Principles of Biochemistry, Volume 2 - A. Lehninger 1985

Bioenergetics and Metabolism
The Citric Acid Cycle
The citric acid cycle is regulated

Let us now examine how The Citric Acid Cycle itself is regulated (Fig. 16-15). In most cases, The rate of metabolic cycles is determined by their initial steps. It is believed that the same holds true for The Citric Acid cycle. The overall rate of its operation in many Tissues is dictated by the first reaction:

Class="center">Ацетил-СоА + Оксалоацетат → Цитрат + СоА.

Naturally, the rate of the citrate synthase reaction is regulated by the concentrations of its substrates—specifically, acetyl-CoA, which in turn depends on The activity of the Pyruvate dehydrogenase complex. This reaction is also regulated by the concentration of the second substrate, oxaloacetate; it is even possible that this factor plays a primary role, given that the concentration of oxaloacetate in Cell/35.html">Mitochondria is very low and depends on metabolic conditions. Citrate synthase activity is likewise influenced by the concentration of succinyl-CoA, one of the later Intermediates of the cycle. As soon as the concentration of succinyl-CoA exceeds the normal steady-state level, citrate synthase is immediately inhibited because succinyl-CoA lowers its affinity for acetyl-CoA. Fatty acids, which serve as precursors of acetyl-CoA, also inhibit citrate synthase through allosteric effects. In some Cells, citrate and NADH act as inhibitors of citrate synthase as well.

Fig. 16-14. Regulation of the pyruvate dehydrogenase reaction via covalent interconversion of the active and inactive forms of the enzyme. Ca²⁺ ions promote The formation of the active enzyme form by stimulating phosphopiruvate dehydrogenase phosphatase.

Fig. 16-15. Regulation of the citric acid cycle during pyruvate oxidation in animal cells. ATP, NADH, acetyl-CoA, and Ca²⁺ control the rate of acetyl-CoA formation from pyruvate, whereas the overall rate of the citric acid cycle is regulated by oxaloacetate concentration, as well as by the activities of citrate synthase and isocitrate dehydrogenase.

In most cells, The oxidation of isocitrate to α-ketoglutarate and CO₂, which can be catalyzed by two different isocitrate dehydrogenases, appears to be regulated by allosteric stimulation of the NAD-dependent enzyme by ADP. At the same time, NADH and NADPH act as negative modulators of isocitrate dehydrogenase activity. The α-ketoglutarate dehydrogenase complex is inhibited by its reaction product, succinyl-CoA. Thus, at least three steps in the citric acid cycle are regulated, although the precise details of this regulation vary somewhat among different cell types.

Under normal conditions, the rate of Glycolysis is coordinated with the rate of the citric acid cycle; The Cell breaks down only as much glucose into pyruvate as is necessary to supply the citric acid cycle with "fuel," i.e., the acetyl groups of acetyl-CoA. Neither pyruvate, lactate, nor acetyl-CoA normally accumulates in large amounts in aerobic cells; their concentrations are maintained at a steady state corresponding to dynamic equilibrium. This coordination between the rate of glycolysis and the citric acid cycle is not only due to the inhibition of the former by high concentrations of ATP and NADH—components shared by both glycolytic and respiratory stages of glucose oxidation—but is also mediated in part by citrate concentration. Citrate, the product of the first step of the citric acid cycle, acts as an allosteric inhibitor of Phosphofructokinase, which catalyzes the phosphorylation of fructose-6-phosphate during glycolysis (Section 15.13 and Fig. 15.15).