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Chapter 05 Cell Respiration and Metabolism Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Introduction Metabolism a. All of the reactions in the body that require energy transfer. Can be divided into: 1) Anabolism: requires the input of energy to synthesize large molecules 2) Catabolism: releases energy by breaking bonds between large molecules to form smaller molecules Catabolism Drives Anabolism The catabolic reactions that break down glucose, fatty acids, and amino acids serve as energy sources for the anabolism of ATP. Involves many oxidation-reduction reactions. Complete catabolism of glucose requires oxygen as the final electron acceptor. 1) Called aerobic cellular respiration. 2) Breaking down glucose requires many enzymatically catalyzed steps, the first of which are anaerobic. I. Glycolysis and the Lactic Acid Pathway Aerobic respiration of glucose Occurs in three steps: 1) Glycolysis – occurs in the cytoplasm; anaerobic 2) Citric acid (Krebs) cycle – occurs in the matrix of the mitochondria; aerobic 3) Electron transport – occurs on cristae of mitochondria inner membrane; aerobic C6H12O6 + O2 6 CO2 + 6 H2O + ATP Overview of Energy Metabolism Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Glycogen in liver Glucose from digestive tract Glucose from liver Capillary Glucose in blood plasma Interstitial fluid Plasma membrane Glucose in cell cytoplasm Glycolysis Pyruvic acid Anaerobic Cytoplasm Lactic acid Metabolism in skeletal muscle into mitochondrion Citric acid cycle Electron transport Aerobic CO2 + H2O Respiration Mitochondrion Glycolysis 1. First step in catabolism of glucose 2. Occurs in the cytoplasm of the cell 3. Glucose phosphorylated twice (using 2 ATP) and converted into fructose 1,6-biphosphate 4. F 1,6-biP is split into two 3-Phosphoglyceraldehyde (3carbon molecule) 5. Each 3-carbon molecule proceed through similar reactions 3-P glyceraldehyde is phosphorylated to become 1,3-biphosphoglyceric acid. Two H+ is used to reduce NAD NADH Glycolysis 6. A phosphate is released from 1,3-BiP glyceric acid to form 3-Phosphoglyceric acid Pi + ADP ATP 7. 3-P glyceric acid isomerizes to 2-Phosphoglyceric acid 8. 2-P glyceric acid becomes Phosphoenolpyruvic acid 9. A phosphate is released from phosphoenolpyruvic acid to form Pyruvic acid Pi + ADP ATP Glycolysis Pathway Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Glucose (C6H12O6) ATP 1 ADP Glucose 6-phosphate 2 Fructose 6-phosphate ATP 3 ADP Fructose 1,6-biphosphate 4 3–Phosphoglyceraldehyde Dihydroxyacetone phosphate 3–Phosphoglyceraldehyde Pi Pi NADH 5 NADH 2H 5 2H NAD NAD 1,3–Biphosphoglyceric acid ATP 1,3–Biphosphoglyceric acid ATP 6 ADP 6 ADP 3–Phosphoglyceric acid 3–Phosphoglyceric acid 7 2–Phosphoglyceric acid 7 2–Phosphoglyceric acid 8 Phosphoenolpyruvic acid ATP 8 Phosphoenolpyruvic acid ATP 9 ADP 9 ADP Pyruvic acid (C3H4O3) Pyruvic acid (C3H4O3) *Net Yield in Glycolysis One Glucose (6-carbon molecule) two Pyruvic acid (3-carbon molecule) C6H12O6 2 molecules C3H4O3 + 4H+ 4 hydrogen ions used to reduce 2 molecules of NAD. 2NAD + 4H+ 2NADH + 2H+ *Net Energy Gain in Glycolysis Glycolysis is exergonic, so some energy is produced and used to drive the reaction ADP + Pi ATP 4 ATPs are generated. Glucose requires activation at the beginning from 2 ATP molecules. Phosphorylation of glucose prevents it from diffusing back through the plasma membrane Net gain in glycolysis = 2 ATP Use and Expenditure of Energy in Glycolysis Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 1 ATP ADP ATP 2 NADH ADP 2 NAD Free energy Glucose 2 2 ATP 2 ADP + 2 Pi 3 2 ATP 2 ADP + 2 Pi Pyruvic acid *Reactants and Products of Glycolysis Glucose + 2 NAD + 2 ADP + 2 Pi 2 Pyruvic acid + 2 NADH + 2 ATP Lactic Acid Pathway When there is no oxygen to complete the breakdown of glucose, NADH has to give its electrons to pyruvic acid. This results in the reformation of NAD and the conversion of pyruvic acid to lactic acid. