Chemistry Final PDF - Introduction to General, Organic, and Biological Chemistry

CHEMISTRY An Introduction to General, Organic, and Biological Chemistry 18 Metabolic Pathways and ATP Production LUKE IS 48 YEARS OLD AND WORKS AS A tablets per month for pain and uses herbs, garlic, ginkgo, para...

CHEMISTRY An Introduction to General, Organic, and Biological Chemistry 18 Metabolic Pathways and ATP Production LUKE IS 48 YEARS OLD AND WORKS AS A tablets per month for pain and uses herbs, garlic, ginkgo, paramedic. Recently, bloodwork from his annual physical and antioxidants. Although herbs, antioxidants, and examination indicated a plasma cholesterol level of ibuprofen can cause liver inflammation, they would not 256 mg/dL. Clinically, cholesterol levels are considered usually cause the elevation of liver enzymes reported in elevated if the total plasma cholesterol level exceeds Luke’s blood tests. A hepatitis profile showed that Luke 200 mg/dL. Luke’s doctor ordered a liver profile that was positive for antibodies to both hepatitis B and C. His showed elevated liver enzymes: alanine transaminase doctor diagnosed Luke with chronic hepatitis C virus (HCV) (ALT) 282 Units/L (normal ALT 5 to 35 Units/L) and infection. Hepatitis C is an infection caused by a virus that aspartate transaminase (AST) 226 Units/L (normal AST attacks the liver and leads to inflammation. Most people 5 to 50 Units/L). Luke’s doctor ordered a medication to infected with the hepatitis C virus have no symptoms. lower Luke’s plasma cholesterol. Hepatitis C is usually passed by contact with contaminated During Luke’s career as a paramedic, he was exposed blood or by needles shared during illegal drug use. As several times to blood and was accidently stuck by a needle part of his treatment, Luke attended a class on living with containing infected blood. Luke takes 8 to 10 ibuprofen hepatitis C given by Belinda, a public health nurse. CAREER Public Health Nurse (PHN) Hepatitis C virus is a common cause of liver disease and a major health problem worldwide. Patients with HCV require lifelong monitoring and are usually cared for by specialist teams including a public health nurse. A public health nurse works in public health departments, correctional facilities, occupational health facilities, schools, and organizations that aim to improve health at the community level. They often focus on high-risk populations such as the elderly, the homeless, teen mothers, and those at risk for a communicable disease such as hepatitis. CLINICAL UPDATE Treatment of Luke’s Hepatitis C When the levels of Luke’s liver enzymes remained elevated, his doctor prescribed a therapy of antiviral agents that inhibit the replication of the hepatitis C virus. Read more about this treatment and how it affected the levels of Luke’s liver enzymes in the CLINICAL UPDATE Treatment of Luke’s Hepatitis C, page 684. 649 650 CHAPTER 18 Metabolic Pathways and ATP Production LOOKING AHEAD 18.1 Metabolism and ATP Energy 18.1 Metabolism and LEARNING GOAL Describe the three stages of catabolism and the role of ATP. ATP Energy 18.2 Digestion of Foods When we eat food, the polysaccharides, fats, and proteins are digested to smaller molecules that can be absorbed into the cells of our body. As the glucose, fatty acids, and amino acids are 18.3 Coenzymes in Metabolic Pathways broken down further, energy is released. Because we do not use all the energy from our foods at one time, we store energy in the cells as high-energy adenosine triphosphate (ATP). Our cells 18.4 Glycolysis: Oxidation use the energy stored in ATP when they do work such as contracting muscles, synthesizing large of Glucose molecules, sending nerve impulses, and moving substances across cell membranes. 18.5 The Citric Acid Cycle The term metabolism refers to all the chemical reactions that provide energy and the 18.6 Electron Transport and substances required for continued cell growth. There are two types of metabolic reactions: Oxidative Phosphorylation catabolic and anabolic. In catabolic reactions, complex molecules are broken down to 18.7 Oxidation of Fatty Acids simpler ones with an accompanying release of energy. Anabolic reactions utilize energy 18.8 Degradation of Amino available in the cell to build large molecules from simple ones. Acids This chapter focuses on the catabolic processes that happen in animal cells. We can think of these catabolic processes as occurring in three stages (see FIGURE 18.1). Stages of Catabolism Stage 1 Proteins Polysaccharides Lipids Digestion and hydrolysis Cell membrane Stage 2 Amino acids Monosaccharides Fatty acids Degradation and some oxidation to smaller molecules Stage 3 Acetyl CoA Release of energy to synthesize ATP Mitochondrion Citric acid cycle NADH FADH2 FIGURE 18.1 In the three stages Electron transport and of catabolism, large molecules from oxidative phosphorylation foods are digested and degraded to give smaller molecules that can be oxidized to produce ATP. ATP Q Where is most of the ATP produced in the cells?  18.1 Metabolism and ATP Energy 651 Stage 1 Catabolism begins with the processes of digestion in which enzymes in the digestive tract break down large molecules into smaller ones. Polysaccharides break down to monosaccharides, fats break down to glycerol and fatty acids, and proteins yield amino acids. These digestion products diffuse into the bloodstream for transport to cells. Stage 2 Within the cells, catabolic reactions continue as the digestion products are broken down further to yield smaller groups, such as the two-carbon acetyl group. Stage 3 The major release of energy takes place in the mitochondria, where the two-carbon acetyl group is oxidized in the citric acid cycle and the reduced coen- zymes NADH and FADH2 are produced. As long as the cells have oxygen, NADH TEST and FADH2 can be reoxidized via electron transport to release the energy needed to Try Practice Problems 18.1 to 18.4 synthesize ATP. SAMPLE PROBLEM 18.1 Metabolism TRY IT FIRST Identify each of the following as catabolic or anabolic: