Regulation of the Citric Acid Cycle:- The Citric Acid Cycle Is Regulated at Its Three Exergonic Steps
The flow of metabolites through the citric acid cycle is under stringent regulation. Three factors govern the rate of flux through the cycle: substrate availability, inhibition by accumulating products, and allosteric feedback inhibition of the enzymes that catalyze early steps in the cycle. Each of the three strongly exergonic steps in the cycle—those catalyzed by citrate synthase, isocitrate dehydrogenase, and -ketoglutarate dehydrogenase (Fig. 16–18)—can become the rate-limiting step under some circumstances. The availability of the substrates for citrate synthase (acetyl-CoA and oxaloacetate) varies with the metabolic state of the cell and sometimes limits the rate of citrate formation. NADH, a product of isocitrate and α-ketoglutarate oxidation, accumulates under some conditions, and at high [NADH]/[NAD+] both dehydrogenase reactions are severely inhibited by mass action. Similarly, in the cell, the malate dehydrogenase reaction is essentially at equilibrium (that is, it is substrate-limited, and when [NADH]/[NAD+] is high the concentration of oxaloacetate is low, slowing the first step in the cycle. Product accumulation inhibits all three limiting steps of the cycle: succinyl-CoA inhibits α- ketoglutarate dehydrogenase (and also citrate synthase); citrate blocks citrate synthase; and the end product, ATP, inhibits both citrate synthase and isocitrate dehydrogenase. The inhibition of citrate synthase by ATP is relieved by ADP, an allosteric activator of this enzyme. In vertebrate muscle, Ca2+, the signal for contraction and for a concomitant increase in demand for ATP, activates both isocitrate dehydrogenase and -ketoglutarate dehydrogenase, as well as the PDH complex. In short, the concentrations of substrates and intermediates in the citric acid cycle set the flux through this pathway at a rate that provides optimal concentrations of ATP and NADH.
Under normal conditions, the rates of glycolysis and of the citric acid cycle are integrated so that only as much glucose is metabolized to pyruvate as is needed to supply the citric acid cycle with its fuel, the acetyl groups of acetyl-CoA. Pyruvate, lactate, and acetyl-CoA are normally maintained at steady-state concentrations. The rate of glycolysis is matched to the rate of the citric acid cycle not only through its inhibition by high levels of ATP and NADH, which are common to both the glycolytic and respiratory stages of glucose oxidation, but also by the concentration of citrate. Citrate, the product of the first step of the citric acid cycle, is an important allosteric inhibitor of phosphofructokinase-1 in the glycolytic pathway.
