Introduction to Metabolism
In Chapter 5, individual enzymic reactions were analyzed in an effort to explain the mechanisms of catalysis. However, in cells, these reactions rarely occur in isolation, but rather are organized into multistep sequences called pathways, such as that of glycolysis (Figure 8.1). In a pathway, the product of one reaction serves as the substrate of the subsequent reaction. Different pathways can also intersect, forming an integrated and purposeful network of chemical reactions.
These are collectively called metabolism, which is the sum of all the chemical changes occurring in a cell, a tissue, or the body. Most pathways can be classified as either catabolic (degradative) or anabolic (synthetic). Catabolic reactions break down complex molecules, such as proteins, polysaccharides, and lipids, to a few simple molecules, for example, CO2, NH3 (ammonia), and water.
Anabolic pathways form complex end products from simple precursors, for example, the synthesis of the polysaccharide, glycogen, from glucose. [Note: Pathways that regenerate a component are called cycles.] In the following chapters, this text focuses on the central metabolic pathways that are involved in synthesizing and degrading carbohydrates, lipids, and amino acids.
Figure 8.1.Glycolysis, an example of a metabolic pathway.
A. Metabolic map
It is convenient to investigate metabolism by examining its component pathways. Each pathway is composed of multienzyme sequences, and each enzyme, in turn, may exhibit important catalytic or regulatory features. To provide the reader with the “big picture,” a metabolic map containing the important central pathways of energy metabolism is presented in Figure 8.2.
This map is useful in tracing connections between pathways, visualizing the purposeful “movement” of metabolic intermediates, and picturing the effect on the flow of intermediates if a pathway is blocked, for example, by a drug or an inherited deficiency of an enzyme. Throughout the next three units of this book, each pathway under discussion will be repeatedly featured as part of the major metabolic map shown in Figure 8.2.
Figure 8.2.Important reactions of intermediary metabolism.
Several important pathways to be discussed in later chapters are highlighted. Curved reaction arrows indicate forward and reverse reactions that are catalyzed by different enzymes. The straight arrows indicate forward and reverse reactions that are catalyzed by the same enzyme. Blue text = intermediates of carbohydrate metabolism; brown text = intermediates of lipid metabolism; green text = intermediates of protein metabolism.
B. Catabolic pathways
Catabolic reactions serve to capture chemical energy in the form of adenosine triphosphate (ATP) from the degradation of energy-rich fuel molecules. Catabolism also allows molecules in the diet (or nutrient molecules stored in cells) to be converted into building blocks needed for the synthesis of complex molecules. Energy generation by degradation of complex molecules occurs in three stages as shown in Figure 8.3. [Note: Catabolic pathways are typically oxidative, and require coenzymes such as NAD+.]
Figure 8.3.Three Stages of Catabolism.
1. Hydrolysis of complex molecules
In the first stage, complex molecules are broken down into their component building blocks. For example, proteins are degraded to amino acids, polysaccharides to monosaccharides, and fats (triacylglycerols) to free fatty acids and glycerol.
2. Conversion of building blocks to simple intermediates
In the second stage, these diverse building blocks are further degraded to acetyl coenzyme A (CoA) and a few other, simple molecules. Some energy is captured as ATP, but the amount is small compared with the energy produced during the third stage of catabolism.
3. Oxidation of acetyl CoA
The tricarboxylic acid (TCA) cycle (see Reactions of the TCA Cycle) is the final common pathway in the oxidation of fuel molecules that produce acetyl CoA. Oxidation of acetyl CoA generates large amounts of ATP via oxidative phosphorylation as electrons flow from NADH and FADH2 to oxygen (see Electron Transport Chain).
C. Anabolic pathways
Anabolic reactions combine small molecules, such as amino acids, to form complex molecules, such as proteins (Figure 8.4). Anabolic reactions require energy (are endergonic), which is generally provided by the breakdown of ATP to adenosine diphosphate (ADP) and inorganic phosphate (Pi). Anabolic reactions often involve chemical reductions in which the reducing power is most frequently provided by the electron donor NADPH (see Uses of Nadph).
