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