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. NADH + H+ H H O C C N AD O C H OH H Pyruvic acid LDH H OH C C O C OH H H Lactic acid Lactic Acid Pathway Also called anaerobic metabolism or lactic acid fermentation (Similar to how yeast ferments glucose into alcohol) Still yields a net gain of 2 ATP a. Muscle cells can survive for awhile without oxygen by using lactic acid fermentation. b. RBCs can only use lactic acid fermentation because they lack mitochondria. II. Aerobic Respiration Introduction 1. Equation: C6H12O6 + O2 6 CO2 + 6 H2O 2. Similar to combustion except energy is released in small, enzymatically controlled steps, not in large amounts of heat 3. Begins with glycolysis, which produces: a. 2 molecules pyruvic acid, 2 NADH, and 2 ATP b. The pyruvic acid will be used in a metabolic pathway called the citric acid cycle, and the NADH will be oxidized to make ATP. The Fate of Pyruvic Acid Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. H H NAD H C H C O H + S H CoA C HO NADH + H+ C H C O S CoA O Pyruvic acid Coenzyme A Acetyl coenzyme A + CO2 The fate of pyruvic acid Pyruvic acid leaves the cytoplasm and enters the interior matrix of the mitochondria. Carbon dioxide is removed to form acetic acid. Acetic acid is combined with coenzyme A to form acetyl CoA. 2 Pyruvic acid + Coenzyme A 2 Acetyl CoA + 2 NADH + 2 CO2 Citric Acid Cycle Also called the citric acid cycle or the TCA (tricarboxylic acid) cycle Acetyl CoA combines with oxaloacetic acid to form citric acid. Citric acid starts the citric acid cycle. It is a cycle because citric acid moves through a series of reactions to produce oxaloacetic acid again. Simplified Diagram of the Citric Acid Cycle Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Glycolysis C3 Pyruvic acid CYTOPLASM NAD CO2 Mitochondrial matrix CoA NADH + H+ C2 Acetyl CoA Oxaloacetic acid C 4 CO2 Citric acid cycle α-Ketoglutaric acid C5 CO2 C6 Citric acid 3 NADH + H+ 1 FADH2 1 ATP Important Events in the Citric Acid Cycle One guanosine triphosphate (GTP) is produced, which donates a phosphate group to ADP to form ATP. Three molecules NAD are reduced to NADH. One molecule FAD is reduced to FADH2. These events occur for each acetic acid, so it happens twice for each glucose molecule. The Complete Citric Acid Cycle Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. H H O C C COOH HS – CoA S CoA + H2 O H COOH Acetyl CoA (C2) H C O C H H2 O H C H HO C COOH H C H 1 H2 O COOH 2 H COOH Citric acid (C6) COOH C H C COOH C H COOH Oxaloacetic acid (C4) H2 O COOH 3 cis-Aconitic acid (C6) 8 COOH NADH H C OH H C H H C H H C COOH H C OH + H+ COOH 2H Isocitric acid (C6) NAD COOH NADH + H+ 4 2H Malic acid (C4) NAD 7 H2 O H COOH C C HOOC FADH2 H 2H Fumaric acid (C4) CO2 FAD 6 ATP COOH H C H H C H COOH ADP NADH GDP NAD COOH C H C H C O + H+ 2H GTP H CO2 H COOH α-Ketoglutaric acid (C5) Succinic acid (C4) 5 H2 O Products of the Citric Acid Cycle For each Acetyl CoA: 3 NADH, 1 FADH2,1 ATP, 2 CO2 Since there are 2 Acetyl CoA that contribute to the citric acid cycle... Net yield 6 NADH, 2 FADH2, 2 ATP, 4 CO2 Electron Transport & Oxidative Phosphorylation On the inner membrane (cristae) of the mitochondria are molecules that serve as electron transporters. a. Include FMN, coenzyme Q, and several cytochromes b. These accept electrons from NADH and FADH2. The hydrogens are not transported with the electrons. c. Oxidized FAD