Guyton and Hall Textbook of Medical Physiology, 12th Ed


Metabolism of Carbohydrates, and Formation of Adenosine Triphosphate

image The next few chapters deal with metabolism in the body—the chemical processes that make it possible for the cells to continue living. It is not the purpose of this textbook to present the chemical details of all the various cellular reactions, because this lies in the discipline of biochemistry. Instead, these chapters are devoted to (1) a review of the principal chemical processes of the cell and (2) an analysis of their physiologic implications, especially the manner in which they fit into the overall body homeostasis.

Release of Energy from Foods, and the Concept of “Free Energy”

Most of the chemical reactions in the cells are aimed at making the energy in foods available to the various physiologic systems of the cell. For instance, energy is required for muscle activity, secretion by the glands, maintenance of membrane potentials by the nerve and muscle fibers, synthesis of substances in the cells, absorption of foods from the gastrointestinal tract, and many other functions.

Coupled Reactions

All the energy foods—carbohydrates, fats, and proteins—can be oxidized in the cells, and during this process, large amounts of energy are released. These same foods can also be burned with pure oxygen outside the body in an actual fire, also releasing large amounts of energy; in this case, however, the energy is released suddenly, all in the form of heat. The energy needed by the physiologic processes of the cells is not heat but energy to cause mechanical movement in the case of muscle function, to concentrate solutes in the case of glandular secretion, and to effect other cell functions. To provide this energy, the chemical reactions must be “coupled” with the systems responsible for these physiologic functions. This coupling is accomplished by special cellular enzyme and energy transfer systems, some of which are explained in this and subsequent chapters.

“Free Energy.”

The amount of energy liberated by complete oxidation of a food is called the free energy of oxidation of the food, and this is generally represented by the symbol ΔG. Free energy is usually expressed in terms of calories per mole of substance. For instance, the amount of free energy liberated by complete oxidation of 1 mole (180 grams) of glucose is 686,000 calories.

Adenosine Triphosphate Is the “Energy Currency” of the Body

Adenosine triphosphate (ATP) is an essential link between energy-utilizing and energy-producing functions of the body (Figure 67-1). For this reason, ATP has been called the energy currency of the body, and it can be gained and spent repeatedly.


Figure 67-1 Adenosine triphosphate (ATP) as the central link between energy-producing and energy-utilizing systems of the body. ADP, adenosine diphosphate; Pi, inorganic phosphate.

Energy derived from the oxidation of carbohydrates, proteins, and fats is used to convert adenosine diphosphate (ADP) to ATP, which is then consumed by the various reactions of the body that are necessary for (1) active transport of molecules across cell membranes; (2) contraction of muscles and performance of mechanical work; (3) various synthetic reactions that create hormones, cell membranes, and many other essential molecules of the body; (4) conduction of nerve impulses; (5) cell division and growth; and (6) many other physiologic functions that are necessary to maintain and propagate life.

ATP is a labile chemical compound that is present in all cells. ATP is a combination of adenine, ribose, and three phosphate radicals as shown in Figure 67-2. The last two phosphate radicals are connected with the remainder of the molecule by high-energy bonds, which are indicated by the symbol ~.


Figure 67-2 Chemical structure of adenosine triphosphate (ATP).

The amount of free energy in each of these high-energy bonds per mole of ATP is about 7300 calories under standard conditions and about 12,000 calories under the usual conditions of temperature and concentrations of the reactants in the body. Therefore, in the body, removal of each of the last two phosphate radicals liberates about 12,000 calories of energy. After loss of one phosphate radical from ATP, the compound becomes ADP, and after loss of the second phosphate radical, it becomes adenosine monophosphate (AMP). The interconversions among ATP, ADP, and AMP are the following:


ATP is present everywhere in the cytoplasm and nucleoplasm of all cells, and essentially all the physiologic mechanisms that require energy for operation obtain it directly from ATP (or another similar high-energy compound, guanosine triphosphate [GTP]). In turn, the food in the cells is gradually oxidized, and the released energy is used to form new ATP, thus always maintaining a supply of this substance. All these energy transfers take place by means of coupled reactions.

The principal purpose of this chapter is to explain how the energy from carbohydrates can be used to form ATP in the cells. Normally, 90 percent or more of all the carbohydrates utilized by the body are used for this purpose.

Central Role of Glucose in Carbohydrate Metabolism

As explained in Chapter 65, the final products of carbohydrate digestion in the alimentary tract are almost entirely glucose, fructose, and galactose—with glucose representing, on average, about 80 percent of these. After absorption from the intestinal tract, much of the fructose and almost all the galactose are rapidly converted into glucose in the liver. Therefore, little fructose and galactose are present in the circulating blood. Glucose thus becomes the final common pathway for the transport of almost all carbohydrates to the tissue cells.

