It is evident that the complex network of metabolic reactions must be rigorously regulated. The levels of available nutrients must be monitored and the activity of metabolic pathways must be altered and integrated to create homeostasis, a stable biochemical environment. At the same time, metabolic control must be flexible, able to adjust metabolic activity to the changing external and internal environments of cells. Figure 15.20 illustrates the nutrient pools and their connections that must be monitored and regulated. Metabolism is regulated through control of (1) the amounts of enzymes, (2) their catalytic activities, and (3) the accessibility of substrates.

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The amount of a particular enzyme depends on both its rate of synthesis and its rate of degradation. The level of many enzymes is adjusted primarily by a change in the rate of transcription of the genes encoding them (Section 15). In E. coli, for example, the presence of lactose induces within minutes a more than 50-fold increase in the rate of synthesis of β-galactosidase, an enzyme required for the breakdown of this disaccharide.

The catalytic activity of enzymes is controlled in several ways. Allosteric control is especially important. For example, the first reaction in many biosynthetic pathways is allosterically inhibited by the ultimate product of the pathway, an example of feedback inhibition. This type of control can be almost instantaneous. Another recurring mechanism is the activation and deactivation of enzymes by reversible covalent modification. Reversible modification is often the end point of the signal-transduction cascades discussed in Chapter 13. For example, glycogen phosphorylase, the enzyme catalyzing the breakdown of glycogen, a storage form of glucose, is activated by the phosphorylation of a particular serine residue when glucose is scarce.

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Hormones coordinate metabolic relations between different tissues, often by regulating the reversible modification of key enzymes. For instance, the hormone epinephrine triggers a signal-transduction cascade in muscle, resulting in the phosphorylation and activation of key enzymes and leading to the rapid degradation of glycogen to glucose, which is then used to supply ATP for muscle contraction. Glucagon has the same effect in liver, but the glucose is released into the blood for other tissues to use. As described in Chapter 13, many hormones act through intracellular messengers, such as cyclic AMP (cAMP) and calcium ion, which coordinate the activities of many target proteins.

Many reactions in metabolism are controlled by the energy status of the cell. One index of the energy status is the energy charge, which is the fraction of all of the adenine nucleotide molecules in the form of ATP plus half the fraction of adenine nucleotides in the form of ADP, given that ATP contains two phosphoanhydride linkages, whereas ADP contains one. Hence, the energy charge is defined as

The energy charge can have a value ranging from 0 (all AMP) to 1 (all ATP). A high-energy charge inhibits ATP-generating (catabolic) pathways because the cell has sufficient levels of ATP. ATP-utilizing (anabolic) pathways, on the other hand, are stimulated by a high-energy charge because ATP is available. In plots of the reaction rates of such pathways versus the energy charge, the curves are steep near an energy charge of 0.9, where they usually intersect (Figure 15.21). Evidently, the control of these pathways has evolved to maintain the energy charge within rather narrow limits. In other words, the energy charge, like the pH of a cell, is buffered. The energy charge of most cells ranges from 0.80 to 0.95.

An alternative index of the energy status is the phosphorylation potential, which is directly related to the free-energy storage available in the form of ATP. The phosphorylation potential is defined as

The phosphorylation potential, in contrast with the energy charge, depends on the concentration of inorganic orthophosphate (P_i).

Controlling the availability of substrates is another means of regulating metabolism in all organisms. For instance, glucose breakdown can take place in many cells only if insulin is present to promote the entry of glucose into the cell. In eukaryotes, metabolic regulation and flexibility are enhanced by compartmentalization. The transfer of substrates from one compartment of a cell to another can serve as a control point. For example, fatty acid oxidation takes place in mitochondria, whereas fatty acid synthesis takes place in the cytoplasm. Compartmentalization segregates opposed reactions.