Metabolism of Carbohydrates and Formation of Adenosine Triphosphate

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 text to present the chemical details of all the various cellular reactions, which lie 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 physiological implications, especially the manner in which they fit into overall body homeostasis.

Release of Energy From Foods and “Free Energy”

Many of the chemical reactions in the cells are aimed at making the energy in foods available to the various physiological systems of the cell. For example, 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, releasing large amounts of energy, but 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 many 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 enzymes 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 food oxidation and is generally represented by the symbol ΔG. Free energy is usually expressed in terms of calories per mole of substance. For example, 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 68-1 ). For this reason, ATP has been called the “energy currency” of the body, and it can be gained and spent repeatedly.

Figure 68-1., Adenosine triphosphate as the central link between energy-producing and energy-utilizing systems of the body. ADP, Adenosine diphosphate; P i , 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 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 68-2 . The last two phosphate radicals are connected with the remainder of the molecule by high-energy bonds, which are indicated by the symbol ∼ .

Figure 68-2., Chemical structure of adenosine triphosphate.

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 \leftarrow \overset{- 12.000 cal}{\to} {\begin{matrix} ADP \\ + \\ {PO}_{3} \end{matrix}} \leftarrow \overset{- 12.000 cal}{\to} {\begin{matrix} AMP \\ + \\ 2 {PO}_{3} \end{matrix}}

$ATP \leftarrow \overset{- 12.000 cal}{\to} {\begin{matrix} ADP \\ + \\ {PO}_{3} \end{matrix}} \leftarrow \overset{- 12.000 cal}{\to} {\begin{matrix} AMP \\ + \\ 2 {PO}_{3} \end{matrix}}$

ATP is present everywhere in the cytoplasm and nucleoplasm of all cells, and essentially all the physiological mechanisms that require energy for operation obtain it directly from ATP (or another similar high-energy compound, guanosine triphosphate). 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 via 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% or more of all the carbohydrates utilized by the body are for this purpose.

Central Role of Glucose in Carbohydrate Metabolism

As explained in Chapter 66 , the final products of carbohydrate digestion in the alimentary tract are almost entirely glucose, fructose, and galactose—with glucose representing, on average, about 80% of these products. 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 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 68-3 . Furthermore, the dynamics of the reactions are such that when the liver releases monosaccharides back into the blood, the final product is almost entirely glucose. The reason for this is that liver cells contain large amounts of glucose phosphatase . Therefore, glucose-6-phosphate can be degraded to glucose and phosphate, and the glucose canthen be transported through the liver cell membrane back into the blood.

Figure 68-3., Interconversions of the three major monosaccharides—glucose, fructose, and galactose—in liver cells. ATP, Adenosine triphosphate.

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

Glucose Transport Through Cell Membranes

Before glucose can be used by the body’s tissue cells, it must be transported through the 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 facilitated diffusion . The principles of this type of transport are discussed in Chapter 4 . 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.

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 cells, especially those 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 in most cells 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 and the sensitivity of the various tissues to insulin’s effects on glucose transport. The functions of insulin and its control of carbohydrate metabolism are discussed in detail in Chapter 79 .

Phosphorylation of Glucose

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

Glucose - \overset{Glucokinase or hexokinase}{\to} Glucose - 6 - phosphate

$Glucose - \overset{Glucokinase or hexokinase}{\to} Glucose - 6 - phosphate$

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 liver cells, renal tubular epithelial cells, and intestinal epithelial cells; in these cells, another enzyme, glucose phosphatase , is also available, and when 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 the 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.

Almost 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% of their weight as glycogen, and muscle cells , which can store up to 1% to 3% 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 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 illustrated in Figure 68-4 which shows that glucose-6-phosphate can become glucose-1-phosphate ; this substance 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 68-4., Chemical reactions of glycogenesis and glycogenolysis, also showing 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, and thus glycogen remains stored. When it is necessary to re-form glucose from glycogen, the phosphorylase must first be activated. This activation can be accomplished in several ways, including activation by epinephrine or by glucagon, as described in the next section.

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 formation of cyclic AMP in the cells, which then initiates a cascade of chemical reactions that activates the phosphorylase. This process is discussed in detail in Chapter 79 .

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 liver cells and muscle, thereby contributing (along with other effects of sympathetic stimulation) to preparation of the body for action, as discussed in Chapter 61 .

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, promoting 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 in Chapter 79 .

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 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, thus forming a total of 38 moles of ATP for each mole of glucose metabolized by the cells.

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

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