In liver cells, appropriate enzymes are available to promote interconversions among the monosaccharides—glucose, fructose, and galactose—as shown in Figure 67-3. Furthermore, the dynamics of the reactions are such that when the liver releases the monosaccharides back into the blood, the final product is almost entirely glucose. The reason for this is that the liver cells contain large amounts of glucose phosphatase. Therefore, glucose-6-phosphate can be degraded to glucose and phosphate, and the glucose can then be transported through the liver cell membrane back into the blood.


Figure 67-3 Interconversions of the three major monosaccharides—glucose, fructose, and galactose—in liver cells.

Once again, it should be emphasized that usually more than 95 percent of all the monosaccharides that circulate in the blood are the final conversion product, glucose.

Transport of Glucose Through the Cell Membrane

Before glucose can be used by the body’s tissue cells, it must be transported through the tissue cell membrane into the cellular cytoplasm. However, glucose cannot easily diffuse through the pores of the cell membrane because the maximum molecular weight of particles that can diffuse readily is about 100, and glucose has a molecular weight of 180. Yet glucose does pass to the interior of the cells with a reasonable degree of freedom by the mechanism of facilitated diffusion. The principles of this type of transport are discussed in Chapter 4. Basically, they are the following. Penetrating through the lipid matrix of the cell membrane are large numbers of protein carrier molecules that can bind with glucose. In this bound form, the glucose can be transported by the carrier from one side of the membrane to the other side and then released. Therefore, if the concentration of glucose is greater on one side of the membrane than on the other side, more glucose will be transported from the high-concentration area to the low-concentration area than in the opposite direction.

The transport of glucose through the membranes of most tissue cells is quite different from that which occurs through the gastrointestinal membrane or through the epithelium of the renal tubules. In both cases, the glucose is transported by the mechanism of active sodium-glucose co-transport, in which active transport of sodium provides energy for absorbing glucose against a concentration difference. This sodium-glucose co-transport mechanism functions only in certain special epithelial cells that are specifically adapted for active absorption of glucose. At other cell membranes, glucose is transported only from higher concentration toward lower concentration by facilitated diffusion, made possible by the special binding properties of membrane glucose carrier protein. The details of facilitated diffusion for cell membrane transport are presented in Chapter 4.

Insulin Increases Facilitated Diffusion of Glucose

The rate of glucose transport, as well as transport of some other monosaccharides, is greatly increased by insulin. When large amounts of insulin are secreted by the pancreas, the rate of glucose transport into most cells increases to 10 or more times the rate of transport when no insulin is secreted. Conversely, the amounts of glucose that can diffuse to the insides of most cells of the body in the absence of insulin, with the exception of liver and brain cells, are far too little to supply the amount of glucose normally required for energy metabolism.

In effect, the rate of carbohydrate utilization by most cells is controlled by the rate of insulin secretion from the pancreas. The functions of insulin and its control of carbohydrate metabolism are discussed in detail in Chapter 78.

Phosphorylation of Glucose

Immediately on entry into the cells, glucose combines with a phosphate radical in accordance with the following reaction:


This phosphorylation is promoted mainly by the enzyme glucokinase in the liver and by hexokinase in most other cells. The phosphorylation of glucose is almost completely irreversible except in the liver cells, the renal tubular epithelial cells, and the intestinal epithelial cells; in these cells, another enzyme, glucose phosphatase, is also available, and when this is activated, it can reverse the reaction. In most tissues of the body, phosphorylation serves to capture the glucose in the cell. That is, because of its almost instantaneous binding with phosphate, the glucose will not diffuse back out, except from those special cells, especially liver cells, that have phosphatase.

Glycogen Is Stored in Liver and Muscle

After absorption into a cell, glucose can be used immediately for release of energy to the cell, or it can be stored in the form of glycogen, which is a large polymer of glucose.

All cells of the body are capable of storing at least some glycogen, but certain cells can store large amounts, especially liver cells, which can store up to 5 to 8 percent of their weight as glycogen, and muscle cells, which can store up to 1 to 3 percent glycogen. The glycogen molecules can be polymerized to almost any molecular weight, with the average molecular weight being 5 million or greater; most of the glycogen precipitates in the form of solid granules.

This conversion of the monosaccharides into a high-molecular-weight precipitated compound (glycogen) makes it possible to store large quantities of carbohydrates without significantly altering the osmotic pressure of the intracellular fluids. High concentrations of low-molecular-weight soluble monosaccharides would play havoc with the osmotic relations between intracellular and extracellular fluids.