and NAD are reused. Electron Transport Chain a. Electron transport molecules pass the electrons down a chain, with each being reduced and then oxidized. b. This is an exergonic reaction, and the c. Energy produced is used to combine an ADP to a phosphate ion to make ATP. An oxygen molecule is the last electron acceptor in the chain this process is called oxidative phosphorylation. d. Process is not 100%; difference is released as heat Electron Transport Chain Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. NADH FMN NAD FMNH2 2 H+ Electron energy FADH2 FAD 2 e– Oxidized Fe2+ CoQ Cytochrome b Reduced Fe3+ 2 e– Fe2+ Cytochrome c1 and c Cytochrome a Fe3+ Fe2+ Fe3+ 2 e– Fe2+ H2O Cytochrome a3 Fe3+ 2 e– 2 H+ 1 + – O2 2 Coupling of electron transport to ATP production Chemiosmotic Theory a. Electron transport fuels proton pumps, which pump H+ from the mitochondrial matrix to the space between the inner and outer membranes. b. This sets up a huge concentration gradient of H+ between the membranes. c. H+ can only move through the inner membrane through structures called respiratory assemblies d. Movement of H+ across the membrane provides energy to the enzyme ATP synthase, which converts ADP to ATP. Oxidative Phosphorylation Figure 5.9 The steps of oxidative phosphorylation Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Outer mitochondrial membrane Inner mitochondrial membrane 2 H+ Intermembrane space Third pump Second pump H+ H+ 1 2 H+ ATP synthase H2O First pump 4H+ e– 1 4 H+ 3 2 H + 1 /2 O2 ADP + Pi H+ ATP NAD+ Matrix NADH The Function of Oxygen Act as final electron acceptor. O2 oxididizes cytochrome a3, the last molecule in the electron transport chain, by taking away its electrons and forming water Without a final acceptor, the whole process would come to a halt. The citric acid cycle and electron transport require oxygen to continue. Water is formed in the following reaction: O2 + 4 e- + 4 H+ 2 H2O ATP Balance Sheet 1. Direct (substrate-level) phosphorylation in glycolysis and the citric acid cycle yields 4 ATP. 2. Oxidative phosphorylation in electron transport yields varying amounts of ATP, depending on the cell and conditions. a. Theoretically, each NADH yields 3 ATP and each FADH2 yields 2 ATP. b. In actuality, each NADH yields 2.5 ATP and each FADH2 yields 1.5 ATP This difference accounts for energy needed to move ATP out of the mitochondria ATP yield a. From glycolysis 2 NADH (which may be converted to 2 FADH2 when inside mitochondria) b. From pyruvic acid 2 NADH c. From citric acid cycle 6 NADH and 2 FADH2 If NADH remains NADH: If NADH becomes FADH2: G: 2 NADH x 2.5 = 5 ATP P: 2 NADH x 2.5 = 5 ATP C: 6 NADH x 2.5 = 15 ATP C: 2 FADH2 x 1.5 = 3 ATP G: 2 ATP C: 2 ATP G: 2 FADH2 x 1.5 = 3 ATP P: 2 NADH x 2.5 = 5 ATP C: 6 NADH x 2.5 = 15 ATP C: 2 FADH2 x 1.5 = 3 ATP G: 2 ATP C: 2 ATP Total = 32 ATP Total = 30 ATP Detailed Accounting III. Interconversion of Glucose, Lactic Acid, and Glycogen Glycogenesis and Glycogenolysis Glycogenesis a. Cells can’t store much glucose because it will pull water into the cell via osmosis. b. Glucose is stored as a larger molecule called glycogen in the liver, skeletal muscles, and cardiac muscles. c. Glycogen is formed from glucose via glycogenesis. 