Principles of Biochemistry Volume 2 - A. Lehninger 1985

Bioenergetics and Metabolism
Metabolism: An Overview
The regulation of metabolic pathways occurs at three levels

Three types of mechanisms are involved in the Regulation of Metabolic pathways. The first of these, which responds most rapidly to any environmental change, relies on the action of allosteric Enzymes (Fig. 13-15). Their catalytic activity can be altered by specific substances that exert either a stimulatory or inhibitory effect, known as effectors or modulators (Section 9.18). Typically, allosteric enzymes occupy a position at or near the beginning of a multienzyme sequence and catalyze the rate-limiting step of the entire pathway, which is usually a virtually irreversible reaction. In catabolic processes coupled with the synthesis of ATP from ADP, this very end product—ATP—frequently acts as an allosteric inhibitor of an early catabolic step. Similarly, the end product of a biosynthetic pathway, such as a specific amino acid, often serves as an allosteric inhibitor of an early step in anabolism (Section 9.18). The activity of certain allosteric enzymes is stimulated by specific positive modulators. For example, an allosteric enzyme regulating a catabolic sequence may be subject to the stimulatory influence of positive modulators like ADP or AMP and the inhibitory effect of a negative modulator like ATP. There are also instances where the allosteric enzyme of a given metabolic pathway responds specifically to intermediates or End products of other metabolic pathways, thereby enabling the coordination of rates across different enzyme systems.

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Fig. 13-15. Feedback regulation of a catabolic pathway through the inhibition of an allosteric enzyme by the end product of the process. The letters J, K, L, etc., designate Intermediates of the metabolic pathway, while E₁, E₂, E₃, etc., represent the enzymes catalyzing individual steps. The first step is catalyzed by an allosteric enzyme (E₁), which is inhibited by the end product of the reaction sequence. Allosteric inhibition is indicated by the dashed red arrow connecting the inhibitory metabolite to the reaction catalyzed by the allosteric enzyme. Under cellular conditions, the regulated step (catalyzed by enzyme E₁) is typically a virtually irreversible reaction.

The second type of Metabolic Regulation in higher organisms is hormonal regulation (Fig. 13-16). Hormones are specialized chemical substances (chemical messengers) produced by various Endocrine glands and secreted directly into the bloodstream, which transports them to other Tissues or Organs where they stimulate or inhibit specific metabolic activities. For example, the hormone adrenaline is secreted by The adrenal medulla and carried by the Blood to the Liver, where it stimulates The breakdown of Glycogen to glucose, leading to an elevated blood sugar level. In addition, adrenaline stimulates Glycogenolysis in Skeletal Muscle, a process that results in The formation of lactate and the conservation of energy in the form of ATP. Adrenaline elicits these effects by binding to specific receptor sites On the surface of muscle or liver Cells. This binding acts as a signal that is transmitted to The Cell interior, triggering a covalent modification whereby Glycogen phosphorylase—the first enzyme in the pathway converting glycogen to glucose and other products (Section 9.22)—is converted from a less active form into a more active one (Fig. 13-16).

The third type of metabolic regulatory mechanism involves altering the intracellular concentration of a given enzyme. At any given moment, the concentration of any enzyme is determined by the balance between its rates of Synthesis and degradation. Under certain conditions, The rate of Synthesis of specific enzymes increases dramatically, leading to a corresponding rise in their intracellular concentration. If an animal, for example, is fed a diet rich in CARBOHYDRATES but low in protein, the concentration of liver enzymes that normally catalyze the degradation of Amino Acids to acetyl-CoA becomes extremely low. Because these enzymes are practically unneeded on such a diet, they are not produced in large quantities. However, if the animal is switched to a protein-rich diet, a noticeable increase in the levels of enzymes required for the breakdown of the ingested amino acids occurs in the liver within twenty-four hours. Liver cells thus possess the capacity to turn The Biosynthesis of specific enzymes on or off depending on The Nature of the incoming nutrients. This phenomenon is known as enzyme induction (Fig. 13-17).

Fig. 13-16. Hormonal Regulation of an enzymatic reaction. The binding of the hormone adrenaline to specific receptors on The surface of liver cells leads to the formation of cyclic AMP through the action of a membrane-bound enzyme (adenylyl cyclase). Cyclic AMP Functions as an allosteric activator, or intracellular messenger, which converts glycogen phosphorylase from an inactive to an active form, thereby accelerating The conversion of liver glycogen into blood glucose. This metabolic pathway is described in detail in Chapter 25.

Fig. 13-17. Enzyme induction. A high intracellular concentration of substrate A can stimulate the biosynthesis of enzymes E₁, E₂, and E₃. The levels of these enzymes within the cell rise, thereby facilitating the acceleration of reactions that eliminate the excess substrate A. Consequently, excess substrate A serves as a signal to the Cell Nucleus, prompting it to "turn on" the genes that control The production of enzymes E₁, E₂, and E₃. Gene activation entails the Synthesis of the corresponding Messenger RNA, which is transported to the Ribosomes, where it directs the synthesis of enzymes E₁, E₂, and E₃.