Glycogenesis—Formation of Glycogen

The chemical reactions for glycogenesis are shown in Figure 67-4. From this figure, it can be seen that glucose-6-phosphate can become glucose-1-phosphate; this is converted to uridine diphosphate glucose, which is finally converted into glycogen. Several specific enzymes are required to cause these conversions, and any monosaccharide that can be converted into glucose can enter into the reactions. Certain smaller compounds, including lactic acid, glycerol, pyruvic acid, and some deaminated amino acids, can also be converted into glucose or closely allied compounds and then converted into glycogen.


Figure 67-4 Chemical reactions of glycogenesis and glycogenolysis, showing also interconversions between blood glucose and liver glycogen. (The phosphatase required for the release of glucose from the cell is present in liver cells but not in most other cells.)

Glycogenolysis—Breakdown of Stored Glycogen

Glycogenolysis means the breakdown of the cell’s stored glycogen to re-form glucose in the cells. The glucose can then be used to provide energy. Glycogenolysis does not occur by reversal of the same chemical reactions that form glycogen; instead, each succeeding glucose molecule on each branch of the glycogen polymer is split away by phosphorylation, catalyzed by the enzyme phosphorylase.

Under resting conditions, the phosphorylase is in an inactive form, so that glycogen will remain stored. When it is necessary to re-form glucose from glycogen, the phosphorylase must first be activated. This can be accomplished in several ways, including the following two.

Activation of Phosphorylase by Epinephrine or by Glucagon

Two hormones, epinephrine and glucagon, can activate phosphorylase and thereby cause rapid glycogenolysis. The initial effect of each of these hormones is to promote the formation of cyclic AMP in the cells, which then initiates a cascade of chemical reactions that activates the phosphorylase. This is discussed in detail in Chapter 78.

Epinephrine is released by the adrenal medullae when the sympathetic nervous system is stimulated. Therefore, one of the functions of the sympathetic nervous system is to increase the availability of glucose for rapid energy metabolism. This function of epinephrine occurs markedly in both liver cells and muscle, thereby contributing, along with other effects of sympathetic stimulation, to preparing the body for action, as discussed fully in Chapter 60.

Glucagon is a hormone secreted by the alpha cells of the pancreas when the blood glucose concentration falls too low. It stimulates formation of cyclic AMP mainly in the liver cells, and this in turn promotes conversion of liver glycogen into glucose and its release into the blood, thereby elevating the blood glucose concentration. The function of glucagon in blood glucose regulation is discussed more fully in Chapter 78.

Release of Energy from Glucose by the Glycolytic Pathway

Because complete oxidation of 1 gram-mole of glucose releases 686,000 calories of energy and only 12,000 calories of energy are required to form 1 gram-mole of ATP, energy would be wasted if glucose were decomposed all at once into water and carbon dioxide while forming only a single ATP molecule. Fortunately, cells of the body contain special protein enzymes that cause the glucose molecule to split a little at a time in many successive steps, so that its energy is released in small packets to form one molecule of ATP at a time, forming a total of 38 moles of ATP for each mole of glucose metabolized by the cells.

The next sections describe the basic principles of the processes by which the glucose molecule is progressively dissected and its energy released to form ATP.

Glycolysis—Splitting Glucose to Form Pyruvic Acid

By far the most important means of releasing energy from the glucose molecule is initiated by glycolysis. The end products of glycolysis are then oxidized to provide energy. Glycolysis means splitting of the glucose molecule to form two molecules of pyruvic acid.

Glycolysis occurs by 10 successive chemical reactions, shown in Figure 67-5. Each step is catalyzed by at least one specific protein enzyme. Note that glucose is first converted into fructose-1,6-diphosphate and then split into two three-carbon-atom molecules, glyceraldehyde-3-phosphate, each of which is then converted through five additional steps into pyruvic acid.


Figure 67-5 Sequence of chemical reactions responsible for glycolysis.

Formation of ATP During Glycolysis

Despite the many chemical reactions in the glycolytic series, only a small portion of the free energy in the glucose molecule is released at most steps. However, between the 1,3-diphosphoglyceric acid and the 3-phosphoglyceric acid stages, and again between the phosphoenolpyruvic acid and the pyruvic acid stages, the packets of energy released are greater than 12,000 calories per mole, the amount required to form ATP, and the reactions are coupled in such a way that ATP is formed. Thus, a total of 4 moles of ATP are formed for each mole of fructose-1,6-diphosphate that is split into pyruvic acid.

