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Focus on Metabolism CHAPTER OUTLINE FOCUS 6.1 The Chemistry of Life Molecules Chemical Reactions FOCUS 6.2 Metabolic Pathways Catabolic Pathways Anabolic Pathways Energy-Yielding Nutrients and Energy Balance The Role of Micronutrients in Metabolism FOCUS 6.3 Breaking Down Nutrients to Provide Energy Cellular Respiration: Glucose Catabolism Breaking Down Triglycerides for Energy Using Amino Acids for Energy FOCUS 6.4 The Metabolism of Feasting and Fasting The Fed State The Fasted State F6.1 atom The smallest unit of an element that still retains the properties of that element. ion An atom or molecule that has a positive or negative charge because it has unequal numbers of protons and electrons. molecule A group of two or more atoms of the same or different elements bonded together. The Chemistry of Life All matter on Earth is made of units called atoms. Atoms of different elements have different characteristics. Carbon, hydrogen, oxygen, and nitrogen are the most abundant elements in our bodies and in the foods we eat. The atoms of each element have a characteristic way of losing, gaining, or sharing their electrons when interacting with other atoms to achieve stability. The way that electrons behave enables atoms in the body to exist in electrically charged forms called ions or to join with each other into complex combinations called molecules. The chemistry of all life on Earth is based on organic molecules, which are those that contain carbon bonded to hydrogen. Water is an inorganic molecule because it does not contain carbon-hydrogen bonds. 2 focus-06.indd 2 11/07/12 10:22 PM Figure F6.1 organic molecule A molecule that contains carbon bonded to hydrogen. Chemical bonds Na Na Electron donated Sodium Atom inorganic molecule A molecule that contains no carbon-hydrogen bonds. Sodium Ion Cl Na Electron accepted Sodium chloride Cl Cl Chloride Atom Chloride Ion (a) If an atom or molecule either gives up an electron, as shown by the sodium (Na) atom, or gains an electron, as shown by the chloride (Cl) atom, it becomes an ion. An ionic bond is formed when the electrical charges attract the ions to each other, in this case forming sodium chloride (NaCl), or table salt. + H Hydrogen atoms H H FOCUS ON Metabolism F 6 .1 The Chemistry of Life 3 metabolic pathway A series of chemical reactions inside a living organism that results in the transformation of one molecule into another. H Hydrogen molecule Sugar (b) Covalent bonds form when two atoms share electrons. In this example, two hydrogen (H) atoms share an electron, forming a hydrogen molecule (H2). Molecules The forces that link atoms together are called chemical bonds (Figure F6.1). With the exception of minerals, which are individual elements, all of the nutrients we consume are molecules. Most biological molecules are very large and are built by assembling small molecules, or monomers, into long chains, called polymers (Figure F6.2). Polymers are formed by chemical reactions called condensation or dehydration reactions that link monomers. Each reaction removes two hydrogen atoms and one oxygen atom to form water. Carbohydrate (starch) Amino acids Chemical Reactions Chemical reactions are the foundation of all life processes. A chemical reaction occurs when new bonds form or old bonds break between atoms. After a chemical reaction has occurred, the atoms of the reactants are arranged differently to yield products with new chemical properties. Each chemical reaction involves energy changes. Chemical energy is a form of energy that is stored in the bonds that hold molecules together. The total amount of energy present at the beginning and end of a chemical reaction is the same. Although energy can neither be created nor destroyed, it may be converted from one form to another. The conversion of one molecule into another often involves a series of reactions. The series of biochemical reactions needed to go from a raw material to the final product is called a metabolic pathway. focus-06.indd 3 Protein Fatty acids Lipid (triglyceride) Figure F6.2 Nutrient monomers and polymers Starch is a polymer of glucose, and proteins are polymers of amino acids. Although not true polymers, triglycerides include three fatty acids. 11/07/12 10:22 PM FOCUS ON Metabolism 4 FOCUS ON Metabolism Electron donor Electron acceptor A B e– Oxidation Compound A loses an electron. Oxidation-Reduction Reactions Some chemical reactions involve the transfer of electrons from one atom or molecule to another. The loss, gain, and transfer of electrons are important in biological reactions. A substance that loses an electron is said to be oxidized and one that gains an electron is said to be reduced. Reactions that transfer electrons are called oxidation-reduction reactions and are very important in energy metabolism (Figure F6.3). Reduction Compound B gains an electron. Free Radicals and Antioxidants Reactions in the body sometimes result in the formation of free radicals. A free radical is an atom or molecule with one or more unpaired electrons. Having an unpaired electron makes the molecule unstable, highly reactive, and destructive to nearby Oxidized Reduced molecules. To become stable, a free radical will steal an electron from a donor acceptor surrounding