Guyton and Hall Textbook of Medical Physiology PDF (2021)

CHAPTER 68 UNIT XIII Metabolism of Carbohydrates and Formation of Adenosine Triphosphate The next few ch...

CHAPTER 68 UNIT XIII Metabolism of Carbohydrates and Formation of Adenosine Triphosphate The next few chapters deal with metabolism in the Adenosine Triphosphate Is the “Energy Currency” body—the chemical processes that make it possible of the Body for the cells to continue living. It is not the purpose of Adenosine triphosphate (ATP) is an essential link between this text to present the chemical details of all the vari- energy-utilizing and energy-producing functions of the ous cellular reactions, which lie in the discipline of bio- body (Figure 68-1). For this reason, ATP has been called chemistry. Instead, these chapters are devoted to (1) a the “energy currency” of the body, and it can be gained and review of the principal chemical processes of the cell spent repeatedly. and (2) an analysis of their physiological implications, Energy derived from the oxidation of carbohydrates, proteins, and fats is used to convert adenosine diphosphate especially the manner in which they fit into overall body (ADP) to ATP, which is then consumed by the various reac- homeostasis. tions of the body that are necessary to maintain and propa- gate life. Release of Energy From Foods and “Free Energy” ATP is a labile chemical compound that is present in all Many of the chemical reactions in the cells are aimed cells. ATP is a combination of adenine, ribose, and three at making the energy in foods available to the various phosphate radicals, as shown in Figure 68-2. The last two physiological systems of the cell. For example, energy phosphate radicals are connected with the remainder of the is required for muscle activity, secretion by the glands, molecule by high-energy bonds, which are indicated by the maintenance of membrane potentials by the nerve and symbol ∼. muscle fibers, synthesis of substances in the cells, ab- The amount of free energy in each of these high- sorption of foods from the gastrointestinal tract, and energy bonds per mole of ATP is about 7300 calories many other functions. under standard conditions and about 12,000 calories under the usual conditions of temperature and concen- Coupled Reactions. All the energy foods—carbohy- trations of the reactants in the body. Therefore, in the drates, fats, and proteins—can be oxidized in the cells, body, removal of each of the last two phosphate radi- and during this process, large amounts of energy are re- cals liberates about 12,000 calories of energy. After loss leased. 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, Energy production all in the form of heat. The energy needed by the physi- Proteins ologic processes of the cells is not heat but energy to cause Carbohydrates Oxidation mechanical movement in the case of muscle function, to Fats 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 ADP + Pi ATP is accomplished by special cellular enzymes and energy transfer systems, some of which are explained in this and subsequent chapters.! Energy utilization “Free Energy.” The amount of energy liberated by com- Active ion transport plete oxidation of a food is called the free energy of food Muscle contraction Synthesis of molecules oxidation and is generally represented by the symbol ∆G. Cell division and growth Free energy is usually expressed in terms of calories per mole of substance. For example, the amount of free energy Figure 68-1. Adenosine triphosphate as the central link between liberated by complete oxidation of 1 mole (180 grams) of energy-producing and energy-utilizing systems of the body. ADP, glucose is 686,000 calories.! Adenosine diphosphate; Pi, inorganic phosphate. 843 UNIT XIII Metabolism and Temperature Regulation NH2 N C Adenine C N HC Triphosphate C CH N N O O O O CH2 O P O ~ P O ~ P O! C H H C O! O! O! Ribose H C C H OH OH Figure 68-2. Chemical structure of adenosine triphosphate. of one phosphate radical from ATP, the compound be- Cell membrane comes ADP, and after loss of the second phosphate radi- cal, it becomes adenosine monophosphate (AMP). The ATP interconversions among ATP, ADP, and AMP are the Galactose Galactose-1-phosphate following: ⎧ADP ⎫ ⎧AMP ⎫ Uridine diphosphate galactose ATP ← −12 ,000 cal ⎯⎯⎯⎯⎯ ⎯ ⎯ ⎯ ⎯⎯ → ⎪⎨ + ⎪⎬ ← −12 ,000 cal ⎯⎯⎯⎯⎯ ⎯ ⎯ ⎯ ⎯⎯ → ⎪⎨ + ⎪⎬ +12 ,000 cal ⎪ PO ⎪ +12,000 cal ⎪2PO ⎪ ⎩ 3⎭ ⎩ 3⎭ Uridine diphosphate glucose ATP is present everywhere in the cytoplasm and nu- cleoplasm of all cells, and essentially all the physiological Glycogen mechanisms that require energy for operation obtain it di- rectly from ATP (or another similar high-energy compound, Glucose-1-phosphate guanosine triphosphate). In turn, the food in the cells is grad- ually oxidized, and the released energy is used to form new ATP, thus always maintaining a supply of this substance. All ATP these energy transfers take place via coupled reactions. Glucose Glucose-6-phosphate 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.! ATP Fructose Fructose-6-phosphate Central Role of Glucose in Carbohydrate Metabolism As explained in Chapter 66, the final products of carbohy- Glycolysis drate digestion in the alimentary tract are almost entirely Figure 68-3. Interconversions of the three major monosaccharides—glu- glucose, fructose, and galactose—with glucose represent- cose, fructose, and galactose—in liver cells. ATP, Adenosine triphosphate. ing, on average, about 80% of these products. After absorp- tion from the intestinal tract, much of the fructose and almost all the galactose are rapidly converted into glucose then be transported through the liver cell membrane back in the liver. Therefore, little fructose and galactose are pre- into the blood. sent in the circulating blood. Glucose thus becomes the final Once again, it should be emphasized that more than common pathway for transport of almost all carbohydrates 95% of all the monosaccharides that