Principles of Biochemistry Volume 2 - A. Lehninger 1985

Bioenergetics and Metabolism
Electron Transport, Oxidative Phosphorylation, and the Regulation of ATP Synthesis
The regulatory mechanisms of glycolysis, the citric acid cycle, and oxidative phosphorylation are interconnected

Three stages of Carbohydrate Catabolism provide energy: Glycolysis (ch. 15), The Citric Acid Cycle (ch. 16), and Oxidative Phosphorylation. Each of these stages is regulated by its own control mechanisms to ensure that its rate matches The Cell's immediate demand for the products generated at that stage. Furthermore, these three stages are so tightly coordinated that they function as a unified, economical, and self-regulating system, much like a well-oiled mechanical apparatus. This is how ATP—the ultimate product of energy-yielding catabolism—is produced, alongside specific intermediates such as Pyruvate and citrate, which serve as precursors for The Biosynthesis of other cellular components. The integration of these three stages is achieved through the interconnection of their regulatory mechanisms. As shown in Fig. 17-29, the relative concentrations of ATP and ADP (in other words, the mass-action ratio of The ATP system) determine not only the rates of electron transfer and oxidative phosphorylation, but also the rates of The Citric Acid cycle, pyruvate oxidation, and glycolysis. Whenever ATP consumption increases—meaning the ATP concentration drops while ADP and P_i concentrations rise—the rates of electron transfer and oxidative phosphorylation immediately increase as well. Simultaneously, The rate of pyruvate oxidation via the citric acid cycle also rises, thereby enhancing the influx of electrons into the Respiratory Chain. These events, in turn, lead to an increased rate of glycolysis, thus ensuring an enhanced supply of pyruvate. Eventually, the [ATP]/[ADP][P_i] ratio returns to its normally high level. At this point, electron transfer and oxidative phosphorylation slow down because the ADP concentration drops back to the low, resting-state level. The citric acid cycle and glycolysis also slow down because ATP acts as an allosteric inhibitor of both Glycolysis and Pyruvate Oxidation.

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Fig. 17-29. Interdependent Regulation of glycolysis, pyruvate oxidation, the citric acid cycle, and oxidative phosphorylation, determined by the relative concentrations of ATP, ADP, and AMP. Regulatory effects, both inhibitory and stimulatory, are indicated by red bars and arrows. At high ATP concentrations and correspondingly low ADP and AMP concentrations, the rates of glycolysis, pyruvate oxidation, the citric acid cycle, and oxidative phosphorylation are minimal. If cellular ATP consumption sharply increases, causing ADP, AMP, and P_i concentrations to rise, all four of these processes are accelerated. The interplay between glycolysis and the citric acid cycle mediated by citrate (also shown in this scheme) complements the regulatory action of the adenylate system. In addition, elevated concentrations of NADH and acetyl-CoA inhibit the Oxidation of Pyruvate to acetyl-CoA. G6P, glucose-6-phosphate; F6P, fructose-6-phosphate; FDP, fructose 1,6-bisphosphate; G3P, glyceraldehyde 3-phosphate; 3PG, 3-phosphoglycerate; 2PG, 2-phosphoglycerate; PEP, phosphoenolpyruvate; α-KG, α-ketoglutarate.

The regulatory Enzymes of glycolysis and the citric acid cycle also act in concert. When ATP (produced via oxidative phosphorylation) and citrate (the initial intermediate of the citric acid cycle) accumulate above their usual levels, they act synergistically to bring about the allosteric inhibition of Phosphofructokinase (Fig. 17-29), with The Effect of this dual inhibition being greater than the sum of their individual effects. Thus, glycolysis is controlled by an interconnected network of regulatory mechanisms, ensuring that pyruvate is produced only at the rate at which it is consumed by the citric acid cycle, which in turn supplies electrons for oxidative phosphorylation.

In Cancer Cells, this coordination of regulatory controls appears to be disrupted: glycolysis proceeds at a significantly higher rate than is required to supply fuel for the citric acid cycle. Consequently, aerobic cancer cells consume much more glucose from the Blood than normal cells do, yet they fail to oxidize all the pyruvate generated during glycolysis. A large portion of it is instead converted to lactate, which is carried away by the bloodstream.