molecule, forming a new free radical in its place. The newly Figure F6.3 Oxidation-reduction reactions formed free radical then steals an electron from one of its neighbors, In this reaction, molecule A (shown in orange) is oxidized because it gives up an electron. The electron is accepted beginning a chain reaction that can damage thousands of molecules. by molecule B (shown in turquoise), so it is said to be A common example of a free radical is superoxide, which is formed by reduced. the addition of an electron to an oxygen molecule. Superoxide radicals are continuously formed within the mitochondria as a by-product of the normal reactions of metabolism. Although we typically think of free radicals as damagoxidized Refers to a compound that has lost an electron or undering, the immune system uses free radicals to mark foreign invaders and damaged tissue so gone a chemical reaction with they can be destroyed. A balance between free-radical production and the availability of oxygen. antioxidants is needed to prevent the buildup of free radicals, which can cause damage. Antioxidant defenses within the body, including antioxidant nutrients consumed in the reduced Refers to a substance diet, such as vitamin E and vitamin C, protect us from the damaging effects of free radicals that has gained an electron. (Figure F6.4). A e– B oxidation-reduction reaction A reaction in which electrons are transferred from a donor molecule (the reducing agent) to an acceptor molecule (the oxidizing agent). Free radicals Damaged membrane free radical An atom or group of atoms that has at least one unpaired electron and is therefore unstable and highly reactive and can cause cellular damage. antioxidant A substance that significantly decreases the adverse effects of free radicals and other reactive species on normal physiological function. To neutralize reactive electron-scavenging molecules, such as free radicals, vitamin E donates one of its electrons. Vitamin E Vitamin E Vitamin C Vitamin C Vitamin E e– e– Vitamin E The antioxidant function of vitamin E can be restored by another antioxidant vitamin—vitamin C, which gives an electron back to vitamin E. Undamaged membrane Neutralized free radical Figure F6.4 Antioxidant nutrients protect us from free radical damage The unsaturated bonds of fatty acids are particularly susceptible to damage by free radicals. The free radicals steal electrons from the carbon-carbon double bonds, creating a new free radical and initiating a series of reactions that damage the membrane. Antioxidants such as the vitamin E, shown here, neutralize the free radicals by donating an electron. Another oxidation-reduction reaction mediated by vitamin C can then donate an electron to vitamin E to restore its activity. focus-06.indd 4 11/07/12 10:22 PM F6.2 Metabolic Pathways Metabolism refers to all of the chemical reactions and metabolic pathways that occur in the body. Some of these reactions break down complex organic molecules into simpler ones. These are collectively known as catabolism. Metabolic reactions that combine simple molecules to form the body’s complex structural and functional components are collectively known as anabolism. Each of the essential nutrients plays a unique role in metabolism. Catabolic Pathways Catabolic reactions split up large molecules into smaller molecules, atoms, or ions. For instance, when starch is converted into glucose, this is a catabolic reaction as is the breakdown of glucose to form carbon dioxide and water. Overall, catabolic reactions are exergonic; they produce more energy than they consume, releasing the chemical energy stored in the bonds that hold molecules together. Some of this energy is lost as heat, but some can be captured and used to synthesize a molecule called adenosine triphosphate (ATP), which can be used as an energy source by the body (Figure F6.5a). ATP can be thought of as the energy currency of the cell. The chemical bonds of ATP are very high in energy; when they break, this energy is released and can be used to power body processes, such as muscle contraction or nerve conduction—or it can be used for anabolic reactions, which synthesize new molecules needed to maintain and repair body tissues (Figure F6.5b). catabolism The processes by which substances are broken down into simpler molecules releasing energy. anabolism Energy-requiring processes in which simpler molecules are combined to form more complex substances. FOCUS ON Metabolism F 6.2 Metabolic Pathways 5 adenosine triphosphate (ATP) The high-energy molecule used by the body to perform energyrequiring functions. Anabolic Pathways When two or more atoms, ions, or molecules combine to form new and larger molecules, the processes are called anabolic reactions. Glucose, fatty acids, and amino acids that are not broken down for energy are used in anabolic pathways to synthesize structural, regulatory, or storage molecules (see Figure F6.5b). Glucose molecules can be used to synthesize glycogen, a storage form of carbohydrate. If the body has enough glycogen, glucose can also be used to synthesize fatty acids. Fatty acids can be used to synthesize triglycerides that are stored as body fat. Amino acids can be used to synthesize the various proteins that the body needs, such as muscle proteins, enzymes, and blood