Part 3 Metabolism and Energy Balance Energy Metabolism Life depends on energy from the sun. During photosynthesis, plants transform solar energy into chemical energy in the form of carbohydrates. During energy metabolism, we transform this chemical energy into ATP. Learn more at health.nih.gov.
9.1 Metabolism: Chemical Reactions in the Body 9.2 ATP Production from Carbohydrates 9.3 ATP Production from Fats 9.4 Protein Metabolism 9.5 Alcohol Metabolism 9.6 Regulation of Energy Metabolism 9.7 Fasting and Feasting Medical Perspective: Inborn Errors of MetabolismSTUDENT LEARNING OUTCOMESafter studying this chapter, you will be able to1. Explain the differences among metabolism, 5. Identify the conditions that lead to ketogenesis catabolism, and anabolism. and its importance in survival during fasting.2. Describe aerobic and anaerobic metabolism of 6. Describe the process of gluconeogenesis. glucose. 7. Discuss how the body metabolizes alcohol.3. Illustrate how energy is extracted from 8. Compare the fate of energy from glucose, fatty acids, amino acids, and alcohol macronutrients during the fed and fasted using metabolic pathways, such as glycolysis, states. beta-oxidation, the citric acid cycle, and the electron transport system. 9. Describe common inborn errors of metabolism.4. Describe the role that acetyl-CoA plays in cell metabolism.The macronutrients and alcohol are rich sources of energy; however, the energy they provide isneither in the form that cells can use nor in the amount needed to carry out the thousands of chemicalreactions that occur every day in the human body. Thus, the body must have a process for breakingdown energy-yielding compounds to release and convert their chemical energy to a form the body canuse.1 That process is energy metabolism—an elaborate, multistep series of energy-transforming chemicalreactions. Energy metabolism occurs in all cells every moment of every day for your entire lifetime; it isslowest when we are resting and fastest when we are physically active. Understanding energy metabolism clarifies how carbohydrates, proteins, fats, and alcoholare interrelated and how they serve as fuel for body cells. In this chapter, you will see how themacronutrients and alcohol are metabolized and discover why proteins can be converted to glucosebut most fatty acids cannot. Studying energy metabolism pathways in the cell also sets the stage forexamining the roles of vitamins and minerals. As you’ll see in this and subsequent chapters, manymicronutrients contribute to the enzyme activity that supports metabolic reactions in the cell.2 Thus,both macronutrients and micronutrients are required for basic metabolic processes. 281
282 Part 3 Metabolism and Energy Balance Proteins Glycogen 9.1 Metabolism: Chemical Reactions in the BodyProtein TriglyceridesCarbohydrate and otherFat lipids Metabolism refers to the entire network of chemical processes involved in maintaining C life. It encompasses all the sequences of chemical reactions that occur in the body. Some A of these biochemical reactions enable us to release and use energy from carbohydrate, T A fat, protein, and alcohol. They also permit us to synthesize 1 substance from another and B A prepare waste products for excretion.1 A group of biochemical reactions that occur in a O N L A progression from beginning to end is called a metabolic pathway. Compounds formed I B in 1 of the many steps in a metabolic pathway are called intermediates. S O M L All of the pathways that take place within the body can be categorized as either ana- I bolic or catabolic. Anabolic pathways use small, simpler compounds to build larger, more S M complex compounds (Fig. 9-1). The human body uses compounds, such as glucose, fatty acids, cholesterol, and amino acids, as building blocks to synthesize new compounds, CO2 Amino acids such as glycogen, hormones, enzymes, and other proteins, to keep the body functioning H2O Sugars Fatty acids and to support normal growth and development. For example, to make glycogen (a stor- NH3 Glycerol age form of carbohydrate), we link many units of the simple sugar glucose. Energy must be expended for anabolic pathways to take place. Conversely, catabolic pathways break down compounds into small units. The gly-Figure 9-1 Anabolism relies on catabolism cogen molecule discussed in the anabolism example is broken down into many glucoseto provide the energy (ATP) required to buildcompounds. molecules when blood levels of glucose drop. Later, the complete catabolism of this glu- cose results in the release of carbon dioxide (CO2) and water (H2O). Energy is released during catabolism: some is trapped for cell use and the rest is lost as heat. The body strives for a balance between anabolic and catabolic processes. However, there are times when one is more prominent than the other. For example, during growth there is a net anabolic state because more tissue is being synthesized than broken down. However, during weight loss or a wasting disease, such as cancer, more tissue is being broken down than synthesized. Energy for the Cell Cells use energy for the following purposes: building compounds, contracting muscles, con- ducting nerve impulses, and pumping ions (e.g., across cell membranes).1 This energy comes from catabolic reactions that break the chemical bonds between the atoms in carbohydrate, fat, protein, and alcohol. This energy is originally produced during photosynthesis, when plants use solar energy to make glucose and other Catabolism organic (carbon-containing) compounds (see Chapter 5). The chemical reactions in photosyn- Proteins Carbohydrates Lipids AlcoholStage 1 thesis form compounds that contain more energyDigestion: breakdown 1 than the building blocks used—carbon dioxideof complex molecules and water. Virtually all organisms use the sun—to their component either indirectly, as we do, or directly—as their Amino acids Monosaccharides Fatty acids,building blocks glycerol source of energy.1 ATP As shown in Figure 9-2, the series of cata-Stage 2 2 CO2 bolic reactions that produce energy for body cellsConversion of buildingblocks to acetyl-CoA begins with digestion and continues when mono-(or other simple Acetyl-CoA saccharides, amino acids, fatty acids, glycerol, andintermediates) alcohol are sent through a series of metabolic path- 3 ways, which finally trap a portion of the energyStage 3 they contain into a compound called adenosineMetabolism ofacetyl-CoA to CO2 ATP triphosphate (ATP)—the main form of energy Citric acidand formation of ATP cycle CO2 the body uses. Heat, carbon dioxide, and water (and electron also result from these catabolic pathways. The heat transport chain) produced helps maintain body temperature. Plants can use the carbon dioxide and water to produceFigure 9-2 Three stages of catabolism. glucose and oxygen via photosynthesis.
chapter 9 Energy Metabolism 283Adenosine Triphosphate (ATP)Only the energy in ATP and related compounds can be used directly by the cell.3 A moleculeof ATP consists of the organic compound adenosine (comprised of the nucleotide adenineand the sugar ribose) bound to 3 phosphate groups (Fig. 9-3). The bonds between the phos-phate groups contain energy and are called high-energy phosphate bonds. Hydrolysis of thehigh-energy bonds releases this energy. To release the energy in ATP, cells break a high-energyphosphate bond, which creates adenosine diphosphate (ADP) plus Pi, a free (inorganic)phosphate group (Fig. 9-4). Hydrolysis of ADP results in the compound adenosine mono-phosphate (AMP) in a reaction muscles are capable of performing during intense exercisewhen ATP is in short supply (ADP + ADP → ATP + AMP). ATP can be regenerated by add-ing the phosphates back to AMP and ADP. Figure 9-3 ATP is a storage form of energy Adenine for cell use because it contains high-energy bonds. Pi is the abbreviation for an inorganic phosphate group. Ribose Pi Pi Pi Adenosine High-energy bonds High-energy bonds Figure 9-4 ATP stores and yields energy. ATP is the high-energy state; ADP is the lower-energy P ~P ~P ATP state. When ATP is broken down to ADP plus Pi , energy is released for cell use. When energy is trapped by ADP plus Pi ATP can be formed. , Pi Pi P ~P ADP Energy released Energy used in catabolic in anabolic pathways pathways Every cell requires energy from ATP to synthesize new compounds (anabolic path-ways), to contract muscles, to conduct nerve impulses, and to pump ions across membranes.Catabolic pathways in cells release energy, which allows ADP to combine with Piand form ATP. Every cell has pathways to break down and resynthesize ATP. A A Biochemist , Viewcell is constantly breaking down ATP in one site while rebuilding it in another.This recycling of ATP is an important strategy because the body contains onlyabout 0.22 lb (100 g) of ATP at any given time, but a sedentary adult uses about s88 lb (40 kg) of ATP each day. The requirement increases even more during NH2exercise—during 1 hour of strenuous exercise, an additional 66 lb (30 kg) ofATP are used. In fact, the runner who currently holds the American record for N Adenine Nthe men’s marathon was estimated to use 132 lb (65 kg) to run the race.24 High-energy phosphate bonds N NOxidation-Reduction Reactions: Key Processes O O Oin Energy Metabolism O �O P O P O P OThe synthesis of ATP from ADP and Pi involves the transfer of energy fromenergy-yielding compounds (carbohydrate, fat, protein, and alcohol). This pro- O� O� O�cess uses oxidation-reduction reactions, in which electrons (along with hydrogen OH OHions) are transferred in a series of reactions from energy-yielding compoundseventually to oxygen. These reactions form water and release much energy, Ribosewhich can be used to produce ATP.
284 Part 3 Metabolism and Energy Balance The mnemonic “LeO [loss of electrons is A substance is oxidized when it loses 1 or more electrons. For example, copper isoxidation] the lion says Ger [gain of electrons oxidized when it loses an electron:is reduction]” can help you differentiate Cu+ ∆ Cu2+ + e-between oxidation and reduction. A substance is reduced when it gains 1 or more electrons. For example, iron is re- duced when it gains an electron: Fe3+ + e- ∆ Fe2+ , The movement of electrons governs oxidation-reduction processes. If 1 substance loses A Biochemist s View electrons (is oxidized), another substance must gain electrons (is reduced). These processes go together; one cannot occur without the other.2 In the previous examples, the electron lost CH2OH by copper can be gained by the iron, resulting in this overall reaction;: Cu+ + Fe3+ → Cu2++ Fe2+ O H H Oxidation-reduction reactions involving organic (carbon-containing) compounds are H somewhat more difficult to visualize. Two simple rules help identify whether these com- OH H pounds are oxidized or reduced: HO OH If the compound gains oxygen or loses hydrogen, it has been oxidized. H OH If it loses oxygen or gains hydrogen, the compound has been reduced. Enzymes control oxidation-reduction reactions in the body. Dehydrogenases, one Glucose class of these enzymes, remove hydrogens from energy-yielding compounds or their O breakdown products. These hydrogens are eventually donated to oxygen to form water. In the process, large amounts of energy are converted to ATP.1 C O� Two B-vitamins, niacin and riboflavin, assist dehydrogenase enzymes and, in turn, play a role in transferring the hydrogens from energy-yielding compounds to oxygen in the meta- C O bolic pathways of the cell.2 In the following reaction, niacin functions as the coenzyme nicoti- CH3 namide adenine dinucleotide (NAD). NAD is found in cells in both its oxidized form (NAD) and reduced form (NADH). During intense (anaerobic) exercise, the enzyme lactate dehy- Pyruvate drogenase helps reduce pyruvate (made from glucose) to form lactate. During reduction, 2 hydrogens, derived from NADH + H+, are gained. Lactate is oxidized back to pyruvate by losing 2 hydrogens. NAD+ is the hydrogen acceptor. That is, the oxidized form of niacin coenzyme Compound that combines (NAD+) can accept 1 hydrogen ion and 2 electrons to become the reduced form NADH + with an inactive protein, called an H+. (The plus [+] on NAD+ indicates it has 1 less electron than in its reduced form. The extra apoenzyme, to form a catalytically hydrogen ion [H+] remains free in the cell.) By accepting 2 electrons and 1 hydrogen ion, active protein, called a holoenzyme. In NAD+ becomes NADH + H+, with no net charge on the coenzyme. this manner, coenzymes aid in enzyme function. NADH ϩ Hϩ NADϩ O O OH O The term antioxidant is typically used CH3 C C OϪ CH3 C C OϪto describe a compound that can donateelectrons to oxidized compounds, putting them Pyruvate (Oxidized) Hinto a more reduced (stable) state. Oxidized NADH ϩ Hϩ NADϩcompounds tend to be highly reactive; they Lactate (Reduced)seek electrons from other compounds tostabilize their chemical conﬁguration. Dietary Riboflavin plays a similar role. In its oxidized form, the coenzyme form is known asantioxidants, such as vitamin E, donate flavin adenine dinucleotide (FAD). When it is reduced (gains 2 hydrogens, equivalent toelectrons to these highly reactive compounds, 2 hydrogen ions and 2 electrons), it is known as FADH2.in turn, putting these oxidized compounds into The reduction of oxygen (O) to form water (H2O) is the ultimate driving force for life be-a less reactive state (see Chapter 12). cause it is vital to the way cells synthesize ATP. Thus, oxidation-reduction reactions are a key to life. Knowledge Check 1. What is the main form of energy used by the body? 2. What are catabolic and anabolic reactions? 3. What is the difference between oxidation and reduction reactions? 4. How do niacin and riboﬂavin play a role in metabolism?