a. digestion of polysaccharides b. synthesis of proteins SOLUTION a. The breakdown of large molecules is catabolic. b. The synthesis of large molecules is anabolic. STUDY CHECK 18.1 Identify the oxidation of glucose to CO2 and H2O as catabolic or anabolic. ANSWER The oxidation of glucose to smaller molecules is catabolic. Cell Structure for Metabolism To understand metabolic reactions, we need to look at where these reactions take place in the cell (see FIGURE 18.2). Nucleus Cell membrane Cytosol Cytoplasm Outer membrane Ribosomes Inner membrane Intermembrane space FIGURE 18.2 The diagram illustrates some of the major components of a Matrix typical animal cell. Mitochondrion Q What is the function of the mitochondria in a cell? In animals, a cell membrane separates the materials inside the cell from the aqueous environment surrounding the cell. The nucleus contains the genes that control DNA replica- tion and protein synthesis. The cytoplasm consists of all the materials between the nucleus and the cell membrane. The cytosol, the fluid part of the cytoplasm, is an aqueous solution of electrolytes and enzymes that catalyze many of the cell’s chemical reactions. 652 CHAPTER 18 Metabolic Pathways and ATP Production Within the cytoplasm are specialized structures that carry out specific functions in the cell, some of which are labeled in Figure 18.2. The ribosomes are the sites of protein syn- thesis. The mitochondria are the energy-releasing factories of the cells. A mitochondrion has an outer and an inner membrane, with an intermembrane space between them. The fluid section surrounded by the inner membrane is called the matrix. Enzymes located in the matrix and along the inner membrane catalyze the oxidation of carbohydrates, fats, and amino acids. All these oxidation pathways eventually produce CO2 and H2O, and release energy, which is used to form energy-rich compounds. TABLE 18.1 summarizes some of the functions of these components in animal cells. TABLE 18.1 Functions of Some Major Components in Animal Cells Component Description and Function Cell membrane Separates the contents of a cell from the external environment and contains structures that communicate with other cells Cytoplasm Consists of the cellular contents between the cell membrane and nucleus Cytosol Fluid part of the cytoplasm that contains enzymes for many of the cell’s chemical reactions Mitochondrion Contains the structures for the synthesis of ATP from energy-releasing reactions Nucleus Contains genetic information for the replication of DNA and the synthesis of protein Ribosome Site of protein synthesis using mRNA templates ATP and Energy In our cells, the energy released from the oxidation of the food we eat is stored in the form of a “high-energy” compound called adenosine triphosphate (ATP). The ATP molecule is composed of the base adenine, a ribose sugar, and three phosphate groups. High-energy Adenosine phosphate bonds NH2 N O O O N Adenine Phosphate N N CH2 O P O P O P O- groups O H H O- O- O- H H OH OH Ribose Adenosine monophosphate (AMP) Adenosine diphosphate (ADP) Adenosine triphosphate (ATP) When ATP undergoes hydrolysis, the products are adenosine diphosphate (ADP), a phos- phate group abbreviated as Pi and energy of 7.3 kcal per mole of ATP (31 kJ/mole). We can write this reaction as ATP + H2O h ADP + Pi + 7.3 kcal/mole (31 kJ/mole) ENGAGE The ADP can also hydrolyze to form adenosine monophosphate (AMP) and phosphate (Pi). Why are anabolic reactions that ADP + H2O h AMP + Pi + 7.3 kcal/mole (31 kJ/mole) require energy always linked Every time we contract muscles, move substances across cellular membranes, send with the hydrolysis of a high- energy compound like ATP? nerve signals, or synthesize an enzyme, we use energy from ATP hydrolysis. In a cell that is doing work (anabolic processes), 1 to 2 million ATP molecules may be hydrolyzed in one  18.2 Digestion of Foods 653 second. The amount of ATP hydrolyzed in one day can be as much as our body mass, even though only about 1 g of ATP is present in our cells at any given time. TEST When we take in food, the resulting catabolic reactions provide energy to regenerate Try Practice Problems 18.5 ATP in our cells. Then 7.3 kcal/mole (31 kJ/mole) is used to make ATP from ADP and Pi and 18.6 (see FIGURE 18.3). ADP + Pi + 7.3 kcal/mole (31 kJ/mole) h ATP + H2O Catabolic reactions (energy releasing) 7.3 kcal/mole (31 kJ/mole) + ADP + Pi ATP (energy used) (energy stored) -7.3 kcal/mole (-31 kJ/mole) Anabolic reactions (energy requiring) FIGURE 18.3 ATP, the energy-storage molecule, links energy-releasing reactions with energy-requiring Adenosine reactions in the cells. Phosphate group Q What type of reaction provides energy for ATP synthesis? PRACTICE PROBLEMS 18.1 Metabolism and ATP Energy LEARNING GOAL Describe the three stages of catabolism and the role c. hydrolysis of ATP to ADP and Pi of ATP. d. digestion of proteins in the stomach 18.1 What stage of catabolism involves the digestion of 18.4 Identify each of the following as catabolic or anabolic: polysaccharides? a. digestion of fats to fatty acids and glycerol b. hydrolysis of proteins into amino acids 18.2 What stage of catabolism involves the conversion of small c. synthesis of nucleic acids from nucleotides molecules to CO2, H2O, and energy for the synthesis of ATP? d. glucose and galactose form the disaccharide lactose 18.3 Identify each of the following as catabolic or anabolic: 18.5 Why is ATP considered an energy-rich compound? a. synthesis of lipids from glycerol and fatty acids b. glucose adds Pi to form glucose-6-phosphate 18.6 How much energy is obtained from the hydrolysis of ATP? 18.2 Digestion of Foods REVIEW Identifying Fatty Acids (15.2) LEARNING GOAL Identify the sites and products of digestion for carbohydrates, Drawing Structures for Triacyl- triacylglycerols, and proteins. glycerols (15.3) In stage 1 of catabolism, foods undergo digestion, a process that converts large molecules Identifying the Primary, Secondary, to smaller ones that can be absorbed by the