proteins. Excess amino acids can be converted into fatty acids and stored as body fat. Anabolic reactions are endergonic; they consume more energy than they produce. They require ATP as a source of energy. Figure F6.5 (b) ATP links catabolic and anabolic reactions Glucose Amino acids Fatty acids (a) High-energy bonds P P Catabolic pathways Anabolic pathways Nutrients used as fuel Nutrients used as raw materials P 3 phosphate groups Adenosine ATP Muscle contraction, kidney function, and other body work Adenosine triphosphate (ATP) (a) ATP consists of an adenosine molecule attached to three phosphate groups. The bonds between the phosphate groups are very high in energy, which is released when the bonds are broken. focus-06.indd 5 (b) Glucose, amino acids, and fatty acids delivered to body cells can be used either in catabolic reactions to produce ATP or as raw materials in anabolic reactions that use ATP to synthesize molecules needed by the body. 11/07/12 10:22 PM FOCUS ON Metabolism 6 FOCUS ON Metabolism Energy out Energy in Energy out Energy in Carbohydrate Diet Protein Fat When you eat more than you need Glycogen Glucose Body protein Amino acids Energy Fatty acids Adipose tissue When you eat less than you need Figure F6.6 Energy balance When you eat more than you need at the time, some energy is put into body stores. When you haven’t eaten in a while, you retrieve energy from these stores. Energy-Yielding Nutrients and Energy Balance To stay alive, energy must be available to the body at all times. Excess energy can be stored for later use. When the amount of energy supplied by the diet is insufficient to meet needs, energy reserves can be tapped to fuel body processes. All the energy in the human body originates from the energy–yielding nutrients: carbohydrates, fats, and proteins. After you have eaten, catabolic pathways break down ingested nutrients to provide ATP and anabolic pathways synthesize molecules needed for tissue growth, maintenance, and repair as well as energy storage. Carbohydrate can be stored as glycogen and excess calories, whether consumed as carbohydrate, fat, or protein, can be stored as triglycerides in adipose tissue. Between meals, catabolic pathways break down these energy stores to provide the ATP needed to sustain life. Over time, if the amount of energy consumed in the energy-yielding nutrients is equal to the amount needed to fuel body activity and maintain and repair body tissues, the amount of stored energy and hence body weight remain the same (Figure F6.6). The Role of Micronutrients in Metabolism enzymes Protein molecules that accelerate the rate of specific chemical reactions without being changed themselves. cofactor An inorganic ion or organic molecule required for enzyme activity. coenzyme A small organic molecule (not a protein but sometimes a vitamin) that is necessary for the proper functioning of many enzymes. focus-06.indd 6 The chemical reactions of metabolism are facilitated by enzymes. These protein molecules catalyze, or speed up, the reactions. To be active, most enzymes require the assistance of helper molecules called cofactors. Some enzymes or enzyme complexes require more than one cofactor. Some cofactors are inorganic molecules, while others are organic. Many of the minerals required in the diet (iron, zinc, copper, selenium, magnesium, manganese, and molybdenum) serve as inorganic cofactors in metabolism. Organic cofactors are called coenzymes. Many of the vitamins that are required in the diet serve as precursors to coenzymes or as coenzymes themselves. There are also coenzymes that are not vitamins because they can be synthesized in the body in sufficient amounts. Coenzymes act as carriers of electrons or chemical groups that are added, removed, or transferred in the chemical reactions of metabolism (Figure F6.7). For example, folate coenzymes carry single-carbon groups and are involved in reactions that add a carbon to a molecule. Niacin coenzymes shuttle electrons in anabolic and catabolic reactions throughout metabolism. Coenzymes are continuously recycled as part of metabolism. 11/07/12 10:22 PM Vitamin 7 FOCUS ON Metabolism F 6 . 3 Breaking Down Nutrients to Provide Energy Chemical Group 1 The vitamin combines with a chemical group to form the functional coenzyme (active vitamin). Incomplete enzyme Functional coenzyme Active enzyme 2 The functional coenzyme combines with the incomplete enzyme to form the active enzyme. Molecule 3 The active enzyme binds to one or more molecules and accelerates the chemical reaction to form one or more new molecules. New molecule 4 The new molecules are released, and the enzyme and coenzyme (vitamin) can be reused or separated. Figure F6.7 Coenzymes Coenzymes bind to enzymes to promote their activity. They act as carriers of electrons, atoms, or chemical groups that participate in the reaction. All the B vitamins are coenzymes, but not all vitamins function as coenzymes. F6.3 Breaking Down Nutrients to Provide Energy Inside cells, a set of catabolic reactions called cellular respiration converts the energy stored in the chemical bonds of glucose, fatty acids, and amino acids into ATP. Some of these reactions take place in the cytosol of the cell and proceed in the absence of oxygen. This is referred to as anaerobic metabolism. Others