1) Glucose is phosphorylated, then isomerized to Glucose 1-phosphate 2) Glycogen synthase removes the phosphate and joins glucose together Glycogenesis and Glycogenolysis Glycogenolysis a. The process of removing glucose molecules from glycogen to be used by the body. Glycogen phosphorylase adds Pi group to glucose to form glucose 1-phosphate b. G1P is isomerized into Glucose 6-phosphate c. G6P can now enter glycolysis d. In the liver, glucose 6-phosphatase can remove phosphate from G6P to yield Glucose, which is now free to enter the circulation. Glycogenesis and Glycogenolysis Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. GLYCOGEN Pi Pi 1 2 Glucose 1-phosphate Pi Glucose (blood) ADP ATP Glucose 6-phosphate Liver only Many tissues Fructose 6-phosphate GLYCOLYSIS Glucose (blood) The Cori Cycle 1. During exercise, skeletal muscles rapidly utilize glucose and produce a high amount of lactic acid. 2. Some lactic acid is converted to CO2 and H2O 3. Excess lactic acid is carried in the blood to the liver. 4. Within the liver, the enzyme lactic acid dehydrogenase converts lactic acid to pyruvic acid and NADH. The Cori Cycle 5. Pyruvic acid is then converted to glucose 6phosphate. a. This can be used to make glycogen or glucose b. Pyruvic acid Glucose = gluconeogenesis (making “new” glucose from noncarbohydrate molecules) c. Glucose is carried in the blood to the muscle cells, which completes the Cori Cycle. The Cori Cycle Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Skeletal muscles Liver Glycogen Glycogen Exercise 1 Rest 9 Blood Glucose 6-phosphate Glucose 6-phosphate Glucose 8 7 6 2 Pyruvic acid Pyruvic acid 5 3 Lactic acid Blood 4 Lactic acid Common Metabolic Process Terms IV. Metabolism of Lipids and Proteins Introduction Lipids and proteins can also be used for energy via the same pathways used for the metabolism of pyruvic acid. When more food energy is taken into the body than is needed to meet energy demands, we can’t store ATP for later. Instead, glucose is converted into glycogen and fat, and ATP production is inhibited Conversion of glucose into glycogen and fat Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Glycogen Glucose 1-phosphate Glucose Glucose 6-phosphate Fructose 6-phosphate Fructose 1,6-biphosphate Glycerol Fat 3-Phosphoglyceraldehyde Pyruvic acid Fatty acids Acetyl CoA C6 C4 Oxaloacetic acid Citric acid Citric acid cycle C5 -Ketoglutaric acid Lipid Metabolism As ATP levels rise after an energy-rich meal, production of ATP is inhibited: a. Glucose doesn’t complete glycolysis to form pyruvic acid, and the acetyl CoA already formed is joined together to produce a variety of lipids, including cholesterol, ketone bodies, and fatty acids. b. Fatty acids combine with glycerol to form triglycerides in the adipose tissue and liver = lipogenesis. Acetyl CoA Lipids Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Bile acids Steroids Cholesterol Ketone bodies Acetyl CoA Citric acid (Krebs cycle) Fatty acids Triacylglycerol (triglyceride) Phospholipids CO2 White Adipose Tissue (White Fat) a. Fat stored in adipose tissue as triglycerides b. Great way to store energy: 1 gram fat = 9 kcal energy. 1) In a nonobese 155-pound man, 80-85% of his stored energy is in fat. (140,000 calories) c. Lipolysis: breaking triglycerides down into fatty acids and glycerol using the enzyme lipase. 1) Fatty acids can then enter the blood as blood-borne energy carriers and be used for energy elsewhere. 2) Glycerol is taken up by the liver and converted to glucose through gluconeogenesis β-oxidation of Fat Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Fatty acid β H H C C H H O C OH CoA 1 ATP AMP + PPi Fatty acid H H O C C C H H CoA FAD 2 FADH2 H H O C C C Fatty acid 1.5 ATP CoA H H2O 3 CoA HO H O C C C H H Fatty acid Fatty acid now two carbons shorter CoA NAD 4 NADH O H O C C C Fatty acid 5 2.5 ATP + H+ CoA Acetyl CoA Citric acid cycle 10 ATP Fatty Acids as an Energy Source β-oxidation: Enzymes remove acetic acid molecules from fatty acids to form acetyl CoA. a) For every 2 carbons from the fatty acid chain 1 Acetyl CoA, 1 NADH, 1 FADH2 is formed. b) Each