Yet, 2 moles of ATP are required to phosphorylate the original glucose to form fructose-1,6-diphosphate before glycolysis could begin. Therefore, the net gain in ATP molecules by the entire glycolytic process is only 2 moles for each mole of glucose utilized. This amounts to 24,000 calories of energy that becomes transferred to ATP, but during glycolysis, a total of 56,000 calories of energy were lost from the original glucose, giving an overall efficiency for ATP formation of only 43 percent. The remaining 57 percent of the energy is lost in the form of heat.

Conversion of Pyruvic Acid to Acetyl Coenzyme A

The next stage in the degradation of glucose is a two-step conversion of the two pyruvic acid molecules from Figure 67-5 into two molecules of acetyl coenzyme A (acetyl-CoA), in accordance with the following reaction:


Two carbon dioxide molecules and four hydrogen atoms are released from this reaction, while the remaining portions of the two pyruvic acid molecules combine with coenzyme A, a derivative of the vitamin pantothenic acid, to form two molecules of acetyl-CoA. In this conversion, no ATP is formed, but up to six molecules of ATP are formed when the four released hydrogen atoms are later oxidized, as discussed later.

Citric Acid Cycle (Krebs Cycle)

The next stage in the degradation of the glucose molecule is called the citric acid cycle (also called the tricarboxylic acid cycle or the Krebs cycle in honor of Hans Krebs for his discovery of the citric acid cycle). This is a sequence of chemical reactions in which the acetyl portion of acetyl-CoA is degraded to carbon dioxide and hydrogen atoms. These reactions all occur in the matrix of the mitochondrion. The released hydrogen atoms add to the number of these atoms that will subsequently be oxidized (as discussed later), releasing tremendous amounts of energy to form ATP.

Figure 67-6 shows the different stages of the chemical reactions in the citric acid cycle. The substances to the left are added during the chemical reactions, and the products of the chemical reactions are shown to the right. Note at the top of the column that the cycle begins with oxaloacetic acid, and at the bottom of the chain of reactions, oxaloacetic acid is formed again. Thus, the cycle can continue over and over.


Figure 67-6 Chemical reactions of the citric acid cycle, showing the release of carbon dioxide and a number of hydrogen atoms during the cycle.

In the initial stage of the citric acid cycle, acetyl-CoA combines with oxaloacetic acid to form citric acid. The coenzyme A portion of the acetyl-CoA is released and can be used again and again for the formation of still more quantities of acetyl-CoA from pyruvic acid. The acetyl portion, however, becomes an integral part of the citric acid molecule. During the successive stages of the citric acid cycle, several molecules of water are added, as shown on the left in the figure, and carbon dioxide and hydrogen atoms are released at other stages in the cycle, as shown on the right in the figure.

The net results of the entire citric acid cycle are given in the explanation at the bottom of Figure 67-6, demonstrating that for each molecule of glucose originally metabolized, two acetyl-CoA molecules enter into the citric acid cycle, along with six molecules of water. These are then degraded into 4 carbon dioxide molecules, 16 hydrogen atoms, and 2 molecules of coenzyme A. Two molecules of ATP are formed, as follows.

Formation of ATP in the Citric Acid Cycle

The citric acid cycle itself does not cause a great amount of energy to be released; in only one of the chemical reactions—during the change from α-ketoglutaric acid to succinic acid—is a molecule of ATP formed. Thus, for each molecule of glucose metabolized, two acetyl-CoA molecules pass through the citric acid cycle, each forming a molecule of ATP, or a total of two molecules of ATP formed.

Function of Dehydrogenases and Nicotinamide Adenine Dinucleotide in Causing Release of Hydrogen Atoms in the Citric Acid Cycle

As already noted at several points in this discussion, hydrogen atoms are released during different chemical reactions of the citric acid cycle—4 hydrogen atoms during glycolysis, 4 during formation of acetyl-CoA from pyruvic acid and 16 in the citric acid cycle; this makes a total of 24 hydrogen atoms released for each original molecule of glucose. However, the hydrogen atoms are not simply turned loose in the intracellular fluid. Instead, they are released in packets of two, and in each instance, the release is catalyzed by a specific protein enzyme called a dehydrogenase. Twenty of the 24 hydrogen atoms immediately combine with nicotinamide adenine dinucleotide (NAD+), a derivative of the vitamin niacin, in accordance with the following reaction:


This reaction will not occur without intermediation of the specific dehydrogenase or without the availability of NAD+ to act as a hydrogen carrier. Both the free hydrogen ion and the hydrogen bound with NAD+ subsequently enter into multiple oxidative chemical reactions that form tremendous quantities of ATP, as discussed later.