take place in the mitochondria and require oxygen and constitute aerobic metabolism. cellular respiration The reactions that break down glucose, fatty acids, and amino acids in the presence of oxygen to produce carbon dioxide, water, and energy in the form of ATP. Cellular Respiration: Glucose Catabolism anaerobic metabolism Chemical reactions that occur in the absence of oxygen and partially break down glucose to yield pyruvate, water, and two ATP molecules. The complete oxidation of glucose via cellular respiration uses six molecules of oxygen to convert one molecule of glucose into 6 molecules of carbon dioxide, 6 molecules of water, and about 38 molecules of ATP: C6H12O6 1 6 O2 → 6 CO2 1 6 H2O 1 ∼38 ATP Glucose oxygen carbon dioxide water Glucose is the only one of the energy-yielding nutrients that can provide ATP in the absence of oxygen. This affects the way body processes are fueled during intense exercise, when the demand for ATP exceeds the ability to deliver enough oxygen to support aerobic metabolism. focus-06.indd 7 aerobic metabolism Chemical reactions that occur in the presence of oxygen and can completely break down glucose to yield carbon dioxide, water, and as many as 38 ATP molecules. 11/07/12 10:22 PM FOCUS ON Metabolism 8 FOCUS ON Metabolism CO2 O2 Lungs 5 Carbon dioxide is exhaled through the lungs. CO2 O2 1 The respiratory system takes in oxygen and delivers it to the blood. 2 The cardiovascular system circulates the oxygen-rich blood throughout the body. Heart O2 Blood vessels 3 Oxygen is taken up by CO2 CO2 4 Carbon dioxide is carried away from the muscle by the blood. the muscles and other tissues and used in aerobic metabolism, producing carbon dioxide as a waste product. Figure F6.8 Oxygen and carbon dioxide Cells need oxygen for aerobic metabolism. Oxygen is inhaled through the lungs, and it is delivered to cells by the blood. Aerobic metabolism produces carbon dioxide as a metabolic waste product. The carbon dioxide produced by cells is transferred in the blood to the lungs for elimination. The oxygen needed for cellular respiration is brought into the body by the respiratory system and delivered to cells by the circulatory system. The carbon dioxide produced as a by-product of cellular respiration is transported in the blood to the lungs where it is eliminated in exhaled air (Figure F6.8). glycolysis (also called anaerobic metabolism) Metabolic reactions in the cytosol of the cell that split glucose into two 3-carbon pyruvate molecules, yielding two ATP molecules. focus-06.indd 8 Glycolysis: Anaerobic Metabolism The first stage of cellular respiration takes place in the cytosol of the cell and is called glycolysis, meaning “glucose breakdown.” Because oxygen isn’t needed for this reaction, glycolysis is also called anaerobic metabolism. In glycolysis, the 6-carbon sugar glucose is broken into two 3-carbon pyruvate molecules (Figure F6.9). These reactions generate two molecules of ATP for each molecule of glucose and release hydrogen ions and high-energy electrons that are passed to nicotinamide adenine dinucleotide (NAD), a coenzyme form of the vitamin niacin, converting it to NADH. NADH shuttles the electrons and hydrogen ions to the last stage of cellular respiration: the electron transport chain. When oxygen is limited, NADH cannot release the electrons, and no further metabolism of glucose or production of ATP occurs. During intense exercise, the demand for ATP to fuel muscle contraction exceeds the ability of the lungs and circulatory system to deliver oxygen to the muscles and generate the ATP by aerobic pathways. To allow vigorous activity to continue, extra ATP must be generated by anaerobic metabolism. Anaerobic metabolism can use only glucose as an energy source so it rapidly depletes body glucose stores. This limits how long intense activity can be sustained. Lower-intensity exercise relies on aerobic metabolism and can use fatty acids as well as glucose to fuel activity. This allows aerobic exercise to continue for a much longer time period than anaerobic exercise (see Chapter 13). 11/07/12 10:22 PM C 1 Glycolysis C O C C C Cytosol C Anaerobic metabolism 1 Glucose ATP e– NADH C C C 2 Pyruvate 2 CoA Acetyl–CoA formation Mitochondrion 2CO2 e– C C CoA 2 Acetyl–CoA ATP 9 FOCUS ON Metabolism F 6 . 3 Breaking Down Nutrients to Provide Energy NADH 3 Citric acid cycle 4CO2 Aerobic metabolism e– NADH FADH2 High-energy electrons 4 6H2O ATP 6O2 e– ADP e– Electron transport chain Inner membrane H+ H+ molecules of 1 In the cytosol of the cell, glycolysis splits glucose, a six-carbon molecule, into two – pyruvate, a three-carbon molecule. This step releases high-energy electrons (e ) that are picked up by NAD to form NADH, and two molecules of ATP per molecule of glucose. 2 When oxygen is available, pyruvate can be used to produce more ATP in the mitochondria. The first step is to remove one carbon as carbon dioxide from each pyruvate. This produces a two-carbon molecule that combines with coenzyme A (CoA) to form acetyl-CoA and releases high-energy electrons that are picked up by NAD, forming NADH. 3 Each acetyl-CoA enters the citric acid cycle, where two carbons are lost as carbon dioxide, high-energy electrons are released and picked up by NAD or FAD (forming NADH and FADH2, respectively), and a small amount of ATP is produced. 