acetyl CoA that enters the Citric acid cycle will yield 10 ATP A 16-carbon fatty acid: 8 Acetyl CoA = 80 ATP 7 NADH x 2.5 = 17.5 ATP 7 FADH2 x 1.5 = 10.5 ATP Total = 108 ATP Brown Adipose Tissue (Brown Fat) a. Stored in different cells b. Involved in thermogenesis (heat production), especially in newborns c. Adults also have some brown fat that contributes to calories and heat production d. Sympathetic release of norepinephrine causes brown fat to form an uncoupling protein called UCPI; H+ leaks out of inner mitochondrial membrane, less ATP is formed, which leads to use of fatty acids for more heat generation Ketone Bodies When the rate of lipolysis exceeds the rate of fatty acid utilization (as in dieting, starvation, or diabetes), the concentration of fatty acids in the blood increases. Liver cells convert the fatty acids into acetyl CoA Two acetyl CoA combine to form acetoacetic acid and β-hydroxybutyric acid Along with acetone these form ketone bodies. These are water-soluble molecules that circulate in the blood. Build-up in the blood can cause ketosis Amino Acid Metabolism 1. Proteins provide nitrogen for the body 2. Amino acids from dietary proteins are needed to replace proteins in the body. 3. If more amino acids are consumed than are needed, the excess amino acids can be used for energy or converted into carbohydrates or fat. 4. Our bodies can make 12 of the 20 amino acids from other molecules. Eight of them (9 in children) must come from the diet and are called essential amino acids. Essential Amino Acids Transamination a. A reaction which transfer the amine group (NH2) from one AA to form another AA b. Pyruvic acid and several citric acid cycle intermediates (called keto acids) can be converted to amino acids by adding an amine group. 1) Requires vitamin B6 as a coenzyme 2) Each transamination requires a specific enzyme Transamination Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. OH O HO C O O OH C O OH C C H H N C H C O + H H C H H C H C H C H C HO + H C H H C H C H H C H C HO O C O Glutamic acid OH N H O C HO O AST HO α-Ketoglutaric acid Oxaloacetic acid O OH C O O O OH C Aspartic acid O OH C C H H N C H H C O C H + H C H H C H H H ALT C O H C H H C H C HO Glutamic acid + N C H H C H H H C HO O Pyruvic acid O -Ketoglutaric acid Alanine Oxidative Deamination If there are more amino acids than needed, the amine group from glutamic acid can be stripped and excreted as urea in the urine. Oxidative deamination sometimes forms pyruvic acid or another citric acid cycle intermediates. These can be used to make energy or converted to glucose or fat. The formation of glucose from amino acids is called gluconeogenesis and occurs in the Cori cycle. Oxidative Deamination (x2) + H2O Amino Acids as Energy Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Alanine, cysteine, glycine, serine, threonine, tryptophan NH3 Pyruvic acid Urea Leucine, tryptophan, isoleucine NH3 Acetyl CoA Urea Asparagine, aspartate Arginine, glutamate, glutamine, histidine, proline Citric acid Urea NH3 Oxaloacetic acid –Ketoglutaric acid NH3 Citric acid cycle Phenylalanine, tyrosine Urea NH3 Isoleucine, methionine, valine Fumaric acid Succinic acid NH3 Urea Urea Uses of different energy sources Glucose and ketone bodies come from the liver Fatty acids come from adipose tissue Lactic acid and amino acids come from muscle Different Energy Sources Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Glycogen Glucose Phosphoglyceraldehyde Glycerol Triacylglycerol (triglyceride) Lactic acid Pyruvic acid Acetyl CoA Fatty acids Amino acids Protein Urea Ketone bodies C4 Citric acid cycle C5 C6 Relative importance of different energy sources to different organs