The remaining four hydrogen atoms released during the breakdown of glucose—the four released during the citric acid cycle between the succinic and fumaric acid stages—combine with a specific dehydrogenase but are not subsequently released to NAD+. Instead, they pass directly from the dehydrogenase into the oxidative process.

Function of Decarboxylases in Causing Release of Carbon Dioxide

Referring again to the chemical reactions of the citric acid cycle, as well as to those for the formation of acetyl-CoA from pyruvic acid, we find that there are three stages in which carbon dioxide is released. To cause the release of carbon dioxide, other specific protein enzymes, called decarboxylases, split the carbon dioxide away from the substrate. The carbon dioxide is then dissolved in the body fluids and transported to the lungs, where it is expired from the body (see Chapter 40).

Formation of Large Quantities of ATP by Oxidation of Hydrogen—the Process of Oxidative Phosphorylation

Despite all the complexities of (1) glycolysis, (2) the citric acid cycle, (3) dehydrogenation, and (4) decarboxylation, pitifully small amounts of ATP are formed during all these processes—only two ATP molecules in the glycolysis scheme and another two in the citric acid cycle for each molecule of glucose metabolized. Instead, almost 90 percent of the total ATP created through glucose metabolism is formed during subsequent oxidation of the hydrogen atoms that were released at early stages of glucose degradation. Indeed, the principal function of all these earlier stages is to make the hydrogen of the glucose molecule available in forms that can be oxidized.

Oxidation of hydrogen is accomplished, as illustrated in Figure 67-7, by a series of enzymatically catalyzed reactions in the mitochondria. These reactions (1) split each hydrogen atom into a hydrogen ion and an electron and (2) use the electrons eventually to combine dissolved oxygen of the fluids with water molecules to form hydroxyl ions. Then the hydrogen and hydroxyl ions combine with each other to form water. During this sequence of oxidative reactions, tremendous quantities of energy are released to form ATP. Formation of ATP in this manner is called oxidative phosphorylation. This occurs entirely in the mitochondria by a highly specialized process called the chemiosmotic mechanism.


Figure 67-7 Mitochondrial chemiosmotic mechanism of oxidative phosphorylation for forming large quantities of ATP. This figure shows the relationship of the oxidative and phosphorylation steps at the outer and inner membranes of the mitochondrion.

Chemiosmotic Mechanism of the Mitochondria to Form ATP

Ionization of Hydrogen, the Electron Transport Chain, and Formation of Water

The first step in oxidative phosphorylation in the mitochondria is to ionize the hydrogen atoms that have been removed from the food substrates. As described earlier, these hydrogen atoms are removed in pairs: one immediately becomes a hydrogen ion, H+; the other combines with NAD+ to form NADH. The upper portion of Figure 67-7 shows the subsequent fate of the NADH and H+. The initial effect is to release the other hydrogen atom from the NADH to form another hydrogen ion, H+; this process also reconstitutes NAD+ that will be reused again and again.

The electrons that are removed from the hydrogen atoms to cause the hydrogen ionization immediately enter an electron transport chain of electron acceptors that are an integral part of the inner membrane (the shelf membrane) of the mitochondrion. The electron acceptors can be reversibly reduced or oxidized by accepting or giving up electrons. The important members of this electron transport chain include flavoprotein, several iron sulfide proteins, ubiquinone, and cytochromes B, C1, CA, and A3. Each electron is shuttled from one of these acceptors to the next until it finally reaches cytochrome A3, which is called cytochrome oxidase because it is capable of giving up two electrons and thus reducing elemental oxygen to form ionic oxygen, which then combines with hydrogen ions to form water.

Thus, Figure 67-7 shows the transport of electrons through the electron chain and then their ultimate use by cytochrome oxidase to cause the formation of water molecules. During the transport of these electrons through the electron transport chain, energy is released that is used to cause the synthesis of ATP, as follows.

Pumping of Hydrogen Ions into the Outer Chamber of the Mitochondrion, Caused by the Electron Transport Chain

As the electrons pass through the electron transport chain, large amounts of energy are released. This energy is used to pump hydrogen ions from the inner matrix of the mitochondrion (to the right in Figure 67-7) into the outer chamber between the inner and outer mitochondrial membranes (to the left). This creates a high concentration of positively charged hydrogen ions in this chamber; it also creates a strong negative electrical potential in the inner matrix.

Formation of ATP

The next step in oxidative phosphorylation is to convert ADP into ATP. This occurs in conjunction with a large protein molecule that protrudes all the way through the inner mitochondrial membrane and projects with a knoblike head into the inner mitochondrial matrix. This molecule is an ATPase, the physical nature of which is shown in Figure 67-7. It is called ATP synthetase.