body. Tertiary, and Quaternary Struc- tures of Proteins (16.2, 16.3) Describing Enzyme Action (16.4) Digestion of Carbohydrates We begin the digestion of carbohydrates as soon as we chew food. Enzymes produced in the salivary glands hydrolyze some of the a@glycosidic bonds in amylose and amylopectin, producing maltose, glucose, and smaller polysaccharides called dextrins, which contain 654 CHAPTER 18 Metabolic Pathways and ATP Production three to eight glucose units. After swallowing, the partially digested starches enter the Mouth acidic environment of the stomach, where the low pH stops carbohydrate digestion (see Salivary FIGURE 18.4). glands Liver Stomach Mouth Gallbladder Small Salivary intestine amylase O O O O O O O O O O O Pancreas O O O O O O O O O Polysaccharides Dextrins O O O + O Maltose Glucose Carbohydrates begin digestion in the Stomach mouth, lipids in the small intestine, and proteins in the stomach and small Small Intestine intestine. O O O O Pancreatic O O O amylase Dextrins Maltase O O O O + O Maltose Glucose Glucose O Lactase O O O + O Lactose Galactose Glucose O OO Sucrase O O + FIGURE 18.4 In stage 1 of catabolism, the digestion of Sucrose Fructose Glucose carbohydrates begins in the mouth and is completed in the small intestine. Bloodstream Q Why is there little or no digestion of carbohydrates Cells in the stomach? In the small intestine, which has a pH of about 8, enzymes produced in the pancreas hydrolyze the remaining dextrins to maltose and glucose. Then enzymes produced in the mucosal cells that line the small intestine hydrolyze maltose as well as lactose and sucrose. The resulting monosaccharides are absorbed through the intestinal wall into the TEST bloodstream, which carries them to the liver, where the hexoses fructose and galactose are Try Practice Problems 18.7 converted to glucose. Glucose is the primary energy source for muscle contractions, red and 18.8 blood cells, and the brain. CHEMISTRY LINK TO HEALTH Lactose Intolerance The disaccharide in milk is lactose, which is broken down by United States it is prevalent among the African American, Hispanic, lactase in the intestinal tract to monosaccharides that are a source and Asian populations. of energy. Infants and small children produce lactase to break down When lactose is not broken down into glucose and galactose, it cannot the lactose in milk. It is rare for an infant to lack the ability to pro- be absorbed through the intestinal wall and remains in the intestinal tract. duce lactase. However, the production of lactase decreases as many Symptoms of lactose intolerance, which appear approximately 12 to 1 h people age, which causes lactose intolerance. This condition affects after ingesting milk or milk products, include nausea, abdominal cramps, approximately 25% of the people in the United States. A deficiency and diarrhea. The severity of the symptoms depends on how much lactose of lactase occurs in adults in many parts of the world, but in the is present in the food and how much lactase a person produces.  18.2 Digestion of Foods 655 Treatment of Lactose Intolerance One way to reduce the reaction to lactose is to avoid products that contain lactose. Another way is to ingest a product that contains lac- tase. The enzyme lactase is now available as tablets that are taken with meals, drops that are added to milk, or as additives in many dairy prod- ucts such as milk. When lactase is added to milk that is left in the refrigerator for 24 h, the lactose level is reduced by 70 to 90%. Lactase pills or chewable tablets are taken when a person begins to eat a meal that contains dairy foods. If taken too far ahead of the meal, too much Lactaid contains an enzyme that of the lactase will be degraded by stomach acid. If taken following a aids the digestion of lactose. meal, the lactose will have already entered the lower intestine. SAMPLE PROBLEM 18.2 Digestion of Carbohydrates TRY IT FIRST Indicate the carbohydrates that undergo digestion in each of the following sites: a. mouth b. stomach c. small intestine SOLUTION a. polysaccharides b. no carbohydrate digestion c. dextrins, maltose, sucrose, and lactose STUDY CHECK 18.2 Describe the digestion of amylose, a polysaccharide. ANSWER The digestion of amylose begins in the mouth where enzymes hydrolyze some of the glycosidic bonds. In the small intestine, enzymes hydrolyze more glycosidic bonds, and finally maltose is hydrolyzed to yield glucose. Digestion of Fats The digestion of dietary fats begins in the small intestine, when the hydrophobic fat globules ENGAGE mix with bile salts released from the gallbladder. In a process called emulsification, the bile salts Why are triacylglycerols insoluble break the fat globules into smaller droplets called micelles. Enzymes from the pancreas hydro- in the lymph or bloodstream? lyze the triacylglycerols to yield monoacylglycerols and fatty acids, which are then absorbed into the intestinal lining where they recombine to form triacylglycerols. These nonpolar com- pounds are then coated with proteins to form lipoproteins called chylomicrons, which are more polar and soluble in the aqueous environment of the lymph and bloodstream (see FIGURE 18.5). TEST The chylomicrons transport the triacylglycerols to the cells of the heart, muscle, and adipose tissues. When energy is needed in the cells, enzymes hydrolyze the triacylglycerols Try Practice Problems 18.9 to 18.12 to yield glycerol and fatty acids. O CH2 O C (CH2)16 CH3 O CH O C (CH2)16 CH3 O CH2 O C (CH2)16 CH3 A triacylglycerol The fat cells that make up adipose tissue are capable of storing unlimited quantities of triacylglycerols. 