CHaPtEr 9 Energy Metabolism 285 9.2 ATP Production from Carbohydrates A new tool for understanding how individuals differ in the metabolic response to nutrients may lie in the ability to track theCells release energy stored in food fuels and then trap as much of this energy as possible actual metabolic intermediates made duringin the form of ATP. The body cannot afford to lose all energy immediately as heat, even metabolism, such as how we respond tothough some heat is necessary for the maintenance of body temperature. This section ex- exposure to different fatty acids. This approach,amines how ATP is produced from carbohydrates. Subsequent sections will explore how called metabolomics, should be more accurateATP is produced using the energy stored in fats, proteins, and alcohol. Along the way, than looking for differences in DNA betweenyou will see how these energy-yielding processes are interconnected. individuals to predict dietary responses. ATP is generated through cellular respiration. The process of cellular respira-tion oxidizes (removes electrons) food molecules to obtain energy (ATP). Oxygenis the final electron acceptor. As you know, humans inhale oxygen and exhale carbondioxide. When oxygen is readily available, cellular respiration may be aerobic. Whenoxygen is not present, anaerobic pathways are used. Aerobic respiration is far moreefficient than anaerobic metabolism at producing ATP. As an example, the aerobicrespiration of a single molecule of glucose will result in a net gain of 30 to 32 ATP.In contrast, the anaerobic metabolism of a single molecule of glucose is limited to a aerobic Requiring oxygen.net gain of 2 ATP. The 4 overall stages of aerobic cellular respiration of glucose are as follows anaerobic Not requiring oxygen.(Fig. 9-5).1, 4 cytosol Water-based phase of a cell’s Stage 1: Glycolysis. In this pathway, glucose (a 6-carbon compound) is oxidized and cytoplasm; excludes organelles, such as forms 2 molecules of the 3-carbon compound pyruvate, produces NADH + H+, and mitochondria. generates a net of 2 molecules of ATP. Glycolysis occurs in the cytosol of cells. Figure 9-5 The 4 phases of aerobic carbohydrate metabolism. Glycolysis in the cytoplasm produces pyruvate (stage 1 ), which enters mitochondria if oxygen is available. The transition reaction (stage 2 ), citric acid cycle (stage 3 ), and electron transport chain (stage 4 ) occur inside the mitochondria. The electron transport chain receives the electrons that were removed from glucose breakdown products during stages 1 through 3. The result of aerobic glucose breakdown is 30 to 32 ATP depending on the particular cell. , e� 4 NADH � H� Electron transport chain e� 3O2 � 12H� 6H2O NADH � H� e� NADH � H� and FADH2 1 2 Transition Glycolysis reaction 3 Acetyl- Citric acid Glucose 2 Pyruvate CoA cycle 2 CO2 2 CO2 26 or 2 ADP 2 ADP 28 ADP 2 ATP 2 ATP 26 or 28 ATP
286 Part 3 Metabolism and Energy Balance Stage 2: Synthesis of acetyl-CoA. In this stage, pyruvate is further oxidized and joined mitochondria Main sites of energy with coenzyme A (CoA) to form acetyl-CoA. The transition reaction also produces production in a cell. They also contain NADH + H+ and releases carbon dioxide (CO2) as a waste product. The transition the pathway for oxidizing fat for fuel, reaction takes place in the mitochondria of cells. among other metabolic pathways. Stage 3: Citric acid cycle. In this pathway, acetyl-CoA enters the citric acid cycle, result- ing in the production of NADH + H+, FADH2, and ATP. Carbon dioxide is released A number of defects are related to as a waste product. Like the transition reaction, the citric acid cycle takes place withinthe metabolic processes that take place the mitochondria of cells.in mitochondria. A variety of medical Stage 4: Electron transport chain. The NADH + H+ produced by stages 1 through 3interventions, some of which use of cellular respiration and FADH2 produced in stage 3 enter the electron transportspeciﬁc nutrients and related metabolic chain, where NADH + H+ is oxidized to NAD+, and FADH2 is oxidized to FAD. Atintermediates, can be used to treat the the end of the electron transport chain, oxygen is combined with hydrogen ions (H+)muscle weakness and muscle destruction and electrons to form water. The electron transport chain takes place within the mi-typically arising from these disorders. tochondria of cells. Most ATP is produced in the electron transport chain; thus, the mitochondria are the cell’s major energy-producing organelles. acetyl-coa O O Glycolysis Because glucose is the main carbohydrate involved in cell metabolism, we will track its CoA – S CoA – S CH 33 CH step-by-step metabolism as an example of carbohydrate metabolism. Glucose metabolism begins with glycolysis, which means “breaking down glucose.” Glycolysis has 2 roles: CoA is short for coenzyme A. The A stands for to break down carbohydrates to generate energy and to provide building blocks for syn-acetylation because CoA provides the 2-carbon thesizing other needed compounds. During glycolysis, glucose passes through severalacetyl group to start the citric acid cycle. steps, which convert it to 2 units of a 3-carbon compound called pyruvate. The details of glycolysis can be found in Figure 9-6. Synthesis of Acetyl-CoA Pyruvate passes from the cytosol into the mitochondria, where the enzyme pyruvate Pyruvate dehydrogenase converts pyruvate into the compound acetyl-CoA in a process called a tran- CO2 sition reaction5 (Fig. 9-7). This overall reaction is irreversible, which has important met- NAD� abolic consequences. Whereas glycolysis requires only the B-vitamin niacin as NAD, the CoA conversion of pyruvate to acetyl-CoA requires coenzymes from 4 B-vitamins—thiamin, riboflavin, niacin, and pantothenic acid. In fact, CoA is made from the B-vitamin pantoth- NADH � H� enic acid. For this reason, carbohydrate metabolism depends on an ample supply of these Acetyl-CoA vitamins (see Chapter 13).2 The transition reaction oxidizes pyruvate and reduces NAD+. Each glucose yieldsFigure 9-6 Pyruvate dehydrogenase assists 2 acetyl-CoA. As with the NADH + H+ produced by glycolysis, the 2 NADH + 2 H+in the transition reaction where pyruvate ismetabolized to acetyl-CoA. It is acetyl-CoA that produced by the transition reaction will eventually enter the electron transport chain.actually enters the citric acid cycle. In the process, Carbon dioxide is a waste product of the transition reaction and is eventually eliminatedNADH + H+ is produced and CO2 is lost. by way of the lungs. Knowledge Check 1. What is the ﬁrst step to bring glucose into the cell to start glycolysis? 2. How many 3-carbon compounds are made from a 6-carbon glucose molecule? 3. What is the end product of glycolysis? 4. What nutrients are involved in the transition reaction?
chapter 9 Energy Metabolism 287 Glucose ATP ~ ~ The first step of glycolysis is to activate the glucose molecule by attaching 1 1 ADP ~ a phosphate group to it. The attached phosphate group is supplied by ATP, which means that energy is required for this step and that ADP is formed. Glucose 6-phosphate Fructose 6-phosphate ATP ~ ~ The molecule is rearranged and a second phosphate group is added 2 2 ADP ~ using ATP, forming fructose 1,6-bisphosphate. Again, ATP provides the phosphate, making this an energy-requiring step. Fructose 1,6-bisphosphate 3 Fructose 1,6-biphosphate is split in half to form two 3-carbon molecules, each of which has 1 phosphate—glyceraldehyde 3-phosphate and dihydroxyacetone phosphate. Dihydroxyacetone phosphate is eventually converted into glyceraldehyde 3-phosphate. Thus, step 4 onward Glyceraldehyde Dihydroxyacetone occurs twice for each molecule of glucose that enters glycolysis. 3-phosphate 3 phosphate NAD� 4 4 A dehydrogenase enzyme oxidizes each of the two 3-carbon molecules. NADH � H� NAD is reduced, forming 2NADH � 2H�. A phosphate molecule is added to each 3-carbon molecule. 1,3-bisphospho- glycerate ~ ADP ~ 5 5 An enzyme transfers 1 phosphate from each of the 3-carbon molecules to an ADP, forming 2 ATP. This is the first synthesis of the high-energy ATP ~ ~ compound ATP in the pathway. 3-phospho- glycerate 6 6 Water is removed from each of the 3-carbon molecules, which produces H2O two 3-carbon-phosphate molecules. Phospho- ~ enolpyruvate ADP ~ An enzyme transfers 1 phosphate from each of the 3-carbon molecules to 7 7 ATP ~ ~ an ADP, thereby producing a total of 2 ATP. Pyruvate 8 8 The last step in glycolysis is the formation of pyruvate. Generally, pyruvate enters the mitochondria for further metabolism. A total of 2 pyruvates are formed from each glucose that enters glycolysis. Carbon Phosphate group AdenosineFigure 9-7 Glycolysis takes place in the cytosol portion of the cell. This process breaks glucose (a 6-carbon compound) into 2 units of a 3-carbon compoundcalled pyruvate. More details can be found in Appendix A.