Note that catabolism is a convergent process—that is, a wide variety of molecules are transformed into a few common end products. By contrast, anabolism is a divergent process in which a few biosynthetic precursors form a wide variety of polymeric or complex products.
Figure 8.4.Comparison of catabolic and anabolic pathways.
Regulation of Metabolism
The pathways of metabolism must be coordinated so that the production of energy or the synthesis of end products meets the needs of the cell. Furthermore, individual cells do not function in isolation but, rather, are part of a community of interacting tissues. Thus, a sophisticated communication system has evolved to coordinate the functions of the body. Regulatory signals that inform an individual cell of the metabolic state of the body as a whole include hormones, neurotransmitters, and the availability of nutrients. These, in turn, influence signals generated within the cell (Figure 8.5).
Figure 8.5.Some commonly used mechanisms for transmission of regulatory signals between cells.
A. Signals from within the cell (Intracellular)
The rate of a metabolic pathway can respond to regulatory signals that arise from within the cell. For example, the rate of a pathway may be influenced by the availability of substrates, product inhibition, or alterations in the levels of allosteric activators or inhibitors. These intracellular signals typically elicit rapid responses, and are important for the moment-to-moment regulation of metabolism.
B. Communication between cells (Intercellular)
The ability to respond to extracellular signals is essential for the survival and development of all organisms. Signaling between cells provides for long-range integration of metabolism, and usually results in a response that is slower than is seen with signals that originate within the cell.
Communication between cells can be mediated, for example, by surface-to-surface contact and, in some tissues, by formation of gap junctions, allowing direct communication between the cytoplasms of adjacent cells. However, for energy metabolism, the most important route of communication is chemical signaling between cells by bloodborne hormones or by neurotransmitters.
C. Second messenger systems
Hormones or neurotransmitters can be thought of as signals, and their receptors as signal detectors. Each component serves as a link in the communication between extracellular events and chemical changes within the cell. Many receptors signal their recognition of a bound ligand by initiating a series of reactions that ultimately result in a specific intracellular response.
“Second messenger” molecules—so named because they intervene between the original messenger (the neurotransmitter or hormone) and the ultimate effect on the cell—are part of the cascade of events that translates hormone or neurotransmitter binding into a cellular response. Two of the most widely recognized second messenger systems are the calcium/phosphatidylinositol system (see Phosphatidylinositol (PI)), and the adenylyl cyclase system, which is particularly important in regulating the pathways of intermediary metabolism.
D. Adenylyl cyclase
The recognition of a chemical signal by some membrane receptors, such as the ?- and ?2-adrenergic receptors, triggers either an increase or a decrease in the activity of adenylyl cyclase (adenylate cyclase). This is a membrane-bound enzyme that converts ATP to 3?,5?-adenosine monophosphate (also called cyclic AMP or cAMP). The chemical signals are most often hormones or neurotransmitters, each of which binds to a unique type of membrane receptor.
Therefore, tissues that respond to more than one chemical signal must have several different receptors, each of which can be linked to adenylyl cyclase. These receptors, known as G protein-coupled receptors (GPCR), are characterized by an extracellular ligand-binding region, seven transmembrane helices, and an intracellular domain that interacts with G proteins (Figure 8.6).
Figure 8.6.Structure of a typical G protein-coupled receptor (GPCR) of the plasma membrane.
1. GTP-dependent regulatory proteins
The effect of the activated, occupied GPCR on second messenger formation is not direct but, rather, is mediated by specialized trimeric proteins (?, ?, ? subunits) of the cell membrane. These proteins, referred to as G proteins because they bind guanosine nucleotides (GTP and GDP), form a link in the chain of communication between the receptor and adenylyl cyclase. In the inactive form of a G protein, the ?-subunit is bound to GDP (Figure 8.7). Binding of ligand causes a conformational change in the receptor, triggering replacement of this GDP with GTP.