4 Most ATP is produced in the final step of cellular respiration: the electron transport chain. Here, the energy from the high-energy electrons released in previous steps pumps hydrogen ions across the inner mitochondrial membrane. As the hydrogen ions flow back the energy is used to convert ADP to ATP. The electrons are finally combined with oxygen and hydrogen to form water. Figure F6.9 Cellular respiration The reactions of cellular respiration split the bonds between carbon atoms in glucose, releasing energy that is used to add a phosphate group to ADP, to form ATP. ATP is used to power the energy-requiring processes in the body. Acetyl-CoA Formation When oxygen is present, aerobic metabolism can proceed. Formation of acetyl coenzyme A (acetyl-CoA) is a transition step that prepares pyruvate for entrance into the citric acid cycle. In the mitochondria, one carbon is removed from pyruvate and released as CO2. The remaining two-carbon compound combines with a molecule of coenzyme A (CoA) to form acetyl-CoA (see Figure F6.9). High-energy electrons are released and passed to NAD to form NADH, which transports them to the last stage of cellular respiration. Acetyl-CoA then enters the third stage of breakdown: the citric acid cycle. In addition to coenzyme A (which includes the B vitamin pantothenic acid as part of its structure) and NAD, a coenzyme form of riboflavin called flavin adenine focus-06.indd 9 11/07/12 10:22 PM FOCUS ON Metabolism 10 F OCUS O N Metabolism dinucleotide (FAD) and the thiamin coenzyme thiamin pyrophosphate (TPP) are required for the conversion of pyruvate to acetyl-CoA. Citric Acid Cycle In the third stage, acetyl-CoA combines with oxaloacetate, a four-carbon molecule derived from carbohydrate, to form a six-carbon molecule called citric acid and begin the citric acid cycle (see Figure F6.9). The reactions of the citric acid cycle then remove one carbon at a time to produce carbon dioxide. After two carbons have been removed in this manner, a four-carbon oxaloacetate molecule is re-formed, and the cycle can begin again. These chemical reactions produce two ATP molecules per glucose molecule and also release highenergy electrons, which are passed to NAD or FAD to form NADH and FADH2, respectively, for transport to the fourth and last stage of cellular respiration: the electron transport chain. Electron Transport Chain The electron transport chain consists of a series of molecules, most of which are proteins, associated with the inner membrane of the mitochondria and involves a series of oxidation-reduction reactions. The electrons carried by NADH and FADH2 are transferred to this series of electron carriers and passed down the chain. The electrons are finally combined with oxygen and with the addition of two hydrogen ions form water. As the electrons are passed along, their energy is released and used to transport hydrogen ions across the inner mitochondrial membrane, creating an electrical and pH gradient across the membrane. This is analogous to water held behind a dam; when the water flows through the dam past turbines, the energy can be used to generate electrical energy. When the hydrogen ions flow through the membrane past an enzyme called ATP synthase, the energy is used to convert ADP to ATP. Breaking Down Triglycerides for Energy beta-oxidation (-oxidation) The first step in the production of ATP from fatty acids. This pathway breaks the carbon chain of fatty acids into two-carbon units that form acetyl-CoA and releases high-energy electrons that are passed to the electron transport chain. Triglycerides consumed in the diet or stored in the body provide a source of energy. The first step is to split the triglycerides into glycerol and fatty acids (Figure F6.10). The majority of ATP produced from triglyceride metabolism is from the oxidation of fatty acids. In the first step of fatty acid breakdown, called beta-oxidation (-oxidation), the carbon chain of a fatty acid is split into two-carbon units that form acetyl-CoA and release high-energy electrons that are shuttled to the electron transport chain by FADH2 and NADH (Figure F6.11). The acetyl-CoA derived from -oxidation combines with oxaloacetate to enter the citric acid and proceed through aerobic metabolism, as shown in figure F6.11. The highenergy electrons released in both -oxidation and the citric acid cycle are used to generate ATP. When compared to glucose, fatty acid molecules contain less oxygen and more carbon in their structure and thus require more oxidation to become carbon dioxide and water. The amount of ATP generated per gram of fatty acids is therefore greater than can be generated per gram of glucose. This is the reason fat provides more calories than carbohydrate; 9 kcals per gram of fat compared to 4 kcals per gram of glucose. The glycerol from triglyceride breakdown can also be used to produce ATP. Glycerol makes up only a small proportion of the carbon in a triglyceride molecule, so the amount of ATP that results is small. Triglyceride 3 fatty acids + Glycerol Carbon chain (variable length) H O H H C C O C H H H C H C OH HO C H H H H O H C C H O C H H + 3 H2O H C O C OH + HO C H H H O H C C H O H O C H H H C H O C OH HO C H H Figure F6.10 Triglyceride breakdown The breakdown of a triglyceride is a hydrolysis reaction in which the addition of three molecules of water splits the triglyceride into three fatty acids and one molecule of glycerol. focus-06.indd 10 11/07/12 10:22 PM Figure F6.11 Fatty acid metabolism Fatty acids provide most of the energy stored in a triglyceride molecule. C Glycolysis C O C C Cytosol C C Anaerobic metabolism Glucose C 11 ATP C 4 C NADH e– C C C Pyruvate Glycerol CoA Acetyl–CoA formation Mitochondrion CO2 e– NADH FOCUS ON Metabolism F 6 . 