circulate in the blood to the tissue cells. are normally the final conversion product, glucose.! In liver cells, appropriate enzymes are available to pro- mote interconversions among the monosaccharides—glu- Glucose Transport Through Cell Membranes cose, fructose, and galactose—as shown in Figure 68-3. Before glucose can be used by the body’s tissue cells, it must Furthermore, the dynamics of the reactions are such that be transported through the cell membrane into the cellular when the liver releases monosaccharides back into the cytoplasm. However, glucose cannot easily diffuse through blood, the final product is almost entirely glucose. The the pores of the cell membrane because the maximum mo- reason for this is that liver cells contain large amounts of lecular weight of particles that can diffuse readily is about glucose phosphatase. Therefore, glucose-6-phosphate can 100, and glucose has a molecular weight of 180. Yet glucose be degraded to glucose and phosphate, and the glucose can does pass to the interior of the cells with a reasonable degree 844  Chapter 68 Metabolism of Carbohydrates and Formation of Adenosine Triphosphate of freedom by facilitated diffusion. The principles of this type Glycogen Is Stored in the Liver and Muscle of transport are discussed in Chapter 4. Penetrating through After absorption into a cell, glucose can be used im- the lipid matrix of the cell membrane are large numbers of mediately for release of energy to the cell, or it can be protein carrier molecules that can bind with glucose. In this stored in the form of glycogen, which is a large polymer bound form, the glucose can be transported by the carrier UNIT XIII of glucose. from one side of the membrane to the other side and then Almost all cells of the body are capable of storing at least released. Therefore, if the concentration of glucose is greater some glycogen, but certain cells can store large amounts, on one side of the membrane than on the other side, more especially liver cells, which can store up to 5% to 8% of their glucose will be transported from the high-concentration area weight as glycogen, and muscle cells, which can store up to the low-concentration area than in the opposite direction. to 1% to 3% glycogen. The glycogen molecules can be po- Transport of glucose through the membranes of most lymerized to almost any molecular weight, with the average tissue cells is quite different from that which occurs through molecular weight being 5 million or greater; most of the the gastrointestinal membrane or through the epithelium of glycogen precipitates in the form of solid granules. the renal tubules. In both cases, the glucose is transported This conversion of monosaccharides into a high- by the mechanism of active sodium-glucose co-transport, in molecular-weight precipitated compound (glycogen) makes which active transport of sodium provides energy for absorb- it possible to store large quantities of carbohydrates without ing glucose against a concentration difference. This sodium- significantly altering the osmotic pressure of the intracellular glucose co-transport mechanism functions only in certain fluids. High concentrations of low-molecular-weight soluble special cells, especially those epithelial cells that are specifi- monosaccharides would play havoc with the osmotic rela- cally adapted for active absorption of glucose. At other cell tions between intracellular and extracellular fluids. membranes, glucose is transported only from higher concen- tration toward lower concentration by facilitated diffusion, Glycogenesis—Formation of Glycogen made possible by the special binding properties of membrane The chemical reactions for glycogenesis are illustrated in glucose carrier protein. The details of facilitated diffusion for Figure 68-4 which shows that glucose-6-phosphate can be- cell membrane transport are presented in Chapter 4. come glucose-1-phosphate; this substance is converted to Insulin Increases Facilitated Diffusion of Glucose uridine diphosphate glucose, which is finally converted into glycogen. Several specific enzymes are required to cause The rate of glucose transport, as well as transport of some these conversions, and any monosaccharide that can be other monosaccharides, is greatly increased in most cells converted into glucose can enter into the reactions. Certain by insulin. When large amounts of insulin are secreted by smaller compounds, including lactic acid, glycerol, pyruvic the pancreas, the rate of glucose transport into most cells acid, and some deaminated amino acids, can also be con- increases to 10 or more times the rate of transport when no verted into glucose or closely allied compounds and then insulin is secreted. Conversely, the amounts of glucose that converted into glycogen.! can diffuse to the insides of most cells of the body in the ab- sence of insulin, with the exception of liver and brain cells, Glycogenolysis—Breakdown of Stored Glycogen are far too little to supply the amount of glucose normally Glycogenolysis means the breakdown of the cell’s stored required for energy metabolism. glycogen to re-form glucose in the cells. The glucose In effect, the rate of carbohydrate utilization by most can then be used to provide energy. Glycogenolysis does cells is controlled by the rate of insulin secretion from the not occur by reversal of the same chemical reactions pancreas and the sensitivity of the various tissues to insu- that form glycogen; instead, each succeeding glucose lin’s effects on glucose transport. The functions of insulin and its control of carbohydrate metabolism are discussed in detail in Chapter 79.! Cell membrane Phosphorylation of Glucose Glycogen Immediately upon entry into the cells, glucose combines with a phosphate radical in accordance with the following Uridine diphosphate glucose (phosphorylase) reaction: Glucokinase or hexokinase Glucose ⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯ → Glucose-6-phosphate + ATP Glucose-1-phosphate This phosphorylation is promoted mainly by the enzyme glucokinase in the liver and by hexokinase in most other (glucokinase) cells. The phosphorylation of glucose is almost completely Blood Glucose-6-phosphate irreversible except in liver cells, renal tubular epithelial cells, glucose (phosphatase) 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, phos- Glycolysis phorylation serves to capture the glucose in the cell. That is, because of its almost instantaneous binding with phosphate, Figure 68-4. Chemical reactions of glycogenesis and glycogenolysis, also showing interconversions between blood glucose and liver gly- the glucose will not diffuse back out, except from those spe- cogen. (The phosphatase required for the release of glucose from the cial cells, especially liver cells, that have phosphatase.! cell is present in liver cells but not in most other cells.) 