656 CHAPTER 18 Metabolic Pathways and ATP Production FIGURE 18.5 The triacylglycerols are hydrolyzed in the small intestine and Small Intestine re-formed in the intestinal wall where they bind to proteins for transport CH2 Fatty acid CH2 OH through the lymphatic system and Pancreatic lipase bloodstream to the cells. CH Fatty acid + 2H2O CH Fatty acid + 2 Fatty acids Q Why do chylomicrons form in the intestinal wall? CH2 Fatty acid CH2 OH Triacylglycerol 2-Monoacylglycerol Intestinal Wall Monoacylglycerols + 2 Fatty acids Triacylglycerols Protein Lipoproteins (Chylomicrons) Stomach Lymphatic System Pepsin Proteins Polypeptides Bloodstream Small Intestine Trypsin Chymotrypsin Cells Glycerol + Fatty acids Amino acids Intestinal Wall Digestion of Proteins Bloodstream The major role of proteins is to provide amino acids for the synthesis of new proteins for the body and nitrogen atoms for the synthesis of compounds such as nucleotides. The digestion Cells of proteins begins in the stomach, where hydrochloric acid (HCl) at pH 2 denatures the pro- FIGURE 18.6 Proteins are hydrolyzed teins and activates protease enzymes such as pepsin that begin to hydrolyze peptide bonds. in the stomach and the small intestine. Polypeptides move out of the stomach into the small intestine, where other proteases, such Q What enzymes, secreted into as trypsin and chymotrypsin, complete the hydrolysis of the peptides to amino acids. The the small intestine, hydrolyze amino acids are absorbed through the intestinal walls into the bloodstream for transport to peptides? the cells (see FIGURE 18.6). PRACTICE PROBLEMS 18.2 Digestion of Foods LEARNING GOAL Identify the sites and products of digestion for 18.9 What is the role of bile salts in lipid digestion? carbohydrates, triacylglycerols, and proteins. 18.10 How are insoluble triacylglycerols transported to the cells? 18.7 What is the general type of reaction that occurs during the 18.11 Where do dietary proteins undergo digestion in the body? digestion of carbohydrates? 18.12 What are the end products of the digestion of proteins? 18.8 What is the purpose of digestion in stage 1? 18.3 Coenzymes in Metabolic Pathways LEARNING GOAL Describe the components and functions of the coenzymes NAD +, FAD, and coenzyme A. Several metabolic reactions that extract energy from our food involve oxidation and reduc- tion reactions. In chemistry, oxidation is often associated with the loss of H atoms, whereas reduction is associated with the gain of H atoms. Often, we represent two H atoms as two hydrogen ions (2H + ) and two electrons (2 e- ). In both oxidation and reduction, coenzymes are required to carry the hydrogen ions and electrons from or to the reacting substrate.  18.3 Coenzymes in Metabolic Pathways 657 A coenzyme that gains hydrogen ions and electrons is reduced, whereas a coenzyme that loses hydrogen ions and electrons is oxidized. In general, oxidation reactions release energy, and reduction reactions require energy. TABLE 18.2 summarizes the characteristics of oxidation and reduction. TABLE 18.2 Characteristics of Oxidation and Reduction in Metabolic Pathways Oxidation Reduction Loss of electrons (e-) Gain of electrons (e-) + - Loss of hydrogen (H or H and e ) Gain of hydrogen (H or H + and e- ) Gain of oxygen Loss of oxygen Release of energy Input of energy NAD+ NAD+ (nicotinamide adenine dinucleotide) is an important coenzyme in which the vitamin niacin provides the nicotinamide group, which is bonded to ribose and the nucle- otide ADP (see FIGURE 18.7). The oxidized form of NAD+ undergoes reduction when a carbon atom in the nicotinamide ring reacts with two hydrogen atoms (2H + + 2 e- ), leaving one H +. NAD+ NADH (oxidized form) (reduced form) O 2H+ + 2 e- O H H C NH2 + H+ C NH2 + Nicotinamide N O CH2 N (from niacin) O Ribose O P O- H H Ribose ADP H H O OH OH NH2 FIGURE 18.7 The coenzyme NAD+ - (nicotinamide adenine dinucleotide), O P O N N which consists of a nicotinamide ADP O CH2 N portion from the vitamin niacin, O N ribose, and adenosine diphosphate, H H is reduced to NADH + H + when a H H hydrogen ion and two electrons are added to the NAD+. OH OH Q Why is the conversion of NAD+ to + NADH and H + a reduction? NAD The NAD+ coenzyme is required for metabolic reactions that produce carbon–oxygen double bonds (C “ O), such as in the oxidation of alcohols to aldehydes and ketones. An example of such an oxidation–reduction reaction is the oxidation of ethanol in the liver to ethanal, with the corresponding reduction of NAD+ to NADH and H +. O H Alcohol O dehydrogenase CH3 C H + NAD+ CH3 C H + NADH + H+ H Ethanol Ethanal (ethyl alcohol) (acetaldehyde) 658 CHAPTER 18 Metabolic Pathways and ATP Production FAD FAD (flavin adenine dinucleotide) is a coenzyme that contains the nucleotide ADP and ribofla- vin. Riboflavin, vitamin B2, consists of ribitol (a sugar alcohol) and flavin. The oxidized form of FAD undergoes reduction when the two nitrogen atoms in the flavin part of the FAD coenzyme react with two hydrogen atoms (2H + + 2 e- ), reducing FAD to FADH2 (see FIGURE 18.8). FAD FADH2 (oxidized form) (reduced form) Flavin O H H O H CH3 N + 2H + 2 e- CH3 N N N CH3 N N O CH3 N N O CH2 Ribitol H ADP HCOH Ribitol HCOH NH2 HCOH O O N N ADP CH2 O P O P O CH2 O N N O- O- H H H H OH OH FAD FIGURE 18.8 The coenzyme FAD (flavin adenine dinucleotide), made from flavin, ribitol, and adenosine diphosphate, is reduced to FADH2 when two hydrogen atoms are added to the FAD. Q What is the type of reaction in which FAD accepts hydrogen? FAD is used as a coenzyme when an oxidation reaction converts a carbon–carbon single bond to a carbon–carbon double bond (C “ C). An example of such a reaction from the citric acid cycle is the conversion of the carbon–carbon single bond in succinate to a double bond in fumarate, with the corresponding reduction of FAD to FADH2. H H H Succinate - dehydrogenase OOC C C COO- + FAD - OOC C C COO- + FADH2 H H H Succinate Fumarate Coenzyme A Coenzyme A (CoA) is made up of several components: pantothenic acid (vitamin B5), phosphorylated ADP, and aminoethanethiol (see FIGURE 18.9). An important function of coenzyme A is to prepare small acyl groups (represented by the letter A in the name), such as acetyl, for reactions with enzymes. The reactive feature of coenzyme A is the thiol group ( ¬ SH), which bonds to a two-carbon acetyl group to produce the energy-rich thioester acetyl CoA. ENGAGE O O Is coenzyme A oxidized or reduced