3 Breaking Down Nutrients to Provide Energy 2 C C CoA Acetyl–CoA Citric acid cycle CO2 Aerobic metabolism e– ATP NADH FADH2 3 NADH FADH2 e– H2O ATP O2 e– ADP e– Electron transport chain H+ H+ Inner membrane 1 Fatty acid 8 Acetyl–CoA H O C C H S CoA H NADH FADH2 e– H H C H C C C C C C C C C C C C C C O C + 8 CoA OH Fatty acid (palmitic acid) 1 Fatty acids are transported into the mitochondria where b-oxidation splits the carbon chains into two-carbon units that form acetyl-CoA and produces high-energy electrons that are transported by NADH and FADH2. b-Oxidation of the 16-carbon palmitic acid molecule, shown here, yields 8 molecules of acetyl-CoA. 2 If oxygen and enough carbohydrate are available, acetyl-CoA combines with oxaloacetate to enter the citric acid cycle, producing two molecules of carbon dioxide and releasing high-energy electrons that are shuttled by NADH and FADH2 to the electron transport chain. 3 In the final step of aerobic metabolism, the energy in the high-energy electrons released from b-oxidation and the citric acid cycle is trapped and used to produce ATP and water. 4 Glycerol molecules, from triglyceride breakdown, contain three carbon atoms. They can be used to produce small amounts of ATP. Using Amino Acids for Energy Although carbohydrate and fat are more efficient energy sources, amino acids from the diet and from body proteins are also used to provide energy. Before this can occur, the nitrogen-containing amino group must be removed from the amino acids in a process called deamination (Figure F6.12). Deamination requires the coenzyme pyridoxal phosphate (PLP), which is the active form of vitamin B6. The amino group that is released is eventually converted into urea and excreted in the urine. The remaining structure, which is composed of carbon, hydrogen, and oxygen, can be converted into pyruvate, acetyl-CoA, or intermediates in the citric acid cycle to produce ATP (see Figure F6.12). As discussed below, the use of amino acids as an energy source increases both when the diet does not provide enough total energy to meet needs, as in starvation, and when protein is consumed in excess of need. When both protein and energy are plentiful, amino acids can be converted into acetyl-CoA and used to synthesize fat for storage. focus-06.indd 11 deamination The removal of the amino group from an amino acid. 11/07/12 10:22 PM FOCUS ON Metabolism 12 F OCUS O N Metabolism C Glycolysis C O C C C C Cytosol Anaerobic metabolism Glucose ATP e– NADH C C C Pyruvate CoA Acetyl–CoA formation 2 3 Mitochondrion CO2 e– C C CoA Acetyl–CoA NADH Citric acid cycle CO2 e– 4 ATP NADH FADH2 High-energy electrons e– 5 e– Electron transport chain H PLP O H2N 1 C C OH Acid group Amino group Deamination Aerobic metabolism H2O ATP O2 ADP H+ H+ Inner membrane Side chain NH2 Amino acid NH3 Ammonia 1 The amino group is removed by deamination, allowing the carbon 6 compounds that remain to be further metabolized. Deamination requires the vitamin B6 coenzyme pyridoxal phosphate (PLP). 2 NH3 + CO2 Liver ATP H2N 2 Deamination of some amino acids produces three-carbon molecules that can form pyruvate. H2O C 3 Deamination of some amino acids results in molecules that form NH2 acetyl-CoA, which can enter the citric acid cycle. Urea O Urea Figure F6.12 Amino acid metabolism 4 Deamination of some amino acids forms intermediates in the citric acid cycle. Kidney Excreted in urine In order for the body to use amino acids as an energy source, the nitrogen-containing amino group must first be removed. The compounds remaining after the amino group has been removed are composed of carbon, hydrogen, and oxygen and can be broken down to produce ATP or used to make glucose or fatty acids. focus-06.indd 12 5 High-energy electrons from the breakdown of amino acids are transferred to the electron transport chain where the energy is trapped and used to produce ATP and water. 6 The amino group released by deamination produces ammonia, which is toxic. To protect the body, the liver combines ammonia with carbon dioxide to form a less toxic waste product called urea, which can be filtered out of the blood by the kidneys and eliminated from the body in the urine. 11/07/12 10:22 PM F6.4 FOCUS ON Metabolism F 6 . 