhibitor binding.

---

KEY WORDS: alpha-ketoglutarate dehydrogenase, alpha-ketoglutarate, structural analogs of substrate, competitive and noncompetitive inhibition.

---