288 Part 3 Metabolism and Energy Balance , Citric Acid Cycle A Biochemist s View The acetyl-CoA molecules produced by the transition reaction enter the citric acid cycle, O O which also is known as the tricarboxylic acid cycle (TCA cycle) and the Krebs cycle. The citric acid cycle is a series of chemical reactions that cells use to convert the carbons of an C C O� acetyl group to carbon dioxide while harvesting energy to produce ATP.3 O It takes 2 turns of the citric acid cycle to process 1 glucose molecule because glycolysis and the transition reaction yield 2 acetyl-CoA. Each complete turn of the citric acid cycle produces CH2 C O� 2 molecules of CO2 and 1 potential ATP in the form of 1 molecule of guanosine triphosphate Oxaloacetate (GTP), as well as 3 molecules of NADH + H+ and 1 molecule of FADH2. Oxygen does not participate in any of the steps in the citric acid cycle; however, it does participate in the electron O transport chain. The details of the citric acid cycle can be found in Figure 9-8; further details are in Appendix A. CH2 C O� O HO C C O� Pyruvate O NAD� Transition step: CH2 C O� Oxidation generates CoA NADH � H� NADH, CO2 is removed, Citrate (Citric Acid) and coenzyme A is added. CO2 1 To begin the citric acid cycle, the 2-carbon compound acetyl- Acetyl-CoA CoA combines with a 4-carbon compound, oxaloacetate, to CoA form the 6-carbon compound citrate. In the process, the corresponding CoA molecule is released and can be reused. NADH � H� Oxaloacetate Citrate NAD� 2 The 6-carbon citrate is oxidized (hydrogen removed), forming the 5-carbon compound alpha- 5 The 4-carbon fumarate is NADH � H� NAD� ketoglutarate, NADH � H�, oxidized, forming the 4-carbon and CO2. compound oxaloacetate—the compound used to begin the citric acid cycle (step 1)—and CO2 NADH � H�. H2O �-ketoglutarate Fumarate 4 The 4-carbon succinate is NAD� oxidized to the 4-carbon FADH2 compound fumarate. FADH2 is formed. NADH � H� 3 The 5-carbon alpha-ketoglutarate FAD CO2 is oxidized, forming the 4-carbon Succinate compound succinate, NADH � H�, CO2, and guanosine triphosphate (GTP), which is GDP ~ converted to ATP. GTP ~ ~Figure 9-8 How the citric acid cycle works. During ATP ~ ~1 complete turn of the citric acid cycle, the 6-carboncitrate molecule is converted to a 4-carbon oxaloacetatemolecule. The cycle is now ready to begin again with theregenerated oxaloacetate and another acetyl-CoA. SeeFigure A-2 in Appendix A for a more detailed view of thecitric acid cycle. ADP ~
chaPter 9 Energy Metabolism 289Electron Transport Chain Intermediates of the citric acid cycle, such as oxaloacetate, can leave the cycle and goThe final pathway of aerobic respiration is the electron transport chain located in the on to form other compounds, such as glucose.mitochondria. The electron transport chain functions in most cells in the body. Cells Thus, the citric acid cycle should be viewed as athat need a lot of ATP, such as muscle cells, have thousands of mitochondria, whereas trafﬁc circle, rather than as a closed circle.cells that need very little ATP, such as adipose cells, have fewer mitochondria. Almost90% of the ATP produced from the catabolism of glucose is produced by the electrontransport chain. The electron transport chain involves the passage of electrons along a series ofelectron carriers. As electrons are passed from one carrier to the next, small amounts How many ATP are produced byof energy are released. NADH + H+ and FADH2, produced by glycolysis, the transi- 1 molecule of glucose? The metabolismtion reaction, and the citric acid cycle, supply both hydrogen ions and electrons to the of 1 glucose molecule yieldselectron transport chain. The metabolic process, called oxidative phosphorylation, Glycolysis 2 NADH and 2 ATPis the way in which energy derived from the NADH + H+ and FADH2 is transferred Transition reaction 2 NADHto ADP + Pi to form ATP (Fig. 9-9). Oxidative phosphorylation requires the mineralscopper and iron. Copper is a component of an enzyme, whereas iron is a component Citric acid cycle 6 NADH, 2 FADH2,of cytochromes (electron-transfer compound) in the electron transport chain. In ad- and 2 GTPdition to ATP production, hydrogen ions, electrons, and oxygen combine to form total 10 NaDh,water. The details of the electron transport chain are presented in Figure 9-10. 2 FaDh2, 2 GtP, and 2 atP High-energy Low-energy molecule, molecule, such as The NADH and FADH2 generated undergo such as glucose CO2 and H2O H� oxidative phosphorylation in the electron H� transport chain to yield e� NADH � H� e� 2.5 ATP molecules per NADH or FADH2 1.5 ATP molecules per FADH2 NAD� Thus, 28 ATP molecules are synthesized in the electron transport chain. or FAD e� total atP Produced from each Glucose H� Molecule e� H� Pi ATP Glycolysis ATP 2 ATP ADP � 1 —O 2 2 Citric acid cycle GTP 2 ATP H2O Citric acid cycle ATP 28 ATP total 32 atPFigure 9-9 Simplified depiction of electron transfer in energy metabolism. High-energy compounds,such as glucose, give up electrons and hydrogen ions to NAD and FAD. The NADH + H and FADH2 that are + +formed transfer these electrons and hydrogen ions, using specialized electron carriers, to oxygen to formwater (H2O). The energy yielded by the entire process is used to generate ATP from ADP and Pi.The Importance of OxygenNADH + H+ and FADH2 produced during the citric acid cycle can be regenerated into Coenzyme Q-10 is sold as a nutrientNAD+ and FAD only by the eventual transfer of their electrons and hydrogen ions to supplement in health food stores (10 signiﬁesoxygen, as occurs in the electron transport chain. The citric acid cycle has no ability that it is the form found in humans). However,to oxidize NADH + H+ and FADH2 back to NAD+ and FAD. This is ultimately why when the mitochondria need coenzyme Q,oxygen is essential to many life forms—it is a final acceptor of the electrons and hydro- they make it. Thus, to maintain overall health,gen ions generated from the breakdown of energy-yielding nutrients. Without oxygen, coenzyme Q is not needed in the diet or asmost of our cells are unable to extract enough energy from energy-yielding nutrients a supplement. (Such use may be helpful,to sustain life.1 however, in people with heart failure.)
290 Part 3 Metabolism and Energy Balance Cytosol Outer membrane ATP Outer H� H� H� H� ATP Carrier compartment 2 e� 2 synthase ADP molecule Pi Inner I II III 2 e� IV membrane Inner compartment 2 e� 2 e� Pi � ADP 2 e� NADH H� 1 FADH2 H� H� ATP 2 e� 2 H� H� 4 NAD� H2O 1 3 2 O2 1 2 3 4 NADH � H� and FADH2 transfer Pairs of electrons are then As hydrogen ions diffuse One carrier molecule their hydrogen ions and electrons to separated by coenzyme Q back into the inner moves ADP into the inner the electron carriers located on the (CoQ) and each electron is compartment through compartment and a inner mitochondrial membrane. then passed along a group special channels, ATP is different carrier molecule Although NADH � H� and FADH2 of iron-containing produced by the enzyme moves phosphate (Pi) into transfer their hydrogens to the electron cytochromes. At each ATP synthase. At the end of the inner compartment. In transport chain, the hydrogen ions transfer from one the chain of cytochromes, the inner compartment, the (H�), having been separated from cytochrome to the next, the electrons, hydrogen energy generated by the their electron (H H� � e�), are not energy is released. Some ions, and oxygen combine electron transport chain carried down the chain with the of this energy is used to to form water. Oxygen is unites ADP to Pi to form electrons. Instead, the hydrogen ions pump hydrogen ions into the final electron acceptor ATP. ATP is transported out are pumped into the outer the outer compartment. A and is reduced to form of the inner compartment compartment (located between the portion of the energy is water. by a carrier protein inner and outer membrane of a eventually used to generate molecule that exchanges mitochondrion). The NAD� and FAD ATP from ADP and Pi, but ATP for ADP. regenerated from the oxidation of the much is simply released as NADH � H� and FADH2 are now heat. ready to function in glycolysis, the transition reaction, and the citric acid cycle.Figure 9-10 The electron transport chain. In Figure 9-10, step 1, NADH + H+ donatesits chemical energy to an FAD-related Anaerobic Metabolismcompound called ﬂavin mononucleotide(FMN). In contrast, FADH2 donates its chemical Some cells lack mitochondria and, so, are not capable of aerobic respiration. Other cellsenergy at a later point in the electron transport are capable of turning to anaerobic metabolism when oxygen is lacking. When oxygen ischain. This different placement of FAD and absent, pyruvate that is produced through glycolysis is converted into lactate, or lactic acid.NAD+ in the electron transport chain results in Anaerobic metabolism is not nearly as efficient as aerobic respiration because it convertsa difference in ATP production. Each NADH + H+ only about 5% of the energy in a molecule of glucose to energy stored in the high-energyin a mitochondrion releases enough energy to phosphate bonds of ATP.1form the equivalent of 2.5 ATP, whereas each The anaerobic glycolysis pathway encompasses glycolysis and the conversion ofFADH2 releases enough energy to form the pyruvate to lactate (Fig. 9-11). The 1-step reaction, catalyzed by the enzyme pyruvateequivalent of 1.5 ATP.1 dehydrogenase, involves a simple transfer of a hydrogen from NADH + H+ to pyruvate
chaPter 9 Energy Metabolism 291 to form lactate and NAD+. The synthesis of lactate In anaerobic environments, some regenerates the NAD+ required for the continued microorganisms, such as yeast, produce function of glycolysis. The reaction can be sum- ethanol, a type of alcohol, instead of lactate marized as from glucose. Other microorganisms produce various forms of short-chain fatty acids. All Pyruvate + NADH + H+ → Lactate + NAD+ this anaerobic metabolism is referred to as fermentation. For cells that lack mitochondria, such as red blood cells, anaerobic glycolysis is the only meth- od for making ATP because they lack the electron transport chain and oxidative phosphorylation. Glucose Therefore, when red blood cells convert glucose to pyruvate, NADH + H+ builds up in the cell. 2 ATP Eventually, the NAD+ concentration falls too low to permit glycolysis to continue.5 The anaerobic 2 ADP glycolysis pathway produces lactate to regener- ate NAD+. The lactate produced by the red blood 2X P Glyceraldehyde 3–phosphate cell is then released into the bloodstream, picked up primarily by the liver, and used to synthesizeQuick bursts of activity rely on theproduction of lactate to help meet the ATP pyruvate, glucose, or some other intermediate in 2 NAD�energy demand. aerobic respiration. Even though muscles cells contain mito- 2 NADH � H�chondria, during intensive exercise they also produce lactate when NAD+ is depleted. Byregenerating NAD+, the production of lactate allows anaerobic glycolysis to continue. 2X P~ P 1,3–bisphosphoglycerateMuscle cells can then make the ATP required for muscle contraction even if little oxygenis present. However, as you will find out in Chapter 11, it becomes more difficult to con-tract those muscles as the lactate concentration builds up. 2 ADP 2 ATP Knowledge Check 1. How is citric acid in the citric acid cycle formed? 2X Pyruvate 2. How many NADH + H+ are formed in the citric acid cycle? 3. Why is the citric acid cycle called a cycle? 4. What is the purpose of the electron transport chain? 5. What are the end products of the electron transport chain? 2X Lactate Figure 9-11 Anaerobic glycolysis “frees” NAD+ and it returns to the glycolysis pathway to pick up more hydrogen ions and electrons. C A S E ST U DY Melissa is a 45-year-old woman who is obese. ketones. In the book, the author states that anyone going on this At her last physical, her doctor told her that she diet should purchase ketone strips to dip in his or her urine for the needs to lose weight. Melissa purchased a low- detection of ketones. The author strongly suggests these tests, carbohydrate, high-protein diet book and has read especially during the extremely low-carbohydrate part of the it and is now ready to try the diet. She knows it diet. Melissa wonders if she should be considering this diet if the will be difﬁcult to follow because many of the author is telling her to check something and she wonders what foods Melissa likes are rich in carbohydrates, and ketones are. the ﬁrst 2 weeks of the diet eliminates almost What are ketones and why does a very-low-carbohydrate diet all carbohydrates from her diet. Although she produce an increase in ketones in both the blood and the urine? Can is ready to try the diet, she is confused about certain phases of you speculate at this time why low carbohydrates cause ketones? Why the program, especially the part where the author talks about do some fad diets produce ketones?