The high concentration of positively charged hydrogen ions in the outer chamber and the large electrical potential difference across the inner membrane cause the hydrogen ions to flow into the inner mitochondrial matrix through the substance of the ATPase molecule. In doing so, energy derived from this hydrogen ion flow is used by ATPase to convert ADP into ATP by combining ADP with a free ionic phosphate radical (Pi), thus adding another high-energy phosphate bond to the molecule.

The final step in the process is transfer of ATP from the inside of the mitochondrion back to the cell cytoplasm. This occurs by facilitated diffusion outward through the inner membrane and then by simple diffusion through the permeable outer mitochondrial membrane. In turn, ADP is continually transferred in the other direction for continual conversion into ATP. For each two electrons that pass through the entire electron transport chain (representing the ionization of two hydrogen atoms), up to three ATP molecules are synthesized.

Summary of ATP Formation During the Breakdown of Glucose

We can now determine the total number of ATP molecules that, under optimal conditions, can be formed by the energy from one molecule of glucose.

1. During glycolysis, four molecules of ATP are formed and two are expended to cause the initial phosphorylation of glucose to get the process going. This gives a net gain of two molecules of ATP.

2. During each revolution of the citric acid cycle, one molecule of ATP is formed. However, because each glucose molecule splits into two pyruvic acid molecules, there are two revolutions of the cycle for each molecule of glucose metabolized, giving a net production of two more molecules of ATP.

3. During the entire schema of glucose breakdown, a total of 24 hydrogen atoms are released during glycolysis and during the citric acid cycle. Twenty of these atoms are oxidized in conjunction with the chemiosmotic mechanism shown in Figure 67-7, with the release of three ATP molecules per two atoms of hydrogen metabolized. This gives an additional 30 ATP molecules.

4. The remaining four hydrogen atoms are released by their dehydrogenase into the chemiosmotic oxidative schema in the mitochondrion beyond the first stage of Figure 67-7. Two ATP molecules are usually released for every two hydrogen atoms oxidized, thus giving a total of four more ATP molecules.

Now, adding all the ATP molecules formed, we find a maximum of 38 ATP molecules formed for each molecule of glucose degraded to carbon dioxide and water. Thus, 456,000 calories of energy can be stored in the form of ATP, whereas 686,000 calories are released during the complete oxidation of each gram-molecule of glucose. This represents an overall maximum efficiency of energy transfer of 66 percent. The remaining 34 percent of the energy becomes heat and, therefore, cannot be used by the cells to perform specific functions.

Control of Energy Release from Stored Glycogen When the Body Needs Additional Energy: Effect of ATP and ADP Cell Concentrations in Controlling the Rate of Glycolysis

Continual release of energy from glucose when the cells do not need energy would be an extremely wasteful process. Instead, glycolysis and the subsequent oxidation of hydrogen atoms are continually controlled in accordance with the cells’ need for ATP. This control is accomplished by multiple feedback control mechanisms within the chemical schemata. Among the more important of these are the effects of cell concentrations of both ADP and ATP in controlling the rates of chemical reactions in the energy metabolism sequence.

One important way in which ATP helps control energy metabolism is to inhibit the enzyme phosphofructokinase. Because this enzyme promotes the formation of fructose-1,6-diphosphate, one of the initial steps in the glycolytic series of reactions, the net effect of excess cellular ATP is to slow or even stop glycolysis, which in turn stops most carbohydrate metabolism. Conversely, ADP (and AMP as well) causes the opposite change in this enzyme, greatly increasing its activity. Whenever ATP is used by the tissues for energizing a major fraction of almost all intracellular chemical reactions, this reduces the ATP inhibition of the enzyme phosphofructokinase and at the same time increases its activity as a result of the excess ADP formed. Thus, the glycolytic process is set in motion, and the total cellular store of ATP is replenished.

Another control linkage is the citrate ion formed in the citric acid cycle. An excess of this ion also strongly inhibits phosphofructokinase, thus preventing the glycolytic process from getting ahead of the citric acid cycle’s ability to use the pyruvic acid formed during glycolysis.

A third way by which the ATP-ADP-AMP system controls carbohydrate metabolism, as well as controlling energy release from fats and proteins, is the following: Referring to the various chemical reactions for energy release, we see that if all the ADP in the cell has already been converted into ATP, additional ATP simply cannot be formed. As a result, the entire sequence involved in the use of foodstuffs—glucose, fats, and proteins—to form ATP is stopped. Then, when ATP is used by the cell to energize the different physiologic functions in the cell, the newly formed ADP and AMP turn on the energy processes again, and ADP and AMP are almost instantly returned to the ATP state. In this way, essentially a full store of ATP is automatically maintained, except during extreme cellular activity, such as very strenuous exercise.