845 UNIT XIII Metabolism and Temperature Regulation molecule on each branch of the glycogen polymer is split Glucose away by phosphorylation, catalyzed by the enzyme phos- ATP ADP phorylase. Glucose-6-phosphate Under resting conditions, the phosphorylase is in an inactive form, and thus glycogen remains stored. When Fructose-6-phosphate it is necessary to re-form glucose from glycogen, the phosphorylase must first be activated. This activation ATP ADP can be accomplished in several ways, including activa- Fructose-1,6-diphosphate tion by epinephrine or by glucagon, as described in the next section. Dihydroxyacetone phosphate Activation of Phosphorylase by Epinephrine or by Glucagon. Two hormones, epinephrine and glucagon, can 2 (Glyceraldehyde-3-phosphate) activate phosphorylase and thereby cause rapid glycogenoly- 4H sis. The initial effect of each of these hormones is to promote formation of cyclic AMP in the cells, which then initiates a 2 (1,3-Diphosphoglyceric acid) cascade of chemical reactions that activates the phosphory- 2ADP +2ATP lase. This process is discussed in detail in Chapter 79. 2 (3-Phosphoglyceric acid) Epinephrine is released by the adrenal medullae when the sympathetic nervous system is stimulated. Therefore, 2 (2-Phosphoglyceric acid) one of the functions of the sympathetic nervous system is to increase the availability of glucose for rapid energy me- 2 (Phosphoenolpyruvic acid) tabolism. This function of epinephrine occurs markedly in liver cells and muscle, thereby contributing (along with 2ADP 2ATP other effects of sympathetic stimulation) to preparation of 2 (Pyruvic acid) the body for action, as discussed in Chapter 61. Net reaction per molecule of glucose: Glucagon is a hormone secreted by the alpha cells of Glucose + 2ADP + 2PO4−3 2 Pyruvic acid + 2ATP + 4H the pancreas when the blood glucose concentration falls Figure 68-5. Sequence of chemical reactions responsible for too low. It stimulates formation of cyclic AMP mainly in glycolysis. 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 into two three-carbon-atom molecules, glyceraldehyde-3- blood glucose regulation is discussed in Chapter 79.! phosphate, each of which is then converted through five additional steps into pyruvic acid. Release of Energy From Glucose by the Glycolytic Formation of ATP During Glycolysis. Despite the many Pathway chemical reactions in the glycolytic series, only a small por- Because complete oxidation of 1 gram-mole of glucose re- tion of the free energy in the glucose molecule is released leases 686,000 calories of energy and only 12,000 calories at most steps. However, between the 1,3-diphosphoglyceric of energy are required to form 1 gram-mole of ATP, energy acid and the 3-phosphoglyceric acid stages, and again be- would be wasted if glucose were decomposed all at once tween the phosphoenolpyruvic acid and the pyruvic acid into water and carbon dioxide while forming only a single stages, the packets of energy released are greater than ATP molecule. Fortunately, cells of the body contain special 12,000 calories per mole, the amount required to form ATP, enzymes that cause the glucose molecule to split a little at a and the reactions are coupled in such a way that ATP is time in many successive steps, so that its energy is released formed. Thus, a total of 4 moles of ATP are formed for each in small packets to form one molecule of ATP at a time, mole of fructose-1,6-diphosphate that is split into pyruvic thus forming a total of 38 moles of ATP for each mole of acid. glucose metabolized by the cells. Yet, 2 moles of ATP are required to phosphorylate the In the next sections we describe the basic principles of original glucose to form fructose-1,6-diphosphate before the processes by which the glucose molecule is progres- glycolysis can begin. Therefore, the net gain in ATP mol- sively dissected and its energy released to form ATP. ecules by the entire glycolytic process is only 2 moles for each mole of glucose utilized. This amounts to 24,000 calories of Glycolysis—Splitting Glucose to Form Pyruvic Acid energy that becomes transferred to ATP, but during glyco- By far the most important means of releasing energy from lysis, a total of 56,000 calories of energy were lost from the glucose is initiated by glycolysis. The end products of glyco- original glucose, giving an overall efficiency for ATP forma- lysis are then oxidized to provide energy. Glycolysis means tion of only 43%. The remaining 57% of the energy is lost in splitting of the glucose molecule to form two molecules of the form of heat.! pyruvic acid. Glycolysis occurs by 10 successive chemical reactions, Conversion of Pyruvic Acid to Acetyl Coenzyme A shown in Figure 68-5. Each step is catalyzed by at least The next stage in the degradation of glucose is a two- one specific protein enzyme. Note that glucose is first step conversion of the two pyruvic acid molecules converted into fructose-1,6-diphosphate and then split (shown in Figure 68-5) into two molecules of acetyl 846  Chapter 68 Metabolism of Carbohydrates and Formation of