Principles of Biochemistry Volume 2 - A. Lehninger 1985

Bioenergetics and Metabolism
Glycolysis: The Central Pathway of Glucose Catabolism
The sequence of glycolytic reactions itself is regulated at two primary control points

The rate of Glycolysis is regulated not only through the recruitment of free glucose or Glycogen glucosyl residues, as described above, but the sequence of reactions from glucose-6-phosphate to Pyruvate itself is also subject to biological control. There are two main regulated steps in this sequence: one is catalyzed by Phosphofructokinase, and the other by pyruvate kinase.

Phosphofructokinase (PFK) is a complex allosteric enzyme controlled by numerous positive and negative modulators. Dozens of research papers have been devoted to its regulatory mechanisms, which vary across different Cell types. In Skeletal Muscle, phosphofructokinase activity is determined by the concentrations of its substrates (ATP and fructose-6-phosphate) and products (ADP and fructose-1,6-bisphosphate); all of these compounds act as Allosteric regulators. AMP, citrate, Mg²⁺ ions, phosphate, and several other metabolites present in Muscle tissue also play crucial regulatory roles (Table 15-1). However, although PFK regulation depends on the complex interplay of multiple factors, the primary negative modulators of this enzyme are ATP and citrate, while the most potent positive modulators are AMP and fructose-1,6-bisphosphate. Whenever the ATP concentration drops during intense Muscle contraction and energy demand increases, phosphofructokinase activity surges even if the fructose-6-phosphate concentration is extremely low (as evidenced by the hyperbolic dependence of the reaction rate on concentration; Fig. 15-15, A). If, however, the cellular ATP level is already high compared to ADP and AMP, the apparent affinity of phosphofructokinase for fructose-6-phosphate drops sharply (indicated by the sigmoidal shape of the curve in Fig. 15-15, A). In this case, phosphofructokinase catalyzes the reaction only at a relatively high concentration of fructose-6-phosphate. Citrate, an intermediate of The Citric Acid Cycle, enhances the inhibition of phosphofructokinase by high ATP concentrations. Simultaneously, an increase in the concentration of AMP, produced via the adenylate kinase reaction in contracting muscle (see Fig. 14-17), serves as a very potent stimulating modulator, counteracting the inhibitory effect of ATP on the phosphofructokinase reaction (Fig. 15-15, B). As a result of these complex allosteric interactions, the rate of the phosphofructokinase-catalyzed reaction can increase by hundreds of times when skeletal muscle transitions from a resting state to maximum activity.

Class="center">Table 15-1. Some allosteric activators and inhibitors of phosphofructokinase

The second regulated step of glycolysis is the pyruvate kinase reaction. Pyruvate kinase also belongs to allosteric Enzymes. This enzyme occurs in at least three isoforms (Section 9.23), which differ in their tissue distribution and response to various modulators. At high ATP concentrations, the apparent affinity of pyruvate kinase for phosphoenolpyruvate is relatively low, and accordingly, the rate of the pyruvate kinase reaction is modest at ordinary phosphoenolpyruvate concentrations. Pyruvate kinase is also inhibited by acetyl-CoA and long-chain Fatty acids—compounds that play a major role as fuel for The Citric Acid cycle. Thus, when cellular ATP concentration is already high or when there is sufficient fuel for the energy-supplying respiratory process, glycolysis is inhibited via either phosphofructokinase or pyruvate kinase (depending on the conditions). Conversely, at low ATP concentrations, the apparent affinity of pyruvate kinase for phosphoenolpyruvate increases, allowing the enzyme to transfer phosphate groups from phosphoenolpyruvate to ADP even at a relatively low phosphoenolpyruvate concentration. Certain Amino Acids also act as modulators of pyruvate kinase activity, primarily in the Liver.

In all Cells, glycolysis is regulated with exceptional efficiency—reminiscent of computer-like control—allowing fluctuations in the concentrations of various metabolites to fine-tune its overall rate. Such sophisticated regulation is hardly surprising, given that glycolysis is the most ancient catabolic pathway occupying a central position in METABOLISM.