292 Part 3 Metabolism and Energy Balance 9.3 ATP Production from Fats Carnitine is a popular nutritional Just as cells release the energy in carbohydrates and trap it as ATP, they also release andsupplement. In healthy people, cells trap energy in triglyceride molecules. This process begins with lipolysis, the breakingproduce the carnitine needed, and carnitine down of triglycerides into free fatty acids and glycerol. The further breakdown of fatty ac-supplements provide no beneﬁt. In patients ids for energy production is called fatty acid oxidation because the donation of electronshospitalized with acute illnesses, however, from fatty acids to oxygen is the net reaction in the ATP-yielding process. This processcarnitine synthesis may be inadequate. These takes place in the mitochondria.patients may need to have carnitine added Fatty acids for oxidation can come from either dietary fat or fat stored in the bodyto their intravenous feeding (total parenteral as adipose tissue. Following high-fat meals, the body stores excess fat in adipose tissue.nutrition) solutions. However, during periods of low calorie intake or fasting, triglycerides from fat cells are broken down into fatty acids by an enzyme called hormone-sensitive lipase and released in the blood. The activity of this enzyme is increased by hormones such as glucagon, growth hormone, and epinephrine and is decreased by the hormone insulin. The fatty acids are taken up from the bloodstream by cells throughout the body and are shuttled from the cell cytosol into the mitochondria using a carrier called carnitine (Fig. 9-12).6Figure 9-12 Lipolysis. Because of the action GI Tractof hormone-sensitive lipase, fatty acids arereleased from triglycerides in adipose cells and Dietaryenter the bloodstream. The fatty acids are taken fatup from the bloodstream by various cells andshuttled by carnitine into the inner portion of thecell mitochondria. The fatty acid then undergoesbeta-oxidation, which yields acetate molecules Glycerol Fatty acidsequal in number to half of the carbons in thefatty acid. Adipose tissue Cell Triglycerides Hormone- Beta-oxidation sensitive Acetyl Fatty acids Carnitine Fatty acids lipase molecules Glycerol Fatty acids Mitochondria Cytosol Bloodstream ATP Production from Fatty Acids Almost all fatty acids in nature are composed of an even number of carbons, ranging from 2 to 26. The first step in transferring the energy in such a fatty acid to ATP is to cleave the carbons, 2 at a time, and convert the 2-carbon fragments to acetyl-CoA. The process of converting a free fatty acid to multiple acetyl-CoA molecules is called beta-oxidation be- cause it begins with the beta carbon, the second carbon on a fatty acid (counting after the carboxyl [acid] end).1 (See Chapter 6.) During beta-oxidation, NADH + H+ and FADH2 are produced (Fig. 9-13). Thus, as with glucose, a fatty acid is eventually degraded into a number of the 2-carbon compound acetyl-CoA (the exact number produced depends on the number of carbons in the fatty acid). Some of the chemical energy contained in the fatty acid is transferred to NADH + H+ and FADH2.
chapter 9 Energy Metabolism 293 H Figure 9-13 In beta-oxidation, each 2-carbon H H H H H H O fragment cleaved from a fatty acid (acetyl group) yields electrons and hydrogen ions to form NADH H C C C C C C C C OH + H+ and FADH2 as the fragments are split off the parent fatty acid. The 2-carbon acetyl molecule H H H H H H H then typically enters the citric acid cycle (as acetyl-CoA). NADH � H� Beta-carbon FADH2 H H H H H H H O H C C C C C C C C OH H H H H H H H NADH � H� NADH � H� FADH2 FADH2 H H H H H H H O H C C C C C C C C OH H H H H H H H NADH � H� NADH � H� NADH � H� Glucose FADH2 FADH2 FADH2 P ~ The acetyl-CoA enters the citric acid cycle, and 2 carbon dioxides are re- Phosphoenolpyruvateleased, just as with the acetyl-CoA produced from glucose. Thus, the breakdownproduct of both glucose and fatty acids—acetyl-CoA—enter the citric acid cy-cle. One big difference, however, is that a 16-carbon fatty acid yields 104 ATP,whereas the 6-carbon glucose yields only 30 to 32 ATP. The difference in ATPproduction occurs because each 2-carbon segment in the fatty acid goes around Pyruvate Fatty acidsthe citric acid cycle; thus, a 16-carbon fatty acid goes around the citric acid cycle from beta- oxidation8 times. Additionally, each fatty acid carbon results in about 7 ATP, whereas about5 ATP per carbon result from glucose oxidation. This is because fatty acids have CoA ~more carbon-hydrogen bonds and fewer carbon-oxygen atoms than glucose. Thecarbons of glucose exist in a more oxidized state than fat; as a result, fats yield more Acetyl-CoAenergy than carbohydrates (9 kcal/g versus 4 kcal/g).1 Occasionally, a fatty acid has an odd number of carbons, so the cell forms a 3-car-bon compound (propionyl-CoA) in addition to the acetyl-CoA. The propionyl-CoA en-ters the citric acid cycle directly, bypassing acetyl-CoA. It can then go on to yield NADH Oxaloacetate Citrate+ H+ and FADH2, CO2, and even other products, such as glucose (see Section 9.4). Citric acid cycleCarbohydrate Aids Fat MetabolismIn addition to its role in energy production, the citric acid cycle provides compoundsthat leave the cycle and enter biosynthetic pathways. This results in a slowing of thecycle, as eventually not enough oxaloacetate is formed to combine with the acetyl- Figure 9-14 As acetyl-CoA concentrations increase due to beta-oxidation, oxaloacetateCoA entering the cycle. Cells are able to compensate for this by synthesizing addi- levels are maintained by pyruvate fromtional oxaloacetate. One potential source of this additional oxaloacetate is pyruvate carbohydrate metabolism. In this way,(Fig. 9-14). Thus, as fatty acids create acetyl-CoA, carbohydrates (e.g., glucose) are carbohydrates help oxidize fatty acids.
294 Part 3 Metabolism and Energy Balance , needed to keep the concentration of pyruvate high enough to resupply oxaloacetate A Biochemist s View to the citric acid cycle. Overall, the entire pathway for fatty acid oxidation works better when carbohydrate is available. O O CH3 C C O� Ketogenesis Pyruvate Ketone bodies are products of incomplete fatty acid oxidation.7 This occurs mainly CO2 with hormonal imbalances—chiefly, inadequate insulin production to balance glucagon action in the body. These imbalances lead to a significant production of ketone bodies and a condition called ketosis. The key steps in the development of ketosis are shown O O in Figure 9-15. Most ketone bodies are subsequently converted back into acetyl-CoA in other body C C O� cells, where they then enter the citric acid cycle and can be used for fuel. One of the ketone O bodies formed (acetone) leaves the body via the lungs, giving the breath of a person in ketosis a characteristic, fruity smell. CH2 C O� Oxaloacetate Ketosis in Diabetes In type 1 diabetes, little to no insulin is produced. This lack of insulin does not allow for ketone bodies Incomplete breakdown normal carbohydrate and fat metabolism. Without sufficient insulin, cells cannot readily products of fat, containing 3 or 4 utilize glucose, resulting in rapid lipolysis and the excess production of ketone bodies.8 carbons. Most contain a chemical If the concentration of ketone bodies rises too high in the blood, the excess spills into group called a ketone. An example is the urine, pulling the electrolytes sodium and potassium with it. Eventually, severe ion acetoacetic acid. imbalances occur in the body. The blood also becomes more acidic because 2 of the 3 ketosis Condition of having a high concentration of ketone bodies and related breakdown products in the Stage 1 bloodstream and tissues. 1 Insufficient insulin production Blood insulin drops, usually as a result of type 1 diabetes or low carbohydrate intake. Stage 2 Large amounts of fatty acids 2 released by adipose cells A fall in blood insulin promotes lipolysis, which causes fatty acids stored in adipose cells to be released rapidly into the bloodstream. Fatty acids flood into the liver and are 3 broken down into acetyl-CoA. Stage 3 Most of the fatty acids in the blood are taken up by the liver. Stage 4 Acetyl-CoA Ketone bodies As the liver oxidizes the fatty acids to acetyl-CoA, the capacity of the citric acid O O cycle to process the acetyl-CoA molecules decreases. This is mostly because the metabolism of fatty acids to acetyl-CoA 5 CH3 C CH2 C OH yields many ATP. When the cells have Citric acid plenty of ATP, there is no need to use the cycle High amounts of acetyl- citric acid cycle to produce more. CoA unite in pairs to form 4 ketone bodies, such as Stage 5 acetoacetic acid. High amounts of ATP These metabolic changes encourage liver slow the processing cells to combine a 2 acetyl-CoA molecules of acetyl-CoA to ATP. to form a 4-carbon compound. This compound is further metabolized and eventually secreted into the bloodstreamFigure 9-15 Key steps in ketosis. Any as ketone bodies (acetoacetic acid andcondition that limits insulin availability to cells the related compounds, beta-results in some ketone body production. hydroxybutyric acid and acetone).
chaPter 9 Energy Metabolism 295forms of ketone bodies contain acid groups. The resulting condition, known as diabeticketoacidosis, can induce coma or death if not treated immediately, such as with insulin, CRITICAL THINKINGelectrolytes, and fluids (see Chapter 5). Ketoacidosis usually occurs only in ketosis caused The use of a very low carbohydrateby uncontrolled type 1 diabetes; in fasting, blood concentrations of ketone bodies typi- diet to induce ketosis for weight loss iscally do not rise high enough to cause the problem. covered in Chapter 10. Why is careful physician monitoring needed if this type of diet is followed?Ketosis in Semistarvation or FastingWhen a person is in a state of semistarvation or fasting, the amount of glucose in the bodyfalls, so insulin production falls. This fall in blood insulin then causes fatty acids to floodinto the bloodstream and eventually form ketone bodies in the liver. The heart, muscles,and some parts of the kidneys then use ketone bodies for fuel. After a few days of ketosis,the brain also begins to metabolize ketone bodies for energy. This adaptive response is important to semistarvation or fasting. As more body cellsbegin to use ketone bodies for fuel, the need for glucose as a body fuel diminishes. Thisthen reduces the need for the liver and kidneys to produce glucose from amino acids(and from the glycerol released from lipolysis), sparing much body protein from beingused as a fuel source (see Section 9.4). The maintenance of body protein mass is a key tosurvival in semistarvation or fasting—death occurs when about half of the body proteinis depleted, usually after about 50 to 70 days of total fasting.9 Knowledge Check 1. What is anaerobic glycolysis? 2. What cells use anaerobic glycolysis? 3. How do fatty acids enter the citric acid cycle? 4. What conditions must exist in the body to promote the formation of ketones? 9.4 Protein MetabolismThe metabolism of protein (i.e., amino acids) takes place primarily in the liver. Onlybranched-chain amino acids—leucine, isoleucine, and valine—are metabolized mostly atother sites—in this case, the muscles.2 Metabolism is part of everyday life; metabolic Protein metabolism begins after proteins are degraded into amino acids. To use activity increases when we increase physical activityan amino acid for fuel, cells must first deaminate them (remove the amino group) (see and slows during fasting and semi-starvation.Chapter 7). These pathways often require vitamin B-6 to function. Removal of the aminogroup produces carbon skeletons, most of which enter the citric acid cycle. Some carbonskeletons also yield acetyl-CoA or pyruvate.5 Some carbon skeletons enter the citric acid cycle as acetyl-CoA, whereas othersform intermediates of the citric acid cycle or glycolysis (Fig. 9-16). Any part of the carbonskeleton that can form pyruvate (i.e., alanine, glycine, cysteine, serine, and threonine)or bypass acetyl-CoA and enter the citric acid cycle directly (such amino acids includeasparagine, arginine, aspartic acid, histidine, glutamic acid, glutamine, isoleucine, me-thionine, proline, valine, and phenylalanine) are called glucogenic amino acids becausethese carbons can become the carbons of glucose. Any parts of carbon skeletons thatbecome acetyl-CoA (leucine and lysine, as well as parts of isoleucine, phenylalanine, tryp- Branched-chain amino acids are added totophan, and tyrosine) are called ketogenic amino acids because these carbons cannot some liquid meal replacement supplementsbecome parts of glucose molecules. The factor that determines whether an amino acid is given to hospitalized patients. Some ﬂuidglucogenic or ketogenic is whether part or all of the carbon skeleton of the amino acid replacement formulas marketed to athletescan yield a “new” oxaloacetate molecule during metabolism, 2 of which are needed to also contain branched-chain amino acids (seeform glucose. Chapter 11).