Adenosine Triphosphate coenzyme A (acetyl-CoA), in accordance with the fol- O C COOH CH3 CO CoA lowing reaction: (Acetyl coenzyme A) H2C COOH O (Oxaloacetic acid) H2O CoA H2C COOH UNIT XIII 2CH3 C COOH + 2CoA SH (Pyruvic acid) (Coenzyme A) HOC COOH H2C COOH O (Citric acid) H2O H2C COOH 2CH3 C S CoA + 2CO2 + 4H C COOH (Acetyl-CoA) HC COOH (cis-Aconitic acid) Two carbon dioxide molecules and four hydrogen atoms H2O are released from this reaction, while the remaining portions H2C COOH of the two pyruvic acid molecules combine with coenzyme A, HC COOH a derivative of the vitamin pantothenic acid, to form two mol- ecules of acetyl-CoA. In this conversion, no ATP is formed, HOC COOH but up to six molecules of ATP are formed when the four re- H leased hydrogen atoms are later oxidized, as discussed later.! (Isocitric acid) 2H Citric Acid Cycle (Krebs Cycle) H2C COOH The next stage in the degradation of the glucose molecule HC COOH is called the citric acid cycle (also called the tricarboxylic O C COOH acid cycle or the Krebs cycle in honor of Hans Krebs for his (Oxalosuccinic acid) discovery of this cycle). The citric acid cycle is a sequence CO2 of chemical reactions in which the acetyl portion of acetyl- H2C COOH CoA is degraded to carbon dioxide and hydrogen atoms. H2C These reactions all occur in the matrix of mitochondria. O C COOH The released hydrogen atoms add to the number of these (!-Ketoglutaric acid) atoms that will subsequently be oxidized (as discussed lat- H2O CO2 er), releasing tremendous amounts of energy to form ATP. ADP H2C COOH 2H Figure 68-6 shows the different stages of the chemical ATP H2C COOH reactions in the citric acid cycle. The substances to the left (Succinic acid) are added during the chemical reactions, and the products 2H of the chemical reactions are shown to the right. Note at the HC COOH top of the column that the cycle begins with oxaloacetic acid, HOOC CH and at the bottom of the chain of reactions, oxaloacetic acid (Fumaric acid) is formed again. Thus, the cycle can continue repeatedly. H2O In the initial stage of the citric acid cycle, acetyl-CoA H combines with oxaloacetic acid to form citric acid. The co- HO C COOH enzyme A portion of the acetyl-CoA is released and can be used repeatedly to form additional quantities of acetyl-CoA H2C COOH (Malic acid) from pyruvic acid. The acetyl portion, however, becomes 2H an integral part of the citric acid molecule. During the suc- O C COOH cessive stages of the citric acid cycle, several molecules of H2C COOH water are added, as shown on the left in Figure 68-6, and (Oxaloacetic acid) carbon dioxide and hydrogen atoms are released at other Net reaction per molecule of glucose: stages in the cycle, as shown on the right in the figure. 2 Acetyl-CoA + 6H2O + 2ADP The net results of the entire citric acid cycle are provided 4CO2 + 16H + 2CoA + 2ATP in the explanation at the bottom of Figure 68-6, demonstrat- Figure 68-6. Chemical reactions of the citric acid cycle, showing the ing that for each molecule of glucose originally metabolized, 2 release of carbon dioxide and a number of hydrogen atoms during acetyl-CoA molecules enter into the citric acid cycle, along with the cycle. ADP, Adenosine diphosphate; ATP, adenosine triphosphate. 6 molecules of water. These molecules 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. of glucose metabolized, two acetyl-CoA molecules pass Formation of ATP in the Citric Acid Cycle. The citric through the citric acid cycle, each forming a molecule of acid cycle itself does not cause a great amount of energy ATP, or a total of two molecules of ATP formed.! to be released; a molecule of ATP is formed in only one Function of Dehydrogenases and Nicotinamide of the chemical reactions—during the change from α- Adenine Dinucleotide in Causing Release of Hydrogen ketoglutaric acid to succinic acid. Thus, for each molecule Atoms in the Citric Acid Cycle. As already noted at several 847 UNIT XIII Metabolism and Temperature Regulation points in this discussion, hydrogen atoms are released dur- Food substrate ing 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 cy- NADH + H+ cle; thus a total of 24 hydrogen atoms are released for each H+ FMN -2e original molecule of glucose. However, the hydrogen atoms 2H+ NAD+ FeS are not simply turned loose in the intracellular fluid. In- 2H+ Q b stead, they are released in packets of two, and in each case, FeS 6H+ the release is catalyzed by a specific protein enzyme called 2H+ C1 H 2O a dehydrogenase. Twenty of the 24 hydrogen atoms imme- C1 diately combine with nicotinamide adenine dinucleotide a (NAD+), a derivative of the vitamin niacin, in accordance a3 with the following reaction: 2e + 1/2 O2 6H+ H Dehydrogenase ATPase ATP Substrate + NAD+ 3 ADP ADP H Facilitated Diffusion diffusion NADH + H+ + Substrate 3 ATP This reaction will not occur without intermediation of Outer Inner membrane membrane the specific dehydrogenase or without the availability of NAD+ to act as a hydrogen carrier. Both the free hydro- Figure 68-7. Mitochondrial chemiosmotic mechanism of oxidative gen ion and the hydrogen bound with NAD+ subsequently phosphorylation for forming large quantities of adenosine triphos- enter into multiple oxidative chemical reactions that form phate (ATP). This figure shows the relationship of the oxidative and phosphorylation steps at the outer and inner membranes of the mi- large quantities of ATP, as discussed later. tochondrion. ADP, Adenosine diphosphate; FeS, iron sulfide protein; The remaining 4 hydrogen atoms released during the FMN, flavin mononucleotide; NAD+, nicotinamide adenine dinucleo- breakdown of glucose—the 4 released during the citric tide; NADH, reduced nicotinamide adenine dinucleotide; Q, ubiqui- acid cycle between the succinic and fumaric acid stages— none. combine with a specific dehydrogenase but are not subse- quently released to NAD+. Instead, they pass directly from use the electrons eventually to combine dissolved