when an acetyl group CH3 C + HS CoA CH3 C S CoA is added? Acetyl group Coenzyme A Acetyl CoA (thioester)  18.3 Coenzymes in Metabolic Pathways 659 NH2 H O H O OH CH3 O O N N HS CH2 CH2 N C CH2 CH2 N C C C CH2 O P O P O CH2 N N O H CH3 O- O- H H Aminoethanethiol Pantothenic acid H H O OH - Phosphorylated ADP O P O O- Coenzyme A FIGURE 18.9 Coenzyme A is derived from a phosphorylated adenosine diphosphate (ADP) and pantothenic acid bonded by an amide bond to aminoethanethiol, which contains the ¬ SH reactive part of the molecule. Q What part of coenzyme A reacts with a two-carbon acetyl group? SAMPLE PROBLEM 18.3 Coenzymes TRY IT FIRST Describe the reactive part of each of the following coenzymes and the way each partici- pates in metabolic pathways: a. FAD b. NAD+ SOLUTION a. When two nitrogen atoms in the flavin accept 2H (2H + and 2 e- ), FAD is reduced to FADH2. The FAD coenzyme participates in oxidation reactions that produce a carbon– carbon double bond (C “ C). b. When a carbon atom in the nicotinamide accepts 2H (2H + and 2 e- ), NAD+ is reduced to NADH + H +. The NAD+ coenzyme participates in oxidation reactions that produce a carbon–oxygen double bond (C “ O). STUDY CHECK 18.3 Describe the reactive part of coenzyme A and the way it participates in metabolic pathways. ANSWER TEST The thiol group ( ¬ SH) in coenzyme A combines with an acetyl group to form acetyl Try Practice Problems 18.13 coenzyme A, which participates in the transfer of acetyl groups. to 18.18 PRACTICE PROBLEMS 18.3 Coenzymes in Metabolic Pathways LEARNING GOAL Describe the components and functions of the 18.16 Name the enzyme and coenzyme involved in the following coenzymes NAD + , FAD, and coenzyme A. reactions: a. transfer of phosphate b. decarboxylation 18.13 Identify one or more coenzymes with each of the following c. transfer of acetyl group components: a. pantothenic acid b. niacin c. ribitol 18.17 What coenzyme picks up hydrogen when a carbon–carbon double bond is formed? 18.14 What is the main function of coenzyme A? What is its functional group? 18.18 What coenzyme picks up hydrogen when a carbon–oxygen double bond is formed? 18.15 Give the abbreviation for each of the following coenzymes: a. reduced form of NAD+ b. oxidized form of FADH2 660 CHAPTER 18 Metabolic Pathways and ATP Production 18.4 Glycolysis: Oxidation of Glucose LEARNING GOAL Describe the conversion of glucose to pyruvate in glycolysis and the subsequent conversion of pyruvate to acetyl CoA or lactate. Brain The major source of energy for the body is the glucose produced when we digest the carbohydrates in our food, or from glycogen, a polysaccharide stored in the liver and skeletal muscle. Glucose in the bloodstream enters our cells where it undergoes degrada- tion in a pathway called glycolysis. Early organisms used glycolysis to release energy from simple nutrients long before there was any oxygen in Earth’s atmosphere. Glycolysis is an anaerobic process; no oxygen is required. In glycolysis, a six-carbon glucose molecule is broken down to two molecules of three- carbon pyruvate (see FIGURE 18.10). All the reactions in glycolysis take place in the cyto- plasm of the cell. In the first five reactions (1 to 5), called the energy-investing phase, energy from the hydrolysis of two ATP is used to form two three-carbon, energy-rich phosphate compounds. In the last five reactions (6 to 10), called the energy-generating phase, energy from the hydrolysis of the energy-rich phosphate compounds is used to synthesize four ATP. Glycolysis Energy-Investing Phase Glucose C6H12O6 Red blood cells Muscle ATP 1 Glucose is the main energy source for the brain, skeletal muscles, and red ADP Glucose-6-phosphate blood cells. 2 Phosphate Fructose-6-phosphate Carbon atom 3 CORE CHEMISTRY SKILL Fructose-1,6-bisphosphate Identifying the Compounds 4 in Glycolysis Dihydroxyacetone 5 phosphate Glyceraldehyde-3-phosphate Energy-Generating Phase 2 + 2NAD+ 6 2NADH + 2H+ ENGAGE 2 1,3-Bisphosphoglycerate In which steps of glycolysis is ADP 2 phosphorylated to become ATP? 7 2 2 3-Phosphoglycerate 8 2 2-Phosphoglycerate H2O 9 TEST 2 Phosphoenolpyruvate Try Practice Problems 18.19 2 to 18.22 10 2 2 Pyruvate FIGURE 18.10 In glycolysis, the six-carbon glucose molecule is degraded to yield two three- carbon pyruvate molecules. A net of two ATP is produced along with two NADH. Q Where in the glycolysis pathway is glucose cleaved to yield two three-carbon compounds?  18.4 Glycolysis: Oxidation of Glucose 661 Energy-Investing Reactions 1 to 5 CH2OH Reaction 1 Phosphorylation H O H In the initial reaction, a phosphate group from ATP is added to glucose to form glucose- H OH H 6-phosphate and ADP. HO OH O H OH Glucose P = P O- = PO32- ATP O- Hexokinase 1 ADP P OCH2 H O H H OH H HO OH H OH Glucose-6-phosphate Reaction 2 Isomerization Phosphoglucose 2 The glucose-6-phosphate, the aldose from reaction 1, undergoes isomerization to fructose- isomerase 6-phosphate, which is a ketose. P OCH2 O CH2OH H OH H OH OH H Fructose-6-phosphate ATP Reaction 3 Phosphorylation Phosphofructokinase 3 The hydrolysis of another ATP provides a second phosphate group, which converts fructose- ADP 6-phosphate to fructose-1,6-bisphosphate. The word bisphosphate is used to show that the P OCH2 O CH2O P two phosphate groups are on different carbons in fructose and not connected to each other. H OH H OH OH H Fructose-1,6-bisphosphate Reaction 4 Cleavage Aldolase 4 Fructose-1,6-bisphosphate is split into two three-carbon phosphate isomers: dihydroxyac- O etone phosphate and glyceraldehyde-3-phosphate. CH2O P C H C O H C OH CH2OH CH2O P Dihydroxyacetone Glyceraldehyde- phosphate 3-phosphate Reaction 5 Isomerization Triose 5 phosphate Because dihydroxyacetone phosphate is a ketone, it cannot undergo further oxidation. isomerase However, it undergoes isomerization to provide a second molecule of glyceraldehyde- O 3-phosphate, which can be oxidized. Now all six carbon atoms from glucose are contained in two identical triose phosphates. C H H C OH CH2O P Glyceraldehyde-3-phosphate 662 