Anaerobic Release of Energy—“Anaerobic Glycolysis”

Occasionally, oxygen becomes either unavailable or insufficient, so oxidative phosphorylation cannot take place. Yet even under these conditions, a small amount of energy can still be released to the cells by the glycolysis stage of carbohydrate degradation, because the chemical reactions for the breakdown of glucose to pyruvic acid do not require oxygen.

This process is extremely wasteful of glucose because only 24,000 calories of energy are used to form ATP for each molecule of glucose metabolized, which represents only a little over 3 percent of the total energy in the glucose molecule. Nevertheless, this release of glycolytic energy to the cells, which is called anaerobic energy, can be a lifesaving measure for up to a few minutes when oxygen becomes unavailable.

Formation of Lactic Acid During Anaerobic Glycolysis Allows Release of Extra Anaerobic Energy

The law of mass action states that as the end products of a chemical reaction build up in a reacting medium, the rate of the reaction decreases, approaching zero. The two end products of the glycolytic reactions (see Figure 67-5) are (1) pyruvic acid and (2) hydrogen atoms combined with NAD+ to form NADH and H+. The buildup of either or both of these would stop the glycolytic process and prevent further formation of ATP. When their quantities begin to be excessive, these two end products react with each other to form lactic acid, in accordance with the following equation:


Thus, under anaerobic conditions, the major portion of the pyruvic acid is converted into lactic acid, which diffuses readily out of the cells into the extracellular fluids and even into the intracellular fluids of other less active cells. Therefore, lactic acid represents a type of “sinkhole” into which the glycolytic end products can disappear, thus allowing glycolysis to proceed far longer than would otherwise be possible. Indeed, glycolysis could proceed for only a few seconds without this conversion. Instead, it can proceed for several minutes, supplying the body with considerable extra quantities of ATP, even in the absence of respiratory oxygen.

Reconversion of Lactic Acid to Pyruvic Acid When Oxygen Becomes Available Again

When a person begins to breathe oxygen again after a period of anaerobic metabolism, the lactic acid is rapidly reconverted to pyruvic acid and NADH plus H+. Large portions of these are immediately oxidized to form large quantities of ATP. This excess ATP then causes as much as three fourths of the remaining excess pyruvic acid to be converted back into glucose.

Thus, the large amount of lactic acid that forms during anaerobic glycolysis is not lost from the body because, when oxygen is available again, the lactic acid can be either reconverted to glucose or used directly for energy. By far the greatest portion of this reconversion occurs in the liver, but a small amount can also occur in other tissues.

Use of Lactic Acid by the Heart for Energy

Heart muscle is especially capable of converting lactic acid to pyruvic acid and then using the pyruvic acid for energy. This occurs to a great extent during heavy exercise, when large amounts of lactic acid are released into the blood from the skeletal muscles and consumed as an extra energy source by the heart.

Release of Energy from Glucose by the Pentose Phosphate Pathway

In almost all the body’s muscles, essentially all the carbohydrates utilized for energy are degraded to pyruvic acid by glycolysis and then oxidized. However, this glycolytic scheme is not the only means by which glucose can be degraded and used to provide energy. A second important mechanism for the breakdown and oxidation of glucose is called the pentose phosphate pathway (or phosphogluconate pathway), which is responsible for as much as 30 percent of the glucose breakdown in the liver and even more than this in fat cells.

This pathway is especially important because it can provide energy independently of all the enzymes of the citric acid cycle and therefore is an alternative pathway for energy metabolism when certain enzymatic abnormalities occur in cells. It has a special capacity for providing energy to multiple cellular synthetic processes.

Release of Carbon Dioxide and Hydrogen by the Pentose Phosphate Pathway

Figure 67-8 shows most of the basic chemical reactions in the pentose phosphate pathway. It demonstrates that glucose, during several stages of conversion, can release one molecule of carbon dioxide and four atoms of hydrogen, with the resultant formation of a five-carbon sugar, D-ribulose. This substance can change progressively into several other five-, four-, seven-, and three-carbon sugars. Finally, various combinations of these sugars can resynthesize glucose. However, only five molecules of glucose are resynthesized for every six molecules of glucose that initially enter into the reactions. That is, the pentose phosphate pathway is a cyclical process in which one molecule of glucose is metabolized for each revolution of the cycle. Thus, by repeating the cycle again and again, all the glucose can eventually be converted into carbon dioxide and hydrogen, and the hydrogen can enter the oxidative phosphorylation pathway to form ATP; more often, however, it is used for the synthesis of fat or other substances, as follows.


Figure 67-8 Pentose phosphate pathway for glucose metabolism.