oxygen the dehydrogenase into the oxidative process.! of the fluids with water molecules to form hydroxyl ions. Function of Decarboxylases in Causing Release of Then the hydrogen and hydroxyl ions combine with each Carbon Dioxide. Referring again to the chemical reactions other to form water. During this sequence of oxidative reac- of the citric acid cycle, as well as to those for the forma- tions, tremendous quantities of energy are released to form tion of acetyl-CoA from pyruvic acid, we find that there are ATP. Formation of ATP in this manner is called oxidative three stages in which carbon dioxide is released. To cause phosphorylation, which occurs entirely in the mitochon- the release of carbon dioxide, other specific protein en- dria by a highly specialized process called the chemiosmotic zymes, called decarboxylases, split the carbon dioxide away mechanism. from the substrate. The carbon dioxide is then dissolved in the body fluids and transported to the lungs, where it is Chemiosmotic Mechanism of the Mitochondria to Form ATP expired from the body (see Chapter 41).! Ionization of Hydrogen, the Electron Transport Chain, Formation of Large Quantities of ATP by Oxidation and Water Formation. The first step in oxidative phos- of Hydrogen—The Process of Oxidative Phosphor- phorylation in the mitochondria is to ionize the hydrogen ylation atoms that have been removed from the food substrates. Despite all the complexities of (1) glycolysis, (2) the citric As described earlier, these hydrogen atoms are removed in acid cycle, (3) dehydrogenation, and (4) decarboxylation, pairs: one immediately becomes a hydrogen ion, H+, the pitifully small amounts of ATP are formed during all these other combines with NAD+ to form reduced nicotinamide processes—only 2 ATP molecules in the glycolysis scheme adenine dinucleotide (NADH). The upper portion of Fig- and another 2 in the citric acid cycle for each molecule of ure 68-7 shows the subsequent fate of the NADH and H+. glucose metabolized. Instead, almost 90% of the total ATP The initial effect is to release the other hydrogen atom from created through glucose metabolism is formed during sub- the NADH to form another hydrogen ion, H+; this process sequent oxidation of the hydrogen atoms that were released also reconstitutes NAD+ that will be reused repeatedly. at early stages of glucose degradation. Indeed, the principal The electrons that are removed from the hydrogen at- function of all these earlier stages is to make the hydrogen oms to cause the hydrogen ionization immediately enter of the glucose molecule available in forms that can be oxi- an electron transport chain of electron acceptors that are an dized. integral part of the inner membrane (the shelf membrane) Oxidation of hydrogen is accomplished, as illustrated of the mitochondrion. The electron acceptors can be re- in Figure 68-7, by a series of enzymatically catalyzed re- versibly reduced or oxidized by accepting or giving up elec- actions in the mitochondria. These reactions (1) split each trons. The important members of this electron transport hydrogen atom into a hydrogen ion and an electron and (2) chain include flavoprotein (flavin mononucleotide), several 848  Chapter 68 Metabolism of Carbohydrates and Formation of Adenosine Triphosphate iron sulfide proteins, ubiquinone, and cytochromes B, C1, C, 2. During each revolution of the citric acid cycle, 1 mol- A, and A3. Each electron is shuttled from one of these ac- ecule of ATP is formed. However, because each glucose ceptors to the next until it finally reaches cytochrome A3, molecule splits into 2 pyruvic acid molecules, there are which is called cytochrome oxidase because it is capable of 2 revolutions of the cycle for each molecule of glucose giving up 2 electrons and thus reducing elemental oxygen metabolized, giving a net production of 2 more mole- UNIT XIII to form ionic oxygen, which then combines with hydrogen cules of ATP. ions to form water. 3. During the entire schema of glucose breakdown, a Thus, Figure 68-7 shows the transport of electrons total of 24 hydrogen atoms are released during glyco- through the electron chain and then their ultimate use by lysis and during the citric acid cycle. Twenty of these cytochrome oxidase to cause the formation of water mol- atoms are oxidized in conjunction with the chemi- ecules. During the transport of these electrons through the osmotic mechanism shown in Figure 68-7, with the electron transport chain, energy is released that is used to release of 3 ATP molecules per 2 atoms of hydrogen cause the synthesis of ATP, as follows.! metabolized. This process gives an additional 30 ATP Electron Transport Chain Releases Energy Used to molecules. Pump Hydrogen Ions Into the Outer Chamber of the 4. The remaining 4 hydrogen atoms are released by their Mitochondrion. As the electrons pass through the electron dehydrogenase into the chemiosmotic oxidative schema transport chain, large amounts of energy are released. This in the mitochondrion beyond the first stage of Figure energy is used to pump hydrogen ions from the inner ma- 68-7. Two ATP molecules are usually released for every trix of the mitochondrion (to the right in Figure 68-7) into 2 hydrogen atoms oxidized, thus giving a total of 4 more the outer chamber between the inner and outer mitochon- ATP molecules. drial membranes (to the left). This process creates a high Now, adding all the ATP molecules formed, we find a concentration of positively charged hydrogen ions in this maximum of 38 ATP molecules formed for each molecule of chamber; it also creates a strong negative electrical poten- glucose degraded to carbon dioxide and water. Thus, 456,000 tial in the inner matrix.! calories of energy can be stored in the form of ATP, whereas Formation of ATP. The next step in oxidative phos- 686,000 calories are released during the complete oxidation phorylation is to convert ADP into ATP. This conversion of each gram-molecule of glucose. This