CHAPTER 18 Metabolic Pathways and ATP Production O Energy-Generating Reactions 6 to 10 C H In our discussion of glycolysis from this point, the two molecules of glyceraldehyde-3- phosphate produced in step 5 are undergoing the same reactions. For simplicity, we show H C OH the structures and reactions for only one three-carbon molecule for reactions 6 to 10. CH2O P Glyceraldehyde-3-phosphate Pi + NAD+ Glyceraldehyde- 6 Reaction 6 Oxidation and Phosphorylation 3-phosphate NADH dehydrogenase The aldehyde group of each glyceraldehyde-3-phosphate is oxidized to a carboxyl group, + H+ O while the coenzyme NAD+ is reduced to NADH and H +. A phosphate group (Pi) adds to each of the new carboxyl groups to form two molecules of the high-energy compound C O P 1,3-bisphosphoglycerate. H C OH CH2O P 1,3-Bisphosphoglycerate ADP Phosphoglycerate 7 Reaction 7 Phosphate Transfer kinase ATP A phosphate group from each 1,3-bisphosphoglycerate is transferred to two ADP molecules, O yielding two molecules of the high-energy compound ATP. At this point in glycolysis, two ATP are produced, which balance the two ATP consumed in reactions 1 and 3. C O- H C OH CH2O P 3-Phosphoglycerate Phosphoglycerate 8 Reaction 8 Isomerization mutase Two 3-phosphoglycerate molecules undergo isomerization, which moves the phosphate O group from carbon 3 to carbon 2, yielding two molecules of 2-phosphoglycerate. C O- H C O P CH2OH 2-Phosphoglycerate Enolase 9 Reaction 9 Dehydration H2O Each of the phosphoglycerate molecules undergoes dehydration (loss of water), producing O two molecules of phosphoenolpyruvate, a high-energy compound. C O- C O P CH2 Phosphoenolpyruvate ADP Pyruvate 10 Reaction 10 Phosphate Transfer kinase ATP In a second direct phosphorylation, phosphate groups from two phosphoenolpyruvate mol- O ecules are transferred to two ADP to form two pyruvate and two ATP. C O- C O CH3 Pyruvate  18.4 Glycolysis: Oxidation of Glucose 663 SAMPLE PROBLEM 18.4 Reactions in Glycolysis TRY IT FIRST Identify each of the following reactions as an isomerization, phosphorylation, dehydra- tion, or cleavage: a. A phosphate group is transferred to ADP to form ATP. b. 3-Phosphoglycerate is converted to 2-phosphoglycerate. c. Water is removed from 2-phosphoglycerate. SOLUTION a. The transfer of a phosphate group to ADP to form ATP is phosphorylation. b. The change in location of a phosphate group on a carbon chain is isomerization. c. The loss of water is dehydration. STUDY CHECK 18.4 Identify the reaction in which fructose-1,6-bisphosphate splits to form two three-carbon compounds as an isomerization, phosphorylation, dehydration, or cleavage. TEST ANSWER Try Practice Problems 18.23 The splitting of fructose-1,6-bisphosphate is cleavage. to 18.28 Summary of Glycolysis In the glycolysis pathway, a six-carbon glucose molecule is converted to two three-carbon pyruvate molecules. Initially, two ATP are required to form fructose-1,6-bisphosphate. In later reactions, phosphate transfers produce a total of four ATP. Overall, glycolysis yields two ATP and two NADH when a glucose molecule is converted to two pyruvate. O C6H12O6 + 2NAD+ + 2ADP + 2Pi 2CH3 C COO- + 2NADH + 2ATP + 4H+ + 2H2O Glucose Pyruvate Pathways for Pyruvate Stage 1 Polysaccharides The pyruvate produced from glucose can now enter pathways that continue to extract energy. The available pathway depends on whether there is sufficient oxygen in the cell. Under aerobic conditions, oxygen is available to convert pyruvate to acetyl coenzyme A (acetyl CoA). When oxygen levels are low, pyruvate is reduced to lactate (see FIGURE 18.11). Aerobic Conditions Stage 2 In glycolysis, two ATP were generated when one glucose molecule was converted to two Monosaccharides pyruvate. However, much more energy is obtained from glucose when oxygen levels are high in the cells. Under aerobic conditions, pyruvate moves from the cytoplasm into the mitochondria to be oxidized further. In a complex reaction, pyruvate is oxidized, and a carbon atom is removed from pyruvate as CO2. The coenzyme NAD+ is reduced during the oxidation. The resulting two-carbon acetyl compound is attached to CoA, producing acetyl 2ATP G Glucose NAD+ l CoA, an important intermediate in many metabolic pathways. y 2ADP NADH c O O o Pyruvate l - + dehydrogenase y CH3 C C O + HS CoA + NAD 4ADP s i Pyruvate s 2 Pyruvate 4ATP O Glucose obtained from the digestion CH3 C S CoA + CO2 + NADH of polysaccharides is degraded in Acetyl CoA glycolysis to pyruvate. 664 CHAPTER 18 Metabolic Pathways and ATP Production Glucose O O CH3 C C O- Pyruvate Anaerobic conditions Aerobic conditions Cytosol Mitochondria NADH + H+ NAD+ Skeletal muscle HS CoA NAD+ NADH OH O O CH3 CH C O- CH3 C S CoA + CO2 Lactate Acetyl CoA Citric acid cycle FIGURE 18.11 Pyruvate is converted to acetyl CoA under aerobic conditions and to lactate under anaerobic conditions. Q During vigorous exercise, why does lactate accumulate in the muscles? Anaerobic Conditions When we engage in strenuous exercise, the oxygen stored in our muscle cells is quickly depleted. Under anaerobic conditions, pyruvate remains in the cytoplasm where it is reduced to lactate. NAD+ is produced and is used to oxidize more glyceraldehyde-3-phosphate in the glycolysis pathway, which produces a small but needed amount of ATP. O O Lactate OH O After vigorous exercise, rapid dehydrogenase breathing helps to repay the oxygen CH3 C C O- + NADH + H+ CH3 C C O- + NAD+ debt. H Pyruvate Lactate (oxidized) (reduced) The accumulation of lactate causes the muscles to tire and become sore. After exer- cise, a person continues to breathe rapidly to repay the oxygen debt incurred during exercise. Most of the lactate is transported to the liver, where it is converted back into pyruvate. TEST OH Try Practice Problems 18.29 to 18.34 C6H12O6 + 2ADP + 2Pi 2CH3 CH COO- + 2ATP Glucose Lactate  18.5 The Citric Acid Cycle 665 PRACTICE PROBLEMS 18.4 Glycolysis: Oxidation of Glucose LEARNING GOAL Describe the conversion of glucose to pyruvate in 18.28 How many ATP or NADH are produced (or required) in each glycolysis and the subsequent conversion of pyruvate to acetyl CoA or of the following steps in glycolysis? lactate. a. 1,3-bisphosphoglycerate to 3-phosphoglycerate 18.19 What is the starting compound of glycolysis? b. fructose-6-phosphate to fructose-1,6-bisphosphate c. phosphoenolpyruvate to pyruvate 18.20 What is the three-carbon end product of glycolysis? 