Use of Hydrogen to Synthesize Fat; the Function of Nicotinamide Adenine Dinucleotide Phosphate

The hydrogen released during the pentose phosphate cycle does not combine with NAD+ as in the glycolytic pathway but combines with nicotinamide adenine dinucleotide phosphate (NADP+), which is almost identical to NAD+except for an extra phosphate radical, P. This difference is extremely significant because only hydrogen bound with NADP+ in the form of NADPH can be used for the synthesis of fats from carbohydrates (as discussed in Chapter 68) and for the synthesis of some other substances.

When the glycolytic pathway for using glucose becomes slowed because of cellular inactivity, the pentose phosphate pathway remains operative (mainly in the liver) to break down any excess glucose that continues to be transported into the cells, and NADPH becomes abundant to help convert acetyl-CoA, also derived from glucose, into long fatty acid chains. This is another way in which energy in the glucose molecule is used other than for the formation of ATP—in this instance, for the formation and storage of fat in the body.

Glucose Conversion to Glycogen or Fat

When glucose is not immediately required for energy, the extra glucose that continually enters the cells is either stored as glycogen or converted into fat. Glucose is preferentially stored as glycogen until the cells have stored as much glycogen as they can—an amount sufficient to supply the energy needs of the body for only 12 to 24 hours.

When the glycogen-storing cells (primarily liver and muscle cells) approach saturation with glycogen, the additional glucose is converted into fat in liver and fat cells and is stored as fat in the fat cells. Other steps in the chemistry of this conversion are discussed in Chapter 68.

Formation of Carbohydrates from Proteins and Fats—“Gluconeogenesis”

When the body’s stores of carbohydrates decrease below normal, moderate quantities of glucose can be formed from amino acids and the glycerol portion of fat. This process is called gluconeogenesis.

Gluconeogenesis is especially important in preventing an excessive reduction in the blood glucose concentration during fasting. Glucose is the primary substrate for energy in tissues such as the brain and the red blood cells, and adequate amounts of glucose must be present in the blood for several hours between meals. The liver plays a key role in maintaining blood glucose levels during fasting by converting its stored glycogen to glucose (glycogenolysis) and by synthesizing glucose, mainly from lactate and amino acids (gluconeogenesis). Approximately 25 percent of the liver’s glucose production during fasting is from gluconeogenesis, helping to provide a steady supply of glucose to the brain. During prolonged fasting, the kidneys also synthesize considerable amounts of glucose from amino acids and other precursors.

About 60 percent of the amino acids in the body proteins can be converted easily into carbohydrates; the remaining 40 percent have chemical configurations that make this difficult or impossible. Each amino acid is converted into glucose by a slightly different chemical process. For instance, alanine can be converted directly into pyruvic acid simply by deamination; the pyruvic acid is then converted into glucose or stored glycogen. Several of the more complicated amino acids can be converted into different sugars that contain three-, four-, five-, or seven-carbon atoms; they can then enter the phosphogluconate pathway and eventually form glucose. Thus, by means of deamination plus several simple interconversions, many of the amino acids can become glucose. Similar interconversions can change glycerol into glucose or glycogen.

Regulation of Gluconeogenesis

Diminished carbohydrates in the cells and decreased blood sugar are the basic stimuli that increase the rate of gluconeogenesis. Diminished carbohydrates can directly reverse many of the glycolytic and phosphogluconate reactions, thus allowing the conversion of deaminated amino acids and glycerol into carbohydrates. In addition, the hormone cortisol is especially important in this regulation, as follows.

Effect of Corticotropin and Glucocorticoids on Gluconeogenesis

When normal quantities of carbohydrates are not available to the cells, the adenohypophysis, for reasons not completely understood, begins to secrete increased quantities of the hormone corticotropin. This stimulates the adrenal cortex to produce large quantities of glucocorticoid hormones, especially cortisol. In turn, cortisol mobilizes proteins from essentially all cells of the body, making these available in the form of amino acids in the body fluids. A high proportion of these immediately become deaminated in the liver and provide ideal substrates for conversion into glucose. Thus, one of the most important means by which gluconeogenesis is promoted is through the release of glucocorticoids from the adrenal cortex.

Blood Glucose

The normal blood glucose concentration in a person who has not eaten a meal within the past 3 to 4 hours is about 90 mg/dl. After a meal containing large amounts of carbohydrates, this level seldom rises above 140 mg/dl unless the person has diabetes mellitus, which is discussed in Chapter 78.

The regulation of blood glucose concentration is intimately related to the pancreatic hormones insulin and glucagon; this subject is discussed in detail in Chapter 78 in relation to the functions of these hormones.


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