296 Part 3 Metabolism and Energy BalanceFigure 9-16 Gluconeogenesis. Amino acidsthat can yield glucose can be converted to Glucosepyruvate 1 , directly enter the citric acid cycle 3 ,or be converted directly to oxaloacetate 2X 2X 4 . Amino acids that cannot yield glucose areconverted to acetyl Co-A and are metabolized inthe citric acid cycle 2 . The glycerol portion of Glyceraldehyde Glycerol 5triglycerides 5 can be converted to glucose. All 3-phosphateamino acids except ketogenic amino acids can beused to make glucose. Fatty acids with an evennumber of carbons and ketogenic amino acidscannot become glucose 2 . ~ Phosphoenolpyruvate (PEP) Glucogenic amino acids, such as alanine, glycine, cysteine, serine, and threonine 1 Pyruvate Fatty acids CoA ~ Acetyl-CoA Ketogenic amino acids, such as leucine 4 and lysine, and parts of isoleucine, 2 phenylalanine, tryptophan, and tyrosine Oxaloacetate Citric acid cycle Glucogenic amino acids, such as asparagine, arginine, aspartic acid, histidine, glutamic acid, glutamine, 3 gluconeogenesis Generation (genesis) isoleucine, methionine, proline, valine, of new (neo) glucose from certain and phenylalanine (glucogenic) amino acids. Glucogenic amino acids, such as alanine, isoleucine, phenylalanine, threonine, methionine, tyrosine, and aspartate , A Biochemist s View NH3 Gluconeogenesis: Producing Glucose from Glucogenic Amino CH3 CH O Acids and Other Compounds C OH The pathway to produce glucose from certain amino acids—gluconeogenesis—is pres- Alanine ent only in liver cells and certain kidney cells. The liver is the primary gluconeogenic or- gan. A typical starting material for this process is oxaloacetate, which is derived primarily CO2 from the carbon skeletons of some amino acids, usually the amino acid alanine. Pyruvate NH3 also can be converted to oxaloacetate (see Fig. 9-14). Gluconeogenesis begins in the mitochondria with the production of oxaloacetate. The 4-carbon oxaloacetate eventually returns to the cytosol, where it loses 1 carbon di- O O O oxide, forming the 3-carbon compound phosphoenolpyruvate, which then reverses the path back through glycolysis to glucose. It takes 2 of this 3-carbon compound to produce �O C C CH2 C O� the 6-carbon glucose. This entire process requires ATP, as well as coenzyme forms of the Oxaloacetate B-vitamins biotin, riboflavin, niacin, and B-6.5
chaPter 9 Energy Metabolism 297 To learn more about gluconeogenesis, examine Figure 9-16 and trace the pathwaythat converts the amino acid glutamine to glucose. Glutamine first loses its amino groupto form its carbon skeleton, which enters the citric acid cycle directly and is converted bystages to oxaloacetate. Oxaloacetate loses 1 carbon as carbon dioxide, and the 3-carbonphosphoenolpyruvate produced then moves through the gluconeogenic pathway to formglucose. Eventually, 2 glutamine molecules are needed to form 1 glucose Amino acidsmolecule. BloodstreamGluconeogenesis from Typical Fatty Acids Ammonia Amino group � � CO2Is Not Possible (NH3) (�NH2)Typical fatty acids cannot be turned into glucose because those with an Ureaeven number of carbons—the typical form in the body—break down into Oacetyl-CoA molecules. Acetyl-CoA can never re-form into pyruvate; the Liverstep between pyruvate and acetyl-CoA is irreversible. The options for H2N C NH2acetyl-CoA are forming ketones and/or combining with oxaloacetatein the citric acid cycle. However, 2 carbons of acetyl-CoA are added tooxaloacetate at the beginning of the citric acid cycle, and 2 carbons are Kidneysubsequently lost as carbon dioxide when citrate converts back to thestarting material, oxaloacetate. Thus, at the end of 1 cycle, no carbonsfrom acetyl-CoA are left to turn into glucose; it is impossible to converttypical fatty acids into glucose.5 Urea The glycerol portion of a triglyceride is the part that can becomeglucose. Glycerol enters the glycolysis pathway and can follow the glu-coneogenesis pathway from glyceraldehyde 3-phosphate to glucose. Glu-cose yield from glycerol is insignificant.1 BladderDisposal of Excess Amino Groupsfrom Amino Acid MetabolismThe catabolism of amino acids yields amino groups (–NH2), which then areconverted to ammonia (NH3). The ammonia must be excreted because itsbuildup is toxic to cells. The liver prepares the amino groups for excretion in Out of bodythe urine with the urea cycle. Some stages of the urea cycle occur in the cy-tosol and some in the mitochondria. During the urea cycle, 2 nitrogen groups—1 ammonia Figure 9-17 Disposal of excess amino groups.group and 1 amino group—react through a series of steps with carbon dioxide molecules to The nitrogen groups, one as ammonia and theform urea and water. Eventually, urea is excreted in the urine (Fig. 9-17).5 In liver disease, other as an amino group, form part of urea, which is excreted in urine. The nitrogen groupsammonia can build up to toxic concentrations in the blood, whereas in kidney disease the originally came from amino acids that wenttoxic agent is urea. The form of nitrogen in the blood—ammonia or urea—is a diagnostic through transamination reactions and ultimatelytool for detecting liver or kidney disease. deamination to yield the free nitrogen groups. Knowledge Check 1. In order to use amino acids as a fuel, what must happen to the nitrogen attached to the amino acid? 2. Where does the nitrogen attached to an amino acid used as fuel end up? 3. What part of the amino acid is used in the metabolic pathways? 4. What is the name of the pathway that converts amino acids to glucose? 5. Can fat be used to synthesize glucose? Why or why not?
298 Part 3 Metabolism and Energy Balance 9.5 Alcohol Metabolism The alcohol dehydrogenase (ADH) pathway is the main pathway for alcohol metabolism. In the first step of this pathway, alcohol is converted in the cytosol to acetaldehyde by the action of the enzyme alcohol dehydrogenase and the coenzyme NAD+. NAD+ picks up 2 hydrogen ions and 2 electrons from the alcohol to form NADH + H+ and produces the intermediate acetaldehyde (Fig. 9-18). In the next step of the ADH pathway, the acetal- dehyde formed is converted to acetyl-CoA, again yielding NADH + H+ with the aid of the enzyme aldehyde dehydrogenase and coenzyme A. The metabolism of alcohol occurs predominantly in the liver, although approxi- mately 10 to 30% of alcohol is metabolized in the stomach. Different forms (known as polymorphisms) of alcohol dehydrogenase and aldehyde dehydrogenase are found in the stomach and the liver. The acetyl-CoA formed through the ADH pathway has several metabolic fates. Small amounts can enter the citric acid cycle to produce energy. However, the breakdown of alcohol in the ADH pathway utilizes NAD+ and converts it to NADH. As NAD+ sup- plies become limited and NADH levels build, the citric acid cycle slows and blocks the entry of acetyl-CoA. Because of the toxic effects of alcohol and acetaldehyde, the me- tabolism of alcohol takes priority over continuation of the citric acid cycle. Thus, most of the acetyl-CoA is directed toward fatty acid and triglyceride synthesis, resulting in the accumulation of fat in the liver (called steatosis). Clinicians are often alerted to this condi- tion by high levels of triglycerides in the blood. When a person drinks moderate to excessive amounts of alcohol, the ADH path-Alcohol, carbohydrate, protein, and fat all way cannot keep up with the demand to metabolize all the alcohol and acetaldehyde. Tocontribute chemical energy to the body. prevent the toxic effects of alcohol and acetaldehyde, the body utilizes a second pathway, called the microsomal ethanol oxidizing system (MEOS), to metabolize the excess alco- Ethanol O2 2 NAD� NADPH � H� H2O2 1 3 MEOS Alcohol dehydrogenase (High alcohol intake) Catalase NADH � H� 2 H2O 2 H2O NADP� Acetaldehyde NAD� CoA Aldehyde dehydrogenase NADH � H� Acetyl-CoAFigure 9-18 1 At low levels of alcoholintake, the alcohol dehydrogenase pathway inthe cytoplasm is used. 2 At high alcohol intake,the microsomal ethanol oxidizing system (MEOS) Citric acidin the cytoplasm is used. The MEOS uses rather cyclethan yields energy and accounts in general forabout 10% of alcohol metabolism. 3 Catalaseoccurs in the peroxisomes of cells and is a minorpathway.