18.29 What condition is needed in the cell to convert pyruvate to 18.21 How is ATP used in the initial steps of glycolysis? acetyl CoA? 18.22 How many ATP are used in the initial steps of glycolysis? 18.30 What coenzymes are needed for the oxidation of pyruvate to 18.23 How does phosphorylation account for the production of ATP acetyl CoA? in glycolysis? 18.31 Write the overall equation for the conversion of pyruvate to 18.24 Why are there two ATP formed for one molecule of glucose? acetyl CoA. 18.25 What three-carbon intermediates are obtained when fructose- 18.32 What is the product of pyruvate under anaerobic conditions? 1,6-bisphosphate splits? 18.26 Why does one of the three-carbon intermediates undergo 18.33 How does the formation of lactate permit glycolysis to con- isomerization? tinue under anaerobic conditions? 18.27 How many ATP or NADH are produced (or required) in each 18.34 After running a marathon, a runner has muscle pain and of the following steps in glycolysis? cramping. What might have occurred in the muscle cells to a. glucose to glucose-6-phosphate cause this? b. glyceraldehyde-3-phosphate to 1,3-bisphosphoglycerate c. glucose to pyruvate 18.5 The Citric Acid Cycle LEARNING GOAL Describe the oxidation of acetyl CoA in the citric acid cycle. The citric acid cycle is a series of reactions that connects the intermediate acetyl CoA from the catabolic pathways in stage 2 with electron transport and the synthesis of ATP in stage 3. As a central pathway in metabolism, the citric acid cycle uses the two-carbon ace- tyl group of acetyl CoA to produce CO2 and the reduced coenzymes NADH and FADH2. The citric acid cycle is named for the six-carbon citrate ion from citric acid (C6H8O7), a tricarboxylic acid, which forms in the first reaction. The citric acid cycle is also known as the tricarboxylic acid (TCA) cycle or the Krebs cycle, named for H. A. Krebs, who received a Nobel Prize in 1953 for its discovery. Overview of the Citric Acid Cycle Six carbons move through the eight reactions of the citric acid cycle, with each cycle pro- ducing oxaloacetate (four carbons) and 2CO2 (see FIGURE 18.12). Each turn of the cycle Acetyl CoA Citrate Oxaloacetate FIGURE 18.12 In the citric acid CO2 cycle, two carbon atoms are removed as CO2 from six-carbon citrate to give four-carbon succinyl CoA, a-Ketoglutarate which is converted to four-carbon Succinyl CoA oxaloacetate. Q How many carbon atoms are removed in one turn of the CO2 citric acid cycle? 666 CHAPTER 18 Metabolic Pathways and ATP Production includes four oxidation reactions, producing the reduced coenzymes NADH or FADH2 from the energy released during the reactions. One GTP (converted to ATP in the cell) is also produced during the citric acid cycle. FIGURE 18.13 shows the complete citric acid cycle. O CH3 C CoA Acetyl CoA COO- H2O NADH C O + H+ HS CoA CH2 COO- NAD+ 1 COO- Citrate CH2 COO- Oxaloacetate synthase 8 HO C COO- HO C H Malate dehydrogenase CH2 CH2 Aconitase - H2O COO COO- 2 Citrate COO- 7 Malate Fumarase C H COO- H C CH2 COO- H C COO- Fumarate Citric Acid Cycle HO C H FADH2 Succinate COO- 6 dehydrogenase Isocitrate FAD Isocitrate COO- dehydrogenase 3 CH2 NAD+ CH2 COO- HS CoA COO- Succinyl CoA a-Ketoglutarate CH2 NADH Succinate* synthase dehydrogenase + H+ COO- CH2 ADP 5 CO2 HS CoA GTP CH2 C O 4 CO2 CH2 COO- ATP GDP + Pi a-Ketoglutarate C O NADH NAD+ S CoA + H+ Succinyl CoA *Succinate is a symmetrical compound. FIGURE 18.13 Each turn of the citric acid cycle regenerates oxaloacetate and produces 2 CO2, 1 GTP, 3 NADH, and 1 FADH2. Q How many reactions in the citric acid cycle produce a reduced coenzyme?  18.5 The Citric Acid Cycle 667 Reaction 1 Formation of Citrate CORE CHEMISTRY SKILL In the first reaction of the citric acid cycle, the acetyl group (2C) from acetyl CoA bonds Describing the Reactions in the with oxaloacetate (4C) to yield citrate (6C). Citric Acid Cycle Reaction 2 Isomerization The citrate produced in reaction 1 contains a tertiary alcohol group that cannot be oxidized further. In reaction 2, citrate undergoes isomerization to yield isocitrate, which provides a secondary alcohol group that can be oxidized in the next reaction. Reaction 3 Oxidation and Decarboxylation In reaction 3, an oxidation and a decarboxylation occur together. The secondary alcohol group in isocitrate is oxidized to a ketone. A decarboxylation converts a carboxylate group ( ¬ COO- ) to a CO2 molecule producing a@ketoglutarate, which has five carbon atoms. The oxidation reaction also produces hydrogen ions and electrons that reduce NAD+ to NADH and H +. This reduced coenzyme NADH will be important in the energy-releasing reactions in electron transport. Reaction 4 Oxidation and Decarboxylation In reaction 4, a@ketoglutarate undergoes decarboxylation and oxidation to produce a four- carbon group that combines with CoA to form succinyl CoA (4C). As in reaction 3, this oxidation reaction also produces hydrogen ions and electrons that reduce NAD+ to NADH and H +. This forms another reduced NADH that will be important in the energy-releasing reactions in electron transport. Reaction 5 Hydrolysis In reaction 5, succinyl CoA undergoes hydrolysis to give succinate and CoA. The energy released is used to add a phosphate group (Pi) to GDP (guanosine diphosphate), which yields GTP (guanosine triphosphate), a high-energy compound similar to ATP. Eventually, the GTP undergoes hydrolysis with a release of energy that is used to add a phosphate group to ADP to form ATP. This is the only time in the citric acid cycle that ATP is produced by a direct transfer of phosphate. Reaction 6 Oxidation In reaction 6, hydrogen is removed from each of two carbon atoms