outcome represents occurs in conjunction with a large protein molecule that an overall maximum efficiency of energy transfer of 66%. The protrudes all the way through the inner mitochondrial remaining 34% of the energy becomes heat and, therefore, membrane and projects with a knoblike head into the in- cannot be used by the cells to perform specific functions. ner mitochondrial matrix. This molecule is an ATPase, Effect of ATP and ADP Cell Concentrations in Control- the physical nature of which is shown in Figure 68-7. It is ling Glycolysis and Glucose Oxidation called ATP synthetase. The high concentration of positively charged hydrogen Continual release of energy from glucose when the cells do ions in the outer chamber and the large electrical potential not need energy would be an extremely wasteful process. difference across the inner membrane cause the hydrogen Instead, glycolysis and the subsequent oxidation of hydro- ions to flow into the inner mitochondrial matrix through gen atoms are continually controlled in accordance with the substance of the ATPase molecule. In doing so, energy the need of the cells for ATP. This control is accomplished derived from this hydrogen ion flow is used by ATPase to by multiple feedback control mechanisms within the chem- convert ADP into ATP by combining ADP with a free ionic ical schemata. Among the more important of these mecha- phosphate radical (Pi), thus adding another high-energy nisms are the effects of cell concentrations of both ADP and phosphate bond to the molecule. ATP in controlling the rates of chemical reactions in the The final step in the process is transfer of ATP from energy metabolism sequence. the inside of the mitochondrion back to the cell cyto- One important way in which ATP helps control energy plasm. This step occurs by facilitated diffusion outward metabolism is to inhibit the enzyme phosphofructokinase. through the inner membrane and then by simple dif- Because this enzyme promotes the formation of fructose- fusion through the permeable outer mitochondrial 1,6-diphosphate, one of the initial steps in the glycolytic membrane. In turn, ADP is continually transferred in series of reactions, the net effect of excess cellular ATP is the other direction for continual conversion into ATP. to slow or even stop glycolysis, which in turn stops most For each two electrons that pass through the entire elec- carbohydrate metabolism. Conversely, ADP (and AMP as tron transport chain (representing the ionization of two well) causes the opposite change in this enzyme, greatly in- hydrogen atoms), up to three ATP molecules are synthe- creasing its activity. Whenever ATP is used by the tissues sized.! for energizing a major fraction of almost all intracellular chemical reactions, this action reduces the ATP inhibition Summary of ATP Formation During the Breakdown of the enzyme phosphofructokinase and at the same time of Glucose increases its activity as a result of the excess ADP formed. We can now determine the total number of ATP molecules Thus, the glycolytic process is set in motion, and the total that, under optimal conditions, can be formed by the en- cellular store of ATP is replenished. ergy from one molecule of glucose. Another control linkage is the citrate ion formed in the 1. During glycolysis, 4 molecules of ATP are formed and citric acid cycle. An excess of this ion also strongly inhibits 2 are expended to cause the initial phosphorylation of phosphofructokinase, thus preventing the glycolytic process glucose to get the process going, giving a net gain of 2 from getting ahead of the citric acid cycle’s ability to use the molecules of ATP. pyruvic acid formed during glycolysis. 849 UNIT XIII Metabolism and Temperature Regulation A third way by which the ATP-ADP-AMP system con- the glycolytic end products can disappear, thus allowing trols carbohydrate metabolism, as well as controlling ener- glycolysis to proceed far longer than would otherwise be gy release from fats and proteins, is the following: Referring possible. Indeed, glycolysis could proceed for only a few to the various chemical reactions for energy release, we see seconds without this conversion. Instead, it can proceed that if all the ADP in the cell has already been converted for several minutes, supplying the body with considerable into ATP, additional ATP simply cannot be formed. As a re- extra quantities of ATP, even in the absence of respiratory sult, the entire sequence involved in the use of foodstuffs— oxygen.! glucose, fats, and proteins—to form ATP is stopped. Then, Reconversion of Lactic Acid to Pyruvic Acid When when ATP is used by the cell to energize the different physi- Oxygen Becomes Available Again. When a person begins ological functions in the cell, the newly formed ADP and to breathe oxygen again after a period of anaerobic metabo- AMP turn on the energy processes again, and ADP and lism, the lactic acid is rapidly reconverted to pyruvic acid AMP are almost instantly returned to the ATP state. In this and NADH plus H+. Large portions of these substances are way, essentially a full store of ATP is automatically main- immediately oxidized to form large quantities of ATP. This tained, except during extreme cellular activity, such as very excess ATP then causes as much as 75% of the remaining strenuous exercise.! excess pyruvic acid to be converted back into glucose. Thus, the large amount of lactic acid that forms dur- Anaerobic Release of Energy—Anaerobic Glycolysis ing anaerobic glycolysis is not lost from the body because, Occasionally, oxygen becomes either unavailable or insuf- when oxygen is available again, the lactic acid can be either ficient, so oxidative phosphorylation cannot take place. Yet reconverted to glucose or used directly for energy. By far even under these conditions, a small amount of energy can the greatest portion of this reconversion occurs in the liver, still be released to the cells by the glycolysis stage of carbo- but