4 The Metabolism of Feasting and Fasting 13 The Metabolism of Feasting and Fasting When the body is in the fed state, which is during the few hours after a meal, nutrients are available to provide energy and synthesize regulatory and structural molecules as well as to build body stores. When the body is in the fasted state, between meals and during longer periods without food, adjustments need to be made in metabolism to ensure that energy is available to body cells. The human body is like a well-run business. When business is booming, the extra resources are stored for later use and spent on expanding and improving the business. When times are bad, expenditures must be cut and resources must be taken out of storage and used. The Fed State After a meal, the carbohydrate, fat, and protein it provides are digested and the resulting glucose, fatty acids, and amino acids are absorbed. Some of these nutrients are used to supply ATP to fuel body processes; some are used to synthesize important structural and regulatory molecules, and what remains can be converted into storage molecules. Carbohydrate Stores After a carbohydratecontaining meal, insulin is released, allowing glucose to be taken up by muscle and adipose tissue cells and stimulating anabolic pathways (see Chapter 4). Glucose that is not broken down to meet the body’s immediate need for energy can be used to synthesize the glucose storage molecule glycogen. This process, called glycogenesis, takes place in both muscle and liver and is activated by insulin. Muscle glycogen stores provide glucose for the exercising muscle. Liver glycogen supplies glucose to the blood. Glycogen synthesis requires the input of energy, but instead of ATP, a similar high-energy compound called uridine triphosphate (UTP) is used (Figure F6.13). glycogenesis The conversion of glucose to glycogen for storage. Diet Fat Protein Carbohydrate C Body proteins C UTP C O C C C C Amino acids Glucose Glycogen Pyruvate Fat Stores After a meal, some essential fatty NH2 acids are used for the synthesis of cell membranes and regulatory molecules, and other fatty acids are broken down to provide energy. O Acetyl–CoA Fatty acids ingested in excess of needs can be H CH Citric C OH acid stored as fat in adipose tissue. Excess energy H cycle consumed as fat is packaged in chylomicrons Fatty acids ATP ATP Electron and transported directly from the intestines transport to the adipose tissue. Because the fatty acids chain in our body fat come from the fatty acids we Fatty acids eat, what we eat affects the fatty acid composiGlycerol tion of our adipose tissue; therefore, if you eat more saturated fat, there will be more saturated fat stored in your adipose tissue. Once glycogen stores are full, excess energy consumed as carbohydrate can also Triglycerides be converted into fat. Glucose must first go for storage to the liver, where it is broken down to form Figure F6.13 Storing energy acetyl-CoA, which can be used, although Excess energy consumed as dietary fat is efficiently stored as body fat. Excess energy from inefficiently, to synthesize fatty acids, glucose or amino acids can also be converted to body fat, but the metabolic conversions are These fatty acids are then assembled into less efficient. focus-06.indd 13 11/07/12 10:22 PM FOCUS ON Metabolism 14 F OCUS O N Metabolism triglycerides, which are transported to the adipose tissue in VLDLs. Lipoprotein lipase at the membrane of cells lining the blood vessels breaks down the triglycerides from both chylomicrons and VLDLs so that the fatty acids can enter the cells, where they are reassembled into triglycerides for storage (see Figure F6.13). The ability of the body to store fat is theoretically limitless. Fat cells can increase in weight by about 50 times, and new fat cells can be synthesized when existing cells reach their maximum size (see Chapter 7). Because each gram of fat provides 9 kcals, compared with only 4 kcals per gram from carbohydrate or protein, a large amount of energy can be stored in the body as fat without a great increase in body size. Even a lean man, whose body fat is only about 10% of his weight, stores over 50,000 kcals of energy as fat. When Protein Intake Exceeds Need Excess amino acids are not stored in the body. When the diet is adequate in energy and high in protein, amino acids that are not needed to synthesize body proteins or other nitrogen-containing molecules are deaminated and the carbon compounds that remain can be oxidized to produce ATP. If both energy and protein intake exceeds needs, the extra amino acids are converted, although inefficiently, into fatty acids, stored as triglycerides in adipose tissue, and can contribute to weight gain (see Figure F6.13). The Fasted State gluconeogenesis The synthesis of glucose from simple noncarbohydrate molecules. Amino acids from protein are the primary source of carbons for glucose synthesis. Between meals and during longer periods without food, regulatory mechanisms shift metabolism from storing excesses to retrieving energy from body stores. Pathways that produce ATP from the breakdown of energy-yielding nutrients are still in place, but adjustments are made to ensure that blood glucose levels are maintained and to conserve proteins that are essential to body function. Providing Glucose Since the brain must obtain some of its energy from glucose, maintaining blood glucose levels within the normal range is a metabolic priority. When glucose is not being supplied by the diet, it can come from the breakdown of glycogen as well as hormone-sensitive lipase An from synthesis via gluconeogenesis. Both of these pathways are stimulated by release of enzyme present in adipose cells the hormone glucagon (see Chapter 4). Gluconeogenesis, which occurs in liver and kidney that responds to chemical signals cells, is an energy-requiring process that synthesizes glucose from