chaPter 9 Energy Metabolism 299hol. As shown in Figure 9-18, this system uses oxygen and a different niacin-containingcoenzyme (NADP) and produces water and acetaldehyde. When excessive amounts of al- CRITICAL THINKINGcohol are consumed at one time, the ability of these enzyme systems to metabolize alcoholcompletely is exceeded, and the result is alcohol poisoning (see Chapter 8). Your roommate heard that the more The MEOS differs in several ways from the ADH pathway. First, the MEOS uses alcohol you drink the more you canpotential energy (in the form of NADPH + H+, another niacin coenzyme), rather than metabolize, so, if you gradually increaseyielding potential energy (as NADH + H+ in the ADH pathway) in the conversion of your alcohol intake, you can drink allethanol to acetaldehyde. This use of energy may, in part, explain why individuals who you want with no harmful effects. Whatconsume large amounts of alcohol do not gain as much weight as might be expected advice would you give your roommatefrom the amount of alcohol-derived energy they consume. about alcohol and the body’s ability to The body has an additional pathway, called the catalase pathway, for metabolizing metabolize it?alcohol. However, this is a relatively minor pathway in comparison with the ADH andMEOS pathways. Knowledge Check 1. Where does the alcohol dehydrogenase pathway function? 2. Which intermediate in the alcohol dehydrogenase pathway is toxic? 3. In addition to the ADH pathway, what other pathways allow the metabolism of alcohol? 9.6 Regulation of Energy MetabolismAs shown in Figure 9-19, energy metabolism can take many forms in the body. Carbohy-drates can be used for fat synthesis—the acetyl-CoA from the breakdown of carbohydrate isthe building block for fatty acid synthesis. By stringing together glycolysis and the citric acidcycle, cells can convert carbohydrates into carbon skeletons for the synthesis of certain aminoacids and can use the energy in carbohydrates to form ATP. These pathways also can turnthe carbon skeletons of some amino acids into the carbon skeletons of others. They also canconvert carbon skeletons from some amino acids to glucose or have them drive ATP synthe-sis by serving as substrates (precursors) for intermediates in the citric acid cycle. Finally, fattyacids can provide energy for ATP synthesis or produce ketone bodies; however, they cannotbecome glucose. The glycerol part of the triglyceride either can be converted into glucoseand be used for fuel or can contribute to ATP synthesis via participation in glycolysis, thecitric acid cycle, and electron transport chain metabolism (Table 9-1). When it comes to regulating these metabolic pathways, the liver plays the major role—itresponds to hormones and makes use of vita-mins. Additional means of regulating metab- Table 9-1 What Happens Where: A Reviewolism involve ATP concentrations, enzymes,hormones, vitamins, and minerals.1 Pathway Location Glycolysis (glucose → pyruvate) Cytosol Transition reaction (pyruvate → acetyl-CoA) MitochondriaThe Liver Fatty acid oxidation (fatty acid → acetyl-CoA) Mitochondria Glucogenic amino acid oxidation (amino acids → CytosolThe liver is the location of many nutrient pyruvate)interconversions (Fig. 9-20). Most nutrientsmust pass first through the liver after absorp-tion into the body. What leaves the liver is Non-glucogenic amino acid oxidation (amino acids → Mitochondriaoften different from what entered. The key acetyl-CoA)metabolic functions of the liver include con- Alcohol oxidation (ethanol → acetaldehyde) Cytosolversions between various forms of simple (acetaldehyde → acetyl-CoA) Mitochondriasugars, fat synthesis, the production of ke- Citric acid cycle (acetyl-CoA → CO2) Mitochondriatone bodies, amino acid metabolism, urea Gluconeogenesis Begins in mitochondria, then movesproduction, and alcohol metabolism. Nutri- to cytosolent storage is an additional liver function.2
300 Part 3 Metabolism and Energy Balance Glycogen Triglycerides Glucose Glycerol Fatty acids Lactate Pyruvate Amino acids Gluconeogenesis Lipogenesis Ethanol Lipolysis and fatty acid oxidation Phosphoenolpyruvate Acetyl-CoA Ketones Proteins Oxaloacetate Citric acid cycle Amino acids Figure 9-19 Overview of cell metabolism. Note that acetyl-CoA forms a crossroads for many pathways and that the citric acid cycle also can be used to help build compounds. Anabolic and catabolic processes may appear to share the same pathways, but generally this is true for only a few steps. Because a specific set of enzymes must be activated to promote anabolism and a different set to activate catabolism, the cell has significant control over metabolism. Urea NH3 Protein Blood proteins Amino acids Amino acids NH3 Carbon skeleton Stored body fat Glycogen Glucose Glycerol Glucose Fatty acidsFigure 9-20 Most nutrients must pass first Cholesterol Very-low-density lipoproteinthrough the liver after absorption into the body.What leaves the liver is often different from what Alcoholentered.
chaPter 9 Energy Metabolism 301ATP Concentrations CRITICAL THINKINGATP concentration in a cell helps regulate metabolism. High ATP concentrations de-crease energy-yielding reactions, such as glycolysis, and promote anabolic reactions, such If you had unlimited resources toas protein synthesis, that use ATP. High ADP concentrations, on the other hand, stimu- design a drug that inhibits fat synthesis,late energy-yielding pathways.10 which type of metabolism (aerobic or anaerobic) would you look to affect? What unintended metabolicEnzymes, Hormones, Vitamins, and Minerals consequences might result from using such a drug? Reviewing Figure 9-21Enzymes are key regulators of metabolic pathways; both their presence and their rate of might help you answer this question.activity are critical to chemical reactions in the body. Enzyme synthesis and rates of activityare controlled by cells and by the products of the reactions in which the enzymes partici-pate. For example, a high-protein diet leads to increased synthesis of enzymes associatedwith amino acid catabolism and gluconeogenesis. Within hours of a shift to a low-proteindiet, the synthesis of enzymes associated with amino acid metabolism slows.5 Hormones, including insulin, regulate metabolic processes. Low levels of insulin inthe blood promote gluconeogenesis, protein breakdown, and lipolysis. Increased bloodinsulin levels promote the synthesis of glycogen, fat, and protein. Many vitamins and minerals are needed for metabolic pathways to operate (Fig.9-21). Most notable are the B-vitamins thiamin, riboflavin, niacin, pantothenic acid,biotin, vitamin B-6, folate, and vitamin B-12, as well as the minerals iron and copper.Because so many metabolic pathways depend on nutrient input, health problems candevelop from nutrient deficiencies.2 (The roles that vitamins and minerals play in metabo-lism are discussed in greater detail in Chapters 12 through 15.) Knowledge Check 1. Where does glycolysis take place in a cell? 2. What factors determine the regulation of glycolysis and citric acid cycle pathways? 3. What factors regulate energy metabolism? Figure 9-21 Many vitamins and minerals participate in the metabolic pathways. Carbohydrates Alcohol Lipids Proteins (glycogen, in particular) Niacin Vitamin B-6 Vitamin B-12Vitamin B-6 Niacin Fatty acids and gycerol Niacin Folate Vitamin C Niacin Riboflavin Vitamin K Biotin Thiamin Pantothenic Niacin Monosaccharides acid Pantothenic acid Amino acids Biotin Thiamin Thiamin Vitamin B-6 Vitamin B-12 Niacin Vitamin B-6 Biotin Folate Pantothenic Acetyl-CoA Folate Vitamin B-12 acid (pantothenic acid) Vitamin B-12 Biotin Riboflavin Vitamin B-6 Magnesium Thiamin Folate Riboflavin Vitamin B-12 Niacin Iron Copper CO2 � H2O � energy
302 Part 3 Metabolism and Energy Balance 9.7 Fasting and FeastingPostprandial fasting (0 to 6 hours after eating) Both fasting and feasting affect metabolism. The form of each macronutrient and the rate at which it is used vary when the Carbohydrate Fat Protein (glycogen from (from adipose stores) (from body cells) calorie supplies are insufficient or exceed needs. the liver) Fasting In the first few hours of a fast, the body fuels itself with stored Glucose Fatty acids Glycerol Amino acids liver glycogen and fatty acids from adipose tissue. As the fast progresses, body fat continues to be broken down and liver gly- cogen becomes exhausted. Although most cells can use fatty NH3 acids for energy, the nervous system and red blood cells use only Ketone Glucose glucose for energy. To provide the needed glucose, the body bodies Urea begins breaking down lean body tissue and converts glucogenic amino acids, via gluconeogenesis, to glucose (Fig. 9-22).6, 7 During the first few days of a fast, body protein is broken down Energy needs rapidly—in fact, it supplies about 90% of needed glucose, with the remaining 10% coming from glycerol. At this rate of break- down, body protein would be quickly depleted and death wouldShort-term fasting (3 to 5 days) occur within 2 to 3 weeks. (Death would occur regardless of Carbohydrate Fat Protein the amount of body fat a person has because fatty acids cannot (glycogen stores (from adipose stores) (from body cells) be used for gluconeogenesis.) Sodium and potassium depletion are exhausted) also can result during fasting because these elements are drawn into the urine along with ketone bodies. Finally, blood urea lev- els increase because of the breakdown of protein. Fortunately, the body undergoes a series of adaptations Glucose Fatty acids Glycerol Amino acids that prolong survival. One of these adaptations is the slow- ing of metabolic rate and a reduction in energy requirements. This helps slow the breakdown of lean tissue to supply amino NH3 acids for gluconeogenesis. Another adaptation allows the ner- Ketone Glucose vous system to use less glucose (and, hence, less body pro- bodies Urea tein) and more ketone bodies. After several weeks of fasting, half or more of the nervous system’s energy needs are met by ketone bodies; nonetheless, some glucose must still be sup- Energy needs plied via the catabolism of lean body mass. When lean body mass declines by about 50% (usually within 7 to 10 weeks of total fasting), death occurs.Long-term fasting (5 to 7 days and beyond) Carbohydrate (glycogen stores Fat (from adipose stores) Protein (from body cells) Feasting are exhausted) The most obvious result of feasting is the accumulation of body fat. In addition, feasting increases insulin production by the pancreas, which in turn encourages the burning of glu- Glucose Fatty acids Glycerol Amino acids Figure 9-22 Postprandial fasting encourages the use of mostly glucose, as well as some fatty acids and amino acids for energy needs. As the fast progresses, glycogen stores are depleted, which causes the NH3 rapid use of carbon skeletons of certain amino acids from body protein to produce glucose. This supplies glucose to glucose-dependent cells, such Ketone Glucose Urea as red blood cells. Long-term fasting leads to reduced breakdown of body bodies protein and increased use of adipose stores, which are used to produce ketones. Ketones can provide a significant proportion of the fuel required by glucose-dependent cells, thereby sparing body protein and prolonging Energy needs life. Note that the thickness of the arrows in the figures conveys the relative use of each energy source during the stages of fasting.
chaPter 9 Energy Metabolism 303 Carbohydrate Fat Protein Figure 9-23 Feasting encourages glycogen intake intake intake and triglyceride synthesis and storage and allows amino acids to participate in the synthesis of body proteins. Minimal synthesis of fatty acids using glucose or carbon skeletons of amino Glycerol acids occurs unless intake is quite excessive in comparison with overall energy needs. Glucose Fatty acids Amino acids Enzymes, Fuel for muscles, hormones, brain, nervous Glycerol tissues system Glycogen Triglyceridescose for energy, as well as the synthesis of glycogen and, to a lesser extent, protein and Fasting encourages the following:fat (Fig. 9-23).6, 11 Glycogen breakdown Fat consumed in excess of need goes immediately into storage in adipose cells.2 Fat breakdownCompared with the conversion of carbohydrate and protein, relatively little energy isrequired to convert dietary fat into body fat. Therefore, high-fat, high-energy diets pro- Gluconeogenesismote the accumulation of body fat. Synthesis of ketone bodies Protein consumed in excess of need—contrary to popular belief—does not pro- Feasting encourages the following:mote muscle development. Some of the excess protein can reside in amino acid poolsin the body, but the amount is not significant. Amino acids left over in the body after a Glycogen synthesislarge meal can be used to synthesize fatty acids, but this is typically of minor importance Protein synthesisin humans.11 The process of storing amino acids as fat requires ATP and the B-vitamins Fat synthesisbiotin, niacin, and pantothenic acid.2 The energy cost of converting dietary protein to Urea synthesisbody fat is higher than it is for the conversion of dietary fat to body fat. Carbohydrate consumed in excess of need is used first to maximize glycogen stores.Once glycogen stores are filled, carbohydrate consumption stimulates the use of carbohy-drate as fuel and the storage of excess amounts as body fat. This then lessens the need forany fat catabolism. However, the pathway for storing carbohydrate as body fat is not veryactive in humans.11 In addition, it requires the B-vitamins biotin, niacin, and pantothenicacid, and it is energetically expensive to convert carbohydrate to body fat (Table 9-2). Feasting especially encourages the synthesis ofAnyone who consumes more calories from any of the energy-yielding nutrients than what glycogen and the storage of fat.the body can expend will gain weight. Table 9-2 Metabolism of ATP-Yielding Compounds Energy Cost Yields Amino Yields Fat for of Conversion Yields Acids for Body Adipose Tissue to AdiposeNutrient Glucose? Proteins? Stores? Tissue StoresCarbohydrate Yes No Yes, but is High(glucose) inefficientTriglycerides Fatty acids No No Yes Minimal Glycerol Yes, but not a No Yes High major pathwayProtein Yes Yes Yes, but is High(amino acids) inefficient Alcohol No No Yes High
304 Part 3 Metabolism and Energy Balance Take Action Weight Loss and Metabolism A friend is very overweight and describes to you his method of weight loss. He fasted completely for 1 week and is now on a strict diet of 400 to 600 kcal/day under a physician’s supervision. The food energy comes from a liquid formula, which he drinks for breakfast. He skips lunch and eats a small dinner of 3 ounces of protein, ½ cup of vegetables, 1 cup of fruit, and 2 starch items (a small potato, a piece of bread, etc.). He has lost approximately 25 lb in 12 weeks. Based on your knowledge of energy metabolism, answer the following questions he poses. 1. During the fasting stage, what were the likely sources of energy for the body’s cells? What metabolic adaptations occurred to provide glucose for the nervous system? 2. When he began eating 400 to 600 kcal/day, how did the metabolic processes in the body most likely change from the fasting state? The pathways for the synthesis of fat from excess carbohydrate or protein intake, called lipogenesis, are found primarily in the cytosol of liver cells. Synthesis involves a series of steps that link the acetyl-CoA formed from either glucose or amino acids into a 16-carbon saturated fatty acid, palmitic acid. Insulin increases the activity of a key enzyme—fatty acid synthase—used in the pathway. Palmitic acid can later be lengthened to an 18- or 20-carbon chain either in the cytosol or in the mitochondria.1 Ultimately, the fatty acids and glycerol (produced during glycolysis from glyceraldehyde 3-phosphate) are used to synthesize triglycerides, which are subsequently delivered by very-low-density lipoproteins (see Chapter 6) via the bloodstream to adipose tissues for storage. Knowledge Check 1. In the ﬁrst few hours of a fast, what is the primary fuel for the body? 2. What adaptations occur that help slow the breakdown of lean body mass during prolonged fasting? 3. What happens to excess amounts of ingested fat, protein, and carbohydrate?The energy used to perform physical activity CASE STUDY FOLLOW-UPis in the form of ATP, which can be supplied bycarbohydrate, fat, or protein. The proportion A very low carbohydrate therefore excretes them in the urine.supplied by each macronutrient dependson length of time after eating and type and diet that produces ketones The body is using protein (amino acids)intensity of exercise. is not the best way to as a fuel source for the brain and nervous lose body fat. Although system. This loss of amino acids, especially body weight may decline, from muscle, is part of the loss of body the large production of mass. A better weight-loss program would ketones means that the be to reduce total calories to create a calorie body is not capable of deﬁcit and maintain an exercise or ﬁtness oxidizing fatty acids and program.