The GTP-bound form of the ?-subunit dissociates from the ?? subunits and moves to adenylyl cyclase, which is thereby activated. Many molecules of active G? protein are formed by one activated receptor. [Note: The ability of a hormone or neurotransmitter to stimulate or inhibit adenylyl cyclase depends on the type of G? protein that is linked to the receptor. One family of G proteins, designated Gs, stimulates adenylyl cyclase; another family, designated Gi, inhibits the enzyme (not shown in Figure 8.7).]
The actions of the G?–GTP complex are short-lived because G? has an inherent GTPase activity, resulting in the rapid hydrolysis of GTP to GDP. This causes inactivation of the G?, its dissociation from adenylyl cyclase and reassociation with the ?? dimer.
Figure 8.7.The recognition of chemical signals by certain membrane receptors triggers an increase (or, less often, a decrease) in the activity of adenylyl cyclase.
Toxins from Vibrio cholerae (cholera) and Bordetella pertussis (whooping cough) cause inappropriate activation of adenylyl cyclase through covalent modification (ADP-ribosylation) of different G proteins. With cholera, the GTPase activity of G?s is inhibited. With whooping cough, G?i is inactivated
2. Protein kinases
The next key link in the cAMP second messenger system is the activation by cAMP of a family of enzymes called cAMP-dependent protein kinases, for example, protein kinase A (Figure 8.8). Cyclic AMP activates protein kinase A by binding to its two regulatory subunits, causing the release of active catalytic subunits. The active subunits catalyze the transfer of phosphate from ATP to specific serine or threonine residues of protein substrates.
The phosphorylated proteins may act directly on the cell’s ion channels, or, if enzymes, may become activated or inhibited. Protein kinase A can also phosphorylate proteins that bind to DNA, causing changes in gene expression. [Note: Several types of protein kinases are not cAMP-dependent, for example, protein kinase C described on Figure 17.8.]
Figure 8.8.Actions of cAMP.
3. Dephosphorylation of proteins
The phosphate groups added to proteins by protein kinases are removed by protein phosphatases—enzymes that hydrolytically cleave phosphate esters (see Figure 8.8). This ensures that changes in protein activity induced by phosphorylation are not permanent.
4. Hydrolysis of cAMP
cAMP is rapidly hydrolyzed to 5?-AMP by cAMP phosphodiesterase, one of a family of enzymes that cleave the cyclic 3?,5?-phosphodiester bond. 5?-AMP is not an intracellular signaling molecule. Thus, the effects of neurotransmitter- or hormone-mediated increases of cAMP are rapidly terminated if the extracellular signal is removed. [Note: Phosphodiesterase is inhibited by methylxanthine derivatives, such as theophylline and caffeine.1]
Overview of Glycolysis
The glycolytic pathway is employed by all tissues for the breakdown of glucose to provide energy (in the form of ATP) and intermediates for other metabolic pathways. Glycolysis is at the hub of carbohydrate metabolism because virtually all sugars—whether arising from the diet or from catabolic reactions in the body—can ultimately be converted to glucose (Figure 8.9A). Pyruvate is the end product of glycolysis in cells with mitochondria and an adequate supply of oxygen.
This series of ten reactions is called aerobic glycolysis because oxygen is required to reoxidize the NADH formed during the oxidation of glyceraldehyde 3-phosphate (Figure 8.9B). Aerobic glycolysis sets the stage for the oxidative decarboxylation of pyruvate to acetyl CoA, a major fuel of the TCA (or citric acid) cycle. Alternatively, pyruvate is reduced to lactate as NADH is oxidized to NAD+ (Figure 8.9C).
This conversion of glucose to lactate is called anaerobic glycolysis because it can occur without the participation of oxygen. Anaerobic glycolysis allows the production of ATP in tissues that lack mitochondria (for example, red blood cells) or in cells deprived of sufficient oxygen.
A.Glycolysis shown as one of the essential pathways of energy metabolism. B.Reactions of aerobic glycolysis. C.Reactions of anaerobic glycolysis