three-carbon molecules. by breaking down triglycerides These three-carbon molecules come primarily from amino acids derived from protein into fatty acids and glycerol for breakdown (Figure F6.14). When energy is deficient, body proteins, such as enzymes and release into the bloodstream. muscle proteins, are broken down into amino acids. Some of these amino C acids, referred to as glucogenic amino acids, form pyruvate or intermediates in the citric acid cycle, which can then be used to make glucose. O C A small amount of glucose can also be made from glycerol from triglycerC C ide breakdown. Fatty acids and other amino acids, referred to as ketogenic C C amino acids, cannot be used to make glucose because the reactions that Glucose break them down produce primarily two-carbon molecules that form acetyl-CoA. Both ketogenic and glucogenic amino acids can be broken Gluconeogenesis ATP down to provide ATP (see Figure F6.12). Gluconeogenesis is essential for meeting the body’s immediate need Pyruvate Glycerol for glucose when energy and/or carbohydrate intake is very low, but it uses amino acids from proteins that could be used for other essential functions such as growth and maintenance of muscle tissue. Since adequate dietary NH3 carbohydrate eliminates the need to use amino acids from protein to synthesize glucose, carbohydrate is said to “spare protein.” C Citric acid cycle Amino acids Figure F6.14 Substrates for gluconeogenesis The primary source of three-carbon molecules for gluconeogenesis is amino acids that break down to form pyruvate or intermediates in the citric acid cycle. A small amount of glucose can be made from glycerol from triglyceride breakdown. focus-06.indd 14 Short-Term Fast In the fasting state, body fat stores are broken down to release fatty acids as a source of energy. In this situation, the enzyme hormone-sensitive lipase inside the fat cells receives a hormonal signal that turns on enzyme activity so it begins breaking down stored triglycerides. The fatty acids and glycerol are released directly into the blood, where they can be taken up by cells throughout the body to produce ATP. Most tissues in the body can use fatty acids as an energy source, but since fatty acids are unable to cross the blood-brain barrier, they are inaccessible to 11/07/12 10:22 PM Muscle Protein Amino acids Liver Glycogen Amino acids Glucose Blood glucose Blood vessel Glycerol Fatty acids Brain FOCUS ON Metabolism F 6 . 4 The Metabolism of Feasting and Fasting 15 Ketones Triglycerides Glycerol Fatty acids Adipose tissue Most body tissues Figure F6.15 The metabolism of starvation During starvation, gluconeogenesis provides glucose by synthesizing it from three-carbon molecules, derived primarily from amino acids. Compounds that contain two carbons, such as acetyl-CoA derived from fatty acid breakdown, cannot be used to make glucose, and the liver converts them to ketones. the brain. During the first two or three days of starvation, fatty acids are the main fuel for most body tissues. The brain continues to use glucose because the use of fatty acids by other tissues has made more glucose available to the brain. Long-Term Fast The brain requires about 120 g of glucose per day (about 30 teaspoons). If it continues to use glucose at this rate during fasting, large amounts of body protein will need to be broken down to supply it. To spare protein, after about three days of fasting, the brain begins to obtain about half of its energy from molecules known as ketones or ketone bodies. Ketones are smaller molecules than fatty acids, so they can cross into the brain and be used for energy. Ketones are formed in moderate amounts during sleep and at other times when no carbohydrates are available. This occurs because the liver conserves citric acid cycle intermediates such as oxaloacetate that can be used to synthesize glucose by gluconeogenesis. When the amount of acetyl-CoA generated exceeds the availability of oxaloacetate, acetylCoA cannot enter the citric acid cycle, so it is used to make ketones. Ketone production is a normal response to starvation or to a diet very low in carbohydrate. Even during a shortterm fast, the increase in fatty acid breakdown and the limited supply of glucose causes the amount of acetyl-CoA formed to exceed the amount of oxaloacetate present, resulting in an increase in ketone formation. Ketones circulate in the blood and can be used by muscle, heart, and other tissues as an energy source. After about three days of fasting, even the brain adapts and can obtain about half of its energy from ketones. The use of ketones for energy helps spare glucose and decreases the amount of protein that must be broken down to synthesize glucose. The metabolic adaptations that occur during starvation are summarized in Figure F6.15. The production of ketone bodies reduces the amount of glucose required by the brain, but the amount needed still exceeds what can be produced by liver gluconeogenesis from glycerol. The remaining glucose must be supplied by amino acids from breakdown of the body’s own proteins (see Figure F6.15). focus-06.indd 15 ketones or ketone bodies Molecules formed in the liver when there is not sufficient carbohydrate to completely metabolize the two-carbon units produced from fat breakdown. 11/07/12 10:22 PM