chaPter 9 Energy Metabolism 305 Medical PerspectiveI nborn E rrors of Metabo l i s mSome people lack a speciﬁc enzyme to perform normal metabolicfunctions—they are said to have an inborn error of metabolism. Themetabolic pathway in which the enzyme is supposed to participatedoes not function normally. Typically, this causes alternativemetabolic products to be formed, some of which are toxic to thebody. Inborn errors of metabolism occur when a person inherits adefective gene coding for a speciﬁc enzyme from both parents. Bothparents are likely to be carriers of the defective gene—that is, theyhave 1 healthy gene and 1 defective gene for the enzyme in theirchromosomes. When each parent donates the defective form of thegene to the offspring, the offspring has 2 defective copies of thegene and therefore little or no activity of the enzyme that the genenormally would produce. If a person has a defective gene, he or sheproduces a defective protein based on the instructions contained inthat defective gene. It also is possible that 1 or both parents have thedisease and are not simply carriers. Generally, however, individualswho have an inborn error of metabolism are advised to see agenetic counselor to assess the risk of passing on the inborn error ofmetabolism to their offspring (see chapter 1). An infant who does not develop normally may have an inborn error of The following are some characteristics of inborn errors of metabolism. A physician should investigate this possibility.metabolism.12• They appear soon after birth. Such a disorder is suspected when is a public health program that provides early identiﬁcation otherwise physically well children develop a loss of appetite, and follow-up for the treatment of infants with genetic and vomiting, dehydration, physical weakness, or developmental delays metabolic disorders. There are no national mandates to test soon after birth. For some of these conditions, infants are screened newborns. Currently, each state determines which newborn for the potential to have a speciﬁc inborn error of metabolism. screening tests are required—as a result, required tests vary• They are very speciﬁc, involving only 1 or a few enzymes. These widely among states. In 2004, the American College of enzymes usually participate in catabolic pathways (in which Medical Genetics recommended that all states test for compounds are degraded). 29 conditions—only 15 states and the District of Columbia require all of these tests. To learn more, visit www.• No cure is possible, but typically the disorders can be controlled. marchofdimes.com/298_834.asp. The type of control depends on the inborn error—control might include reducing intake of the substance they are unable to metabolize normally, taking pharmacological doses of vitamins, Phenylketonuria (PKU) and replacing a compound that cannot be synthesized.13 PKU is estimated to occur in about 1 per 13,500 to 1 in 19,000 Some of the most common inborn errors of metabolism are births.14 Most carriers can be detected with a simple blood test.phenylketonuria (PKU), galactosemia, and glycogen storage disease. A People of Irish descent are especially affected.15 Today, mostnumber of other, very rare inborn errors of metabolism involve various infants in the United States are diagnosed within a few days of lifeamino acids, fatty acids, and the sugars fructose and sucrose. Typically, because all states require them to be tested for this inborn error ofin large hospitals and in state health departments, physicians, nurses, metabolism.16and registered dietitians can help affected persons and their families The majority of PKU cases occur because the enzymecope with these and other inborn errors of metabolism.12 phenylalanine hydroxylase does not function efﬁciently in the liver. Normally, phenylalanine hydroxylase converts the amino acid phenylalanine into the amino acid tyrosine. If this reactionNewborn Screening does not take place, phenylalanine accumulates in the bloodNewborn screening is the process of testing newborn babies for and tyrosine is deﬁcient. If not corrected within 30 days oftreatable genetic errors of metabolism.14 Newborn screening birth, this phenylalanine buildup leads to the production of toxic
306 Part 3 Metabolism and Energy Balance Medical Perspective continued phenylalanine by-products, such as phenylpyruvic acid, which then can lead to severe, irreversible mental retardation.17 Sufﬁcient phenylalanine hydroxylase activity Normal: Phenylalanine Tyrosine Reduced phenylalanine hydroxylase activity PKU: Phenylalanine Phenylpyruvic acid Phenyllactic acid Other related products As soon as they are diagnosed, infants are started on a phenylalanine-restricted diet.18 Recall that phenylalanine is an essential amino acid, which means that even someone with PKU has to obtain phenylalanine from his or her diet; however, the amount of phenylalanine consumed needs to be controlled carefully to prevent toxic amounts from building up.17, 19 During infancy, nutritional needs can change frequently, so these infants are monitored continually through blood phenylalanine testing. Starting in infancy, special formulas are used to provide nutrients for individuals with PKU. Because infants have high protein needs, satisfying protein requirements—without also having high intakes of phenylalanine—is impossible without these specially prepared formulas. For infants, formulas are designed to provide about 90% of protein needs and 80% of energy needs. Human milk or regular infant formula then can be used to make up the difference and supply small amounts of phenylalanine.12 Later in life, foods can be used to make up the difference, especially foods low in phenylalanine. Fruits and vegetables are naturally low in phenylalanine, and breads and cereals have a moderate amount. Dairy products, eggs, meats, nuts, and cheeses Children with PKU must restrict their intake of high-protein are very high in amino acids, including phenylalanine, and, so, are not allowed in the foods, such as milk and meat. diet. Foods and beverages that contain the alternative sweetener aspartame also are not allowed because aspartame contains phenylalanine (see Chapter 5). Older children and adults can use a formula (such as Phenyl-Free®) that is very low in phenylalanine, which A new drug, sapropterin allows the person to consume more foods but limits phenylalanine intake. Overall, the majority dihydrochloride, 6-R-L-erythro-5,6,7,8- of the person’s nutrient intake throughout life will come from a special formula. tetrahydrobiopterin (BH4), which has Ideally, the low-phenylalanine diet is followed for life.20 At one time, health-care been used in Europe to treat mild forms professionals thought it was appropriate to end the diet after age 6 years because brain of PKU, has been approved for use in development was complete. However, it is now known that discontinuing this diet leads the U.S. Although the drug cannot cure to decreased intelligence and behavior problems, such as aggressiveness, hyperactivity, PKU, it appears to lower blood levels of and decreased attention span.12 phenylalanine.25, 26 If a woman with PKU has abandoned the diet, she needs to return to it at least 6 months before becoming pregnant.21 Otherwise, the fetus—even though it does not have PKU—will be exposed to a high blood phenylalanine level and related toxic products from the mother. This can result in miscarriage or birth defects. All pregnancies for women with PKU are high-risk and require close medical supervision. Galactosemia Galactosemia is a rare genetic disease—the most common form occurs in 1 in 47,000 births.14, 22 It is more common in those of Italian and Irish descent.23 In galactosemia, 2 speciﬁc enzyme defects lead to a reduction in the metabolism of the monosaccharide galactose to glucose (a third form is very rare). Galactose then builds up in the bloodstream, which can lead to very serious bacterial infections, mental retardation, and cataracts in the eyes. An infant with galactosemia typically develops vomiting after a few days of consuming infant formula or breast milk. Both contain much galactose as part of the milk sugar lactose. This child is then switched to a soy formula. In addition, all dairy products and other
chaPter 9 Energy Metabolism 307 lactose-containing products (butter, milk solids), organ meats, and enzyme defects along the pathway from glycogen to glucose. some fruits and vegetables must be avoided. Strict label reading The most common forms cause poor physical growth, low blood also is important for controlling the disease because lactose can be glucose, and liver enlargement. Low blood glucose results because found in a variety of products. Even in well-controlled cases, slight liver glycogen breakdown is typically used to maintain blood mental retardation (e.g., speech delays) and cataracts occur. glucose between meals (see Chapter 5). People with glycogen storage disease typically have to consume frequent meals in order to regulate blood glucose. They also consume raw cornstarch Glycogen Storage Disease between meals because it is slowly digested and helps maintain Glycogen storage disease is a group of diseases that occurs in 1 steady blood glucose. Careful monitoring of blood glucose is very in 60,000 births. In glycogen storage disease, the liver is unable important for these people, so that low blood glucose levels can be to convert glycogen to glucose. There are a number of possible detected and treated quickly.12 Knowledge Check 1. What are the characteristics of inborn errors of metabolism? 2. What is the cause of PKU? 3. What dietary restrictions must those with galactosemia observe? Take Action Newborn Screening in Your State There are no mandatory national newborn screening standards in the U.S., even though dozens of metabolic diseases are detectable by newborn screening tests. Each state has developed its own newborn screening program for infants born there. To learn which metabolism disorder tests are required for newborns in your state, visit this website: genes-r-us.uthscsa.edu. Why don’t all states require the same tests? Once a newborn has tested positive, what resources and professionals can help the family manage the disorder?Summ ary9.1 Metabolism refers to the entire network of chemical down to ADP plus Pi, energy is released from the broken processes involved in maintaining life. It encompasses bond. Every cell contains catabolic pathways, which release all the sequences of chemical reactions that occur in the energy to allow ADP to combine with Pi to form ATP. The body. Some of these biochemical reactions enable us to synthesis of ATP from ADP and Pi involves the transfer of release and use energy from carbohydrate, fat, protein, energy from energy-yielding compounds (carbohydrate, fat, and alcohol. Metabolism is the sum total of all anabolic protein, and alcohol). This process uses oxidation-reduction and catabolic reactions. A molecule of ATP consists of the reactions, in which electrons (along with hydrogen ions) organic compound adenosine (comprised of the nucleotide are transferred in a series of reactions from energy-yielding adenine and the sugar ribose) bound to 3 phosphate groups. compounds eventually to oxygen. The process of cellular ATP is the energy currency for the body. As ATP is broken respiration oxidizes (removes electrons) to obtain energy