in succinate, which pro- duces fumarate, a compound with a trans double bond. The formation of a carbon–carbon double bond (C “ C) produces 2H that are used to reduce the coenzyme FAD to FADH2. This reduced coenzyme FADH2 is important in the energy-releasing reactions in electron transport. Reaction 7 Hydration In reaction 7, a hydration adds water to the double bond of fumarate to yield malate, which is a secondary alcohol. Reaction 8 Oxidation ENGAGE In reaction 8, the last step of the citric acid cycle, the secondary alcohol group in malate is oxidized to a carbonyl group (C “ O), yielding oxaloacetate. For the third time in the citric Which steps of the citric acid cycle involve an oxidation without acid cycle, an oxidation provides hydrogen ions and electrons for the reduction of NAD+ a decarboxylation? to NADH and H +. Summary of Products from the Citric Acid Cycle We have seen that the citric acid cycle begins when a two-carbon acetyl group from ace- tyl CoA combines with a four-carbon oxaloacetate to form a six-carbon citrate. Through 668 CHAPTER 18 Metabolic Pathways and ATP Production Products from One Turn of the oxidation, reduction, and decarboxylation, two carbon atoms are removed from citrate Citric Acid Cycle to yield two CO2 and a four-carbon compound that undergoes reactions to regenerate 2 CO2 oxaloacetate. In the four oxidation reactions of one turn of the citric acid cycle, three NAD+ are 3 NADH and 3H + reduced to three NADH and one FAD is reduced to one FADH2. One GDP is converted to 1 FADH2 GTP, which is used to convert one ADP to ATP. We can write an overall chemical equation 1 GTP (1 ATP) for one complete turn of the citric acid cycle as follows: 1 HS ¬ CoA Acetyl CoA + 3NAD+ + FAD + GDP + Pi + 2H2O HS CoA + 3NADH + 3H+ + FADH2 + GTP + 2CO2 SAMPLE PROBLEM 18.5 Citric Acid Cycle TRY IT FIRST When one acetyl CoA completes the citric acid cycle, how many of each of the following is produced? a. NADH b. ketone group c. CO2 SOLUTION a. One turn of the citric acid cycle produces three molecules of NADH. b. Two ketone groups form when the secondary alcohol groups in isocitrate and malate are oxidized by NAD+. c. Two molecules of CO2 are produced by the decarboxylation of isocitrate and a@ketoglutarate. STUDY CHECK 18.5 What compound is a substrate in the first reaction of the citric acid cycle and a product in the last reaction? TEST ANSWER Try Practice Problems 18.35 to 18.42 oxaloacetate PRACTICE PROBLEMS 18.5 The Citric Acid Cycle LEARNING GOAL Describe the oxidation of acetyl CoA in the citric 18.40 What is the total NADH and total FADH2 produced in one acid cycle. turn of the citric acid cycle? 18.35 What are the products from one turn of the citric acid cycle? 18.41 Refer to the diagram of the citric acid cycle in Figure 18.13 to answer each of the following: 18.36 Write an equation to show how oxaloacetate is converted to a. What are the six-carbon compounds? citrate. b. How is the number of carbon atoms decreased? 18.37 Identify the reaction(s) of the citric acid cycle that involve(s) c. What is the five-carbon compound? a. oxidation and decarboxylation d. What are the decarboxylation reactions? b. dehydration 18.42 Refer to the diagram of the citric acid cycle in Figure 18.13 to c. reduction of NAD+ answer each of the following: 18.38 Identify the reaction(s) of the citric acid cycle that involve(s) a. What is the yield of CO2 molecules? a. reduction of FAD b. What are the four-carbon compounds? b. direct phosphate transfer c. What is the yield of GTP molecules? c. hydration d. In which reactions are secondary alcohols oxidized? 18.39 Which reaction(s) of the citric acid cycle involve(s) the production of a carbon–carbon double bond?  18.6 Electron Transport and Oxidative Phosphorylation 669 18.6 Electron Transport and Oxidative Phosphorylation LEARNING GOAL Describe electron transport and the process of oxidative phosphorylation; calculate the ATP from the complete oxidation of glucose. At this point in stage 3 of catabolism, for each glucose molecule that completes glycolysis, the oxidation of two pyruvate, and the citric acid cycle, four ATP along with 10 NADH and two FADH2 are produced. From One Glucose ATP Reduced Coenzymes Glycolysis 2 2 NADH Oxidation of 2 Pyruvate 2 NADH Citric Acid Cycle with 2 Acetyl CoA 2 6 NADH 2 FADH2 Total for One Glucose 4 10 NADH 2 FADH2 Electron Transport In electron transport, hydrogen ions and electrons from NADH and FADH2 are passed from one electron carrier to the next until they combine with oxygen to form H2O. The energy released during electron transport is used to synthesize ATP from ADP and Pi, a process called oxidative phosphorylation. As long as oxygen is available for the mitochondria in the cell, electron transport and oxidative phosphorylation function to synthesize most of the ATP produced in the cell. A mitochondrion consists of an outer membrane, an intermembrane space, and an inner membrane that surrounds the matrix. Along the highly folded inner membrane are the enzymes and electron carriers required for electron transport. Embedded within these membranes are four distinct protein complexes, labeled I, II, III, and IV. Two electron carri- ers, coenzyme Q and cytochrome c, are not firmly attached to the membrane. They function as mobile carriers shuttling electrons between the protein complexes that are bound to the inner membrane (see FIGURE 18.14). Outer Mitochondrial Membrane + H+ H+ H+ + H+ H H+ H+ H H+ H + H + + H H + Intermembrane H+ H+ H+ H+ H+ + H+ H+ H+ H H+ H + H+ channel Space H+ H+ H+ H+ H+ H+ Cyt c Inner e- III e- Mitochondrial e- CoQ e- e- H+ Membrane IV I H+ H+ H+ II e- NADH NAD+ FADH2 FAD 2H+ + 1O 2 2 H2O ATP synthase Mitochondrial Matrix H+ ADP + Pi ATP FIGURE 18.14 In electron transport, coenzymes NADH and FADH2 are oxidized in enzyme complexes, providing electrons and hydrogen ions for ATP synthesis. Q What pathway is the major source of NADH for electron transport? 670 CHAPTER 18 Metabolic Pathways and ATP Production ENGAGE Complex I Which electron transport