a small amount can also occur in other tissues.! hydrate degradation, because the chemical reactions for the Use of Lactic Acid by the Heart for Energy. Heart mus- breakdown of glucose to pyruvic acid do not require oxygen. cle is especially capable of converting lactic acid to pyruvic This process is extremely wasteful of glucose because acid and then using the pyruvic acid for energy. This pro- only 24,000 calories of energy are used to form ATP for cess occurs to a great extent during heavy exercise, when each molecule of glucose metabolized, which represents large amounts of lactic acid are released into the blood only a little over 3% of the total energy in the glucose mol- from the skeletal muscles and consumed as an extra energy ecule. Nevertheless, this release of glycolytic energy to the source by the heart.! cells, which is called anaerobic energy, can be a lifesaving measure for up to a few minutes when oxygen becomes Release of Energy From Glucose by the Pentose unavailable. Phosphate Pathway Formation of Lactic Acid During Anaerobic Glycolysis In almost all the body’s muscles, essentially all the carbo- Allows Release of Extra Anaerobic Energy. The law of hydrates utilized for energy are degraded to pyruvic acid mass action states that as the end products of a chemical by glycolysis and then oxidized. However, this glycolytic reaction build up in a reacting medium, the rate of the re- scheme is not the only means by which glucose can be action decreases, approaching zero. The two end products degraded and used to provide energy. A second impor- of the glycolytic reactions (see Figure 68-5) are (1) pyruvic tant mechanism for breakdown and oxidation of glucose acid and (2) hydrogen atoms combined with NAD+ to form is called the pentose phosphate pathway (or phosphogluco- NADH and H+. The buildup of either or both of these sub- nate pathway), which is responsible for as much as 30% of stances would stop the glycolytic process and prevent fur- the glucose breakdown in the liver and even more than this ther formation of ATP. When their quantities begin to be in fat cells. excessive, these two end products react with each other to This pathway is especially important because it can pro- form lactic acid, in accordance with the following equation: vide energy independently of all the enzymes of the citric OH acid cycle and therefore is an alternative pathway for en- Lactic ergy metabolism when certain enzymatic abnormalities oc- dehydrogenase cur in cells. It has a special capacity for providing energy to CH3 C COOH + NADH + H+ multiple cellular synthetic processes. (Pyruvic acid) Release of Carbon Dioxide and Hydrogen by the Pentose Phosphate Pathway. Figure 68-8 shows most OH 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 CH3 C COOH + NAD+ and four atoms of hydrogen, with the resultant formation of a five-carbon sugar, -ribulose. This substance can change H progressively into several other five-, four-, seven-, and (Lactic acid) three-carbon sugars. Finally, various combinations of these Thus, under anaerobic conditions, the major portion of sugars can resynthesize glucose. However, only five mol- the pyruvic acid is converted into lactic acid, which diffuses ecules of glucose are resynthesized for every six molecules readily out of the cells into the extracellular fluids and even of glucose that initially enter into the reactions. That is, the into the intracellular fluids of other less active cells. There- pentose phosphate pathway is a cyclical process in which fore, lactic acid represents a type of “sinkhole” into which one molecule of glucose is metabolized for each revolution 850  Chapter 68 Metabolism of Carbohydrates and Formation of Adenosine Triphosphate Glucose-6-phosphate ther stored as glycogen or converted into fat. Glucose 2H is preferentially stored as glycogen until the cells have 6-Phosphoglucono-d-lactone stored as much glycogen as they can—an amount suf- ficient to supply the energy needs of the body for only 12 to 24 hours. UNIT XIII 6-Phosphogluconic acid When the glycogen- storing cells (primarily liver 2H and muscle cells) approach saturation with glycogen, 3-Keto-6-phosphogluconic acid the additional glucose is converted into fat in liver and CO2 fat cells and is stored as fat in the fat cells. Other steps D-Ribulose-5-phosphate in the chemistry of this conversion are discussed in H2O Chapter 69.! D-Xylulose-5-phosphate Gluconeogenesis—Formation of Carbohydrates + From Proteins and Fats D-Ribose-5-phosphate When the body’s stores of carbohydrates decrease below normal, moderate quantities of glucose can be formed from D-Sedoheptulose-7-phosphate amino acids and the glycerol portion of fat. This process is + called gluconeogenesis. D-Glyceraldehyde-3-phosphate Gluconeogenesis is especially important in preventing excessive reductions in blood glucose concentration dur- Fructose-6-phosphate ing fasting. Glucose is the primary substrate for energy in + tissues such as the brain and the red blood cells, and ad- Erythrose-4-phosphate equate amounts of glucose must be present in the blood for several hours between meals. The liver plays a key role in Net reaction: maintaining blood glucose levels during fasting by convert- Glucose + 12NADP+ + 6H2O 6CO2 + 12H + 12NADPH ing its stored glycogen to glucose (glycogenolysis) and by synthesizing glucose, mainly from lactate and amino acids Figure 68-8. Pentose phosphate pathway for glucose metabolism. (gluconeogenesis). Approximately 25% of the liver’s glucose See text for details. 