308 Part 3 Metabolism and Energy Balance (ATP). Oxygen is the final electron acceptor. When oxygen 9.5 The alcohol dehydrogenase (ADH) pathway is the main is readily available, cellular respiration may be aerobic. When pathway for alcohol metabolism. Alcohol is converted oxygen is not present, anaerobic pathways are used. in the cytosol to acetaldehyde by the action of the9.2 Glucose metabolism begins with glycolysis, which literally enzyme alcohol dehydrogenase and the coenzyme NAD+. means “breaking down glucose.” Glycolysis has 2 roles: to NAD+ picks up 2 hydrogen ions and 2 electrons from break down carbohydrates to generate energy and to provide the alcohol to form NADH + H+ and produces the building blocks for synthesizing other needed compounds. intermediate acetaldehyde. Acetaldehyde is converted to During glycolysis, glucose passes through several steps, which acetyl-CoA, again yielding NADH + H+ with the aid of convert it to 2 units of a 3-carbon compound called pyruvate. the enzyme aldehyde dehydrogenase and coenzyme A. Glycolysis nets 2 ATP. Pyruvate passes from the cytosol into Most of the acetyl-CoA is used to synthesize fatty acids the mitochondria, where the enzyme pyruvate dehydrogenase and triglycerides, resulting in the accumulation of fat converts pyruvate into the compound acetyl-CoA in a process in the liver. When an individual consumes too called a transition reaction. Acetyl-CoA molecules enter the much alcohol, a second pathway—called citric acid cycle, which is a series of chemical reactions that the microsomal ethanol oxidizing convert carbons in the acetyl group to carbon dioxide while system (MEOS)—is activated harvesting energy to produce ATP. In the citric acid cycle, to help metabolize the excess acetyl-CoA undergoes many metabolic conversions, which alcohol. result in the production of GTP, ATP, NADH, and FADH2. 9.6 The liver plays the major NADH and FADH2 enter the electron transport chain, role in regulating metabolism. which passes electrons along a series of electron carriers. As Additional means of regulating electrons pass from one carrier to the next, small amounts of metabolism involve enzymes, energy are released. This metabolic process is called oxidative ATP concentrations, and minerals. Many phosphorylation, and it is the pathway in which energy micronutrients (thiamin, niacin, riboflavin, derived from glycolysis, the transition reaction, and the citric biotin, pantothenic acid, vitamin B-6, acid cycle is transferred to ADP + Pi to form ATP and water. magnesium, iron, and copper) play important9.3 The first step in generating energy from a fatty acid is to roles in the metabolic pathway. cleave the carbons, 2 at a time, and convert the 2-carbon 9.7 During fasting, the body breaks down fragments to acetyl-CoA. The process of converting a free both amino acids and fats for energy. The fatty acid to multiple acetyl-CoA molecules is called beta- body undergoes a series of adaptations that oxidation, because it begins with the beta carbon, which prolong survival. One of these adaptations is is the second carbon on a fatty acid chain. Fatty acids the slowing of metabolic rate and the reduction in can be oxidized for energy but cannot be converted into energy requirements. This helps slow the breakdown of glucose. During low carbohydrate intakes and uncontrolled lean tissue to supply amino acids for gluconeogenesis. diabetes, more acetyl-CoA is produced in the liver than can Another adaptation allows the nervous system to use less be metabolized. This excess acetyl-CoA is synthesized into glucose and more ketone bodies. Fat consumed in excess ketone bodies, which can be used as an energy source by of need goes into storage in adipose cells. Compared other tissues or excreted in the urine and breath. with the conversion of carbohydrate and protein,9.4 Protein metabolism begins after proteins are degraded into relatively little energy is required to convert dietary fat amino acids. To use an amino acid for fuel, cells must first into body fat. Therefore, high-fat diets promote the deaminate them (remove the amino group, NH2). Resulting accumulation of body fat. Inborn errors of metabolism carbon skeletons mostly enter the citric acid cycle. Some occur when a person inherits a defective gene coding for a carbon skeletons also yield acetyl-CoA or pyruvate. The specific enzyme from one or both parents. Some of the most process of generating glucose from amino acids is called common inborn errors of metabolism are phenylketonuria gluconeogenesis. Acetyl-CoA molecules cannot participate (PKU), galactosemia, and glycogen storage disease. Strict in gluconeogenesis; thus, ketogenic amino acids cannot diets can help those with these inborn errors of metabolism participate in gluconeogenesis. minimize many of the serious effects of these diseases.
chaPter 9 Energy Metabolism 309Study Questions1. The energy currency in the body is ______________. 7. The oxidation of fatty acids occurs in the ______________. a. NAD a. cell membrane b. FAD b. mitochondria c. TCA c. nucleus d. ATP d. cytosol2. Glycolysis is a biochemical pathway that ______________. Match the deﬁnitions on the right with the terms on the left. a. breaks down glucose b. generates energy 8. beta-oxidation a. breakdown of glucose to c. takes place in the cytosol pyruvate d. all of the above 9. ketosis b. breakdown of fat to 2-carbon units called acetyl-CoA3. Glycolysis begins with______________ and ends with______________. 10. electron transport c. synthesis of glucose from non- chain carbohydrate sources a. pyruvate; water b. pyruvate; glucose 11. gluconeogenesis d. formation of excess ketone c. glucose; pyruvate bodies d. pyruvate; acetyl-CoA 12. glycolysis e. electrons transferred back and forth to make ATP4. When muscle tissue is exercising under anaerobic conditions, the production of ______________ is important 13. Metabolism is regulated by ______________. because it assures a continuous supply of NAD. a. hormones a. glucose-6-phosphate b. enzymes b. pyruvate c. the energy status of the body c. lactic acid d. all of the above d. glycogen 14. During periods of starvation, the body uses protein as a fuel5. The net energy production of ATP via glycolysis is source for the brain and central nervous system in a pathway ______________. called gluconeogenesis. a. 1 ADP a. true b. 2 ATP b. false c. 4 FADH d. 2 GTP 15. Insulin is ______________. e. none of the above a. a coenzyme in the glycolytic pathway6. The common pathway for the oxidation of glucose and fatty b. a cofactor needed for gluconeogenesis acid is ______________ . c. an anabolic hormone d. a catabolic hormone a. glycolysis b. the urea cycle c. the citric acid cycle 11-c; 12-a; 13-d; 14-a; 15-c d. ketosis Answer Key: 1-d; 2-d; 3-c; 4-c; 5-b; 6-c; 7-b; 8-b; 9-d; 10-e;
310 Part 3 Metabolism and Energy Balance Websites To learn more about the topics covered in this chapter, visit these websites. Metabolic Pathways www.johnkyrk.com/glycolysis.html metacyc.org/ Inborn Errors of Metabolism www.marchofdimes.com genes-r-us.uthscsa.edu www.nlm.nih.gov/medlineplus www.aafp.orgReferences 1. Berg J and others. Biochemistry. 5th ed. New York: WH 11. Timlin M, Parks E. Temporal pattern of denovo lipogenesis Freeman; 2002. in the postprandial state in healthy men. Am J Clin Nutr. 2. Gropper S and others. Advanced nutrition and human 2005;81:35. metabolism. 4th ed. Belmont, CA: Thomson/Wadsworth; 12. Trahms C. Medical nutrition therapy for metabolic 2005. disorders. In: Mahan L, Escott-Stump S, eds. Krause’s 3. Mayes P, Bender D. The citric acid cycle: The catabolism food, nutrition and diet therapy. 11th ed. Philadelphia: WB of acetyl-CoA. In: Murray R and others, eds. Harper’s Saunders; 2004. biochemistry. 26th ed. New York: Appleton & Lange 13. Marriage B and others. Nutritional cofactor treatment Medical Books/McGraw-Hill; 2003. in mitochondrial disorders. J Am Diet Assoc. 4. Mayes P, Bender D. Overview of metabolism. In: Murray R 2003;103:1029. and others, eds. Harper’s biochemistry. 26th ed. New York: 14. Kaye C, Committee on Genetics. Newborn screening fact Appleton & Lange Medical Books/McGraw-Hill; 2003. sheets. Pediatrics. 2006;118:934. 5. Champe P and others. Biochemistry. 3rd ed. Philadelphia: 15. Woolf L. A study of the cause of the high incidence of Lippincott Williams & Wilkins; 2005. phenylketonuria in Ireland and west Scotland. J Irish Med 6. Foster D. The role of the carnitine system in human Assoc. 1976;69:398. metabolism. Ann NY Acad Sci. 2004;1033:1. 16. March of Dimes. Newborn screening. 2007; www. 7. Mayes P, Botham K. Oxidation of fatty acids: Ketogenesis. marchofdimes.com. In: Murray R and others, eds. Harper’s biochemistry. 26th 17. Gassio R and others. Cognitive functions in classic ed. New York: Appleton & Lange Medical Books/McGraw- phenylketonuria and mild hyperphenylalanemia: Experience Hill; 2003. in paediatric population. Dev Med Child Neurol. 8. Trachtenbarg D. Diabetic ketoacidosis. Am Family Phys. 2005;47:443. 2005;71:659. 18. National Institutes of Health. Consensus Development 9. VanItallie T, Nufert T. Ketones: Metabolism’s ugly Conference statement: Phenylketonuria: Screening and duckling. Nutrition Reviews. 2003;61:327. management. Pediatrics. 2001;108:972.10. Mayes P and others. Bioenergetics. In: Murray R and 19. Acosta P and others. Nutrient intakes and physical growth others, eds. Harper’s biochemistry. 26th ed. New York: of children with phenylketonuria undergoing nutrition Appleton & Lange Medical Books/McGraw-Hill: 2003. therapy. J Am Diet Assoc. 2003;103:1167.
chapter 9 Energy Metabolism 31120. Ney DM and others. Dietary glycomacropeptide supports 24. Buono MJ, Kolkhorst FW. Estimating ATP synthesis during growth and reduces the concentrations of phenylalanine in a marathon run: A method to introduce metabolism. Adv plasma and brain in a murine model of phenylketonuria. Physiol Educ. 2001;25:70. J Nutr. 2008;138:316. 25. Thompson CA. First drug approved for treatment21. American Academy of Pediatrics, Genetics Committee. of phenylketonuria. Am J Health-Sys Pharm. Maternal phenylketonuria. Pediatrics. 2001;107:427. 2008;65:100.22. Ridel K and others. An updated review of the long-term 26. Michals-Matalon K. Sapropterin dihydrochloride, neurological effects of galactosemia. Pediatr Neurol. 6-R-L-erythro-5,6,7,8-tetrahydrobiopterin, in the 2005;33:153. treatment of phenylketonuria. Expert Opin Invest Drugs.23. Murphy M and others. Genetic basis of transferase-deficient 2008;17:245. galactosemia in Ireland and the population history of the Irish Travellers. Eur J Hum Genet. 1999;7:549.