Question

Succinyl-CoA inhibits both citrate synthase and α-ketoglutarate dehydrogenase. How is succinyl-CoA able to inhibit both enzymes?

Answer 1

The citric acid cycle (TCA-Tricarboxylic acid or Krebs cycle) is a series of chemical reactions in all aerobic organisms used to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins, into ATP (adenosine triphosphate) and CO₂ (carbon dioxide). The rate of the citric acid cycle is precisely adjusted to meet an animal cell's needs for ATP.

Answer and explanation

α -ketoglutarate dehydrogenase is a highly regulated enzyme, catalyses the conversion of α-ketoglutarate to succinyl-CoA and produces NADH. This enzyme is an important catalyst in the fourth step of the cycle, where α-ketoglutarate loses a carbon and combines with CoA to form succinyl CoA. Both the products succinyl CoA and NADH, work as inhibitors at large concentrations. α-Ketoglutarate dehydrogenase is inhibited by succinyl CoA and NADH, the products of the reaction that it catalyzes.

Succinyl-coA, regulates citrate synthase through competitive inhibition by binding to its active site, thus blocking access of the substrate to the binding site. Succinyl-coA is a product of a later step in the Citric acid cycle. The accumulation succinyl CoA in the mitochondrial matrix indicates an abundance of electron carriers (in the form of NADH and FADH₂) and hence free energy (in the form of ATP) in the cell, suggesting that catabolism can be halted. Thus, succinyl-coA serves as a competitive feedback inhibitor of citrate synthase by inhibiting over catalysis of the citric acid cycle and stopping further catabolism.

Citrate synthase acts in the first step of the citric acid cycle by catalyzing the condensation reaction between acetyl-CoA and oxaloacetate to produce a six-carbon intermediate, citrate. ATP is an allosteric inhibitor of citrate synthase. Furthermore it is also inhibited by high concentrations of acetyl-CoA and NADH. The citrate also act as an inhibitor because citrate synthase is inhibited by succinyl CoA, the final product of the citric acid cycle as ATP.