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 of the cycle. Thus, by repeating the cycle again and again, all amounts of glucose from amino acids and other precursors. the glucose can eventually be converted into carbon diox- About 60% of the amino acids in the body proteins can ide and hydrogen, and the hydrogen can enter the oxidative be converted easily into carbohydrates; the remaining 40% phosphorylation pathway to form ATP; more often, how- have chemical configurations that make this conversion ever, it is used for the synthesis of fat or other substances, difficult or impossible. Each amino acid is converted into as follows.! glucose by a slightly different chemical process. For exam- Use of Hydrogen to Synthesize Fat; the Function of ple, alanine can be converted directly into pyruvic acid sim- Nicotinamide Adenine Dinucleotide Phosphate. The hy- ply by deamination; the pyruvic acid is then converted into drogen released during the pentose phosphate cycle does glucose or stored glycogen. Several of the more complicat- not combine with NAD+ as in the glycolytic pathway ed amino acids can be converted into different sugars that but combines with nicotinamide adenine dinucleotide contain three-, four-, five-, or seven-carbon atoms. They phosphate (NADP+), which is almost identical to NAD+ can then enter the phosphogluconate pathway and even- except for an extra phosphate radical, P. This difference is tually form glucose. Thus, by means of deamination plus extremely significant because only hydrogen bound with several simple interconversions, many of the amino acids NADP+ in the form of NADPH can be used for the synthe- can become glucose. Similar interconversions can change sis of fats from carbohydrates (as discussed in Chapter 69) glycerol into glucose or glycogen. and for the synthesis of some other substances. Regulation of Gluconeogenesis When the glycolytic pathway for using glucose becomes slowed because of cellular inactivity, the pentose phosphate Diminished carbohydrates in the cells and decreased blood pathway remains operative (mainly in the liver) to break sugar are the basic stimuli that increase the rate of gluco- down any excess glucose that continues to be transport- neogenesis. Diminished carbohydrates can directly reverse ed into the cells, and NADPH becomes abundant to help many of the glycolytic and phosphogluconate reactions, convert acetyl-CoA, also derived from glucose, into long thus allowing conversion of deaminated amino acids and fatty acid chains. This is another way in which energy in glycerol into carbohydrates. In addition, the hormone cor- the glucose molecule is used other than for the formation tisol is especially important in this regulation, as described of ATP—in this case, for the formation and storage of fat in in the following section. the body.! Effect of Adrenocorticotropic Hormone and Glucocor- ticoids on Gluconeogenesis. When normal quantities of Glucose Conversion to Glycogen or Fat carbohydrates are not available to the cells, the adenohy- When glucose is not immediately required for energy, pophysis, for reasons not completely understood, secretes the extra glucose that continually enters the cells is ei- increased quantities of the hormone adrenocorticotropic 851 UNIT XIII Metabolism and Temperature Regulation hormone (ACTH), also called corticotropin or adrenocor- Giorgi C, Marchi S, Pinton P: The machineries, regulation and cellular ticotropin. This secretion stimulates the adrenal cortex to functions of mitochondrial calcium. Nat Rev Mol Cell Biol 19:713, produce large quantities of glucocorticoid hormones, es- 2018. pecially cortisol. In turn, cortisol mobilizes proteins from Hengist A, Koumanov F, Gonzalez JT: Fructose and metabolic health: governed by hepatic glycogen status? J Physiol 597:3573, 2019. essentially all cells of the body, making these proteins avail- Herzig S, Shaw RJ: AMPK: Guardian of metabolism and mitochondrial able in the form of amino acids in the body fluids. A high homeostasis. Nat Rev Mol Cell Biol 19:121, 2018. proportion of these amino acids immediately becomes Koliaki C, Roden M: Hepatic energy metabolism in human diabetes deaminated in the liver and provides ideal substrates for mellitus, obesity and non-alcoholic fatty liver disease. Mol Cell En- conversion into glucose. Thus, one of the most important docrinol 379:35, 2013. means by which gluconeogenesis is promoted is through Krebs HA: The tricarboxylic acid cycle. Harvey Lect 44:165, 1948. the release of glucocorticoids from the adrenal cortex.! Kuo T, Harris CA, Wang JC: Metabolic functions of glucocorticoid receptor in skeletal muscle. Mol Cell Endocrinol 380:79, 2013. Blood Glucose Letts JA, Sazanov LA: Clarifying the supercomplex: the higher-order The normal blood glucose concentration in a person who organization of the mitochondrial electron transport chain. Nat Struct Mol Biol 24:800, 2017. has not eaten a meal within the past 3 to 4 hours is about Petersen MC, Shulman GI: Mechanisms of insulin action and insulin 90 mg/dl. After a meal containing large amounts of car- resistance. Physiol Rev 98:2133, 2018. bohydrates, this level seldom rises above 140 mg/dl un- Petersen MC, Vatner DF, Shulman GI: Regulation of hepatic glucose less the person has diabetes mellitus, which is discussed in metabolism in health and disease. Nat Rev Endocrinol 13:572, 2017. Chapter 79. Pfanner N, Warscheid B, Wiedemann N: Mitochondrial proteins: from The regulation of blood glucose concentration is in- biogenesis to functional networks. Nat Rev Mol Cell Biol 20:267, timately related to the pancreatic hormones insulin and 2019. glucagon; this subject is discussed in detail in Chapter 79 in Prats C, Graham TE, Shearer J: The dynamic life of the glycogen gran- relation to the functions of these hormones. ule. J Biol Chem 293:7089, 2018. Szabo I, Zoratti M: Mitochondrial channels: ion fluxes and more. Physiol Rev 94:519, 2014. Taylor EB: Functional properties of the mitochondrial carrier system. Bibliography Trends Cell Biol 27:633, 2017. Dienel GA: Brain glucose metabolism: integration of energetics with Wright EM, Loo DD, Hirayama BA: Biology of human sodium glucose function. Physiol Rev 99:949, 2019. transporters. Physiol Rev 91:733, 2011. Gancheva S, Jelenik T, Álvarez-Hernández E, Roden M: Interor- gan metabolic crosstalk in human insulin resistance. Physiol Rev 98:1371, 2018. 852