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Chapter 05 Lecture Outline See separate PowerPoint slides for all figures and tables pre-inserted into PowerPoint without notes. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. I. Glycolysis and the Lactic Acid Pathway A. Introduction 1. 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 down large molecules into small molecules 2. Catabolism Drives Anabolism a. The catabolic reactions that break down glucose, fatty acids, and amino acids serve as energy sources for the anabolism of ATP. b. Involves many oxidation-reduction reactions. c. 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. 3. Aerobic respiration of glucose a. 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 b. 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 B. Glycolysis 1. First step in catabolism of glucose 2. Occurs in the cytoplasm of the cell 3. Glucose is split into two pyruvic acid molecules a. 6-carbon sugar 2 molecules of 3-carbon pyruvic acid b. C6H12O6 2 molecules C3H4O3 4. Note loss of 4 hydrogen ions. These were used to reduce 2 molecules of NAD. a. 2NAD + 4H+ 2NADH + H+ (2NADH) 5. Net Energy Gain in Glycolysis a. Glycolysis is exergonic, so some energy is produced and used to drive the reaction ADP + Pi ATP b. 4 ATP are generated. c. Glucose requires activation at the beginning provided by 2 Pi stripped from 2 ATP molecules. d. This phosphorylates the glucose so that it can not diffuse back through the plasma membrane e. 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 6. Reactants and Products of Glycolysis Glucose + 2 NAD + 2 ADP + 2 Pi 2 pyruvic acid + 2 NADH + 2 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) C. Lactic Acid Pathway 1. 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, cont 2. Also called anaerobic metabolism or lactic acid fermentation (Similar to how yeast ferments glucose into alcohol) 3. 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 A. 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. 4. The fate of pyruvic acid a. Pyruvic acid leaves the cytoplasm and enters the interior matrix of the mitochondria. b. Carbon dioxide is removed to form acetic acid. c. Acetic acid is combined with coenzyme A to form acetyl CoA. d. 1 glucose 2 molecules acetyl CoA + 2 CO2 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 B. Citric Acid Cycle 1. Also called the citric acid cycle or the TCA (tricarboxylic acid) cycle 2. Acetyl CoA combines with oxaloacetic acid to form citric acid. 3. Citric acid starts the citric acid cycle. a. It is a cycle because citric acid moves through a series of reactions to produce oxaloacetic acid again. 4. Important Events in the Citric Acid Cycle a. One guanosine triphosphate (GTP) is produced, which donates a phosphate group to ADP to form ATP. b. Three molecules NAD are reduced to NADH. c. One molecule FAD is reduced to FADH2. d. These events occur for each acetic acid, so it happens twice for each glucose molecule. 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 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 5. Products of the Citric Acid Cycle For each glucose: a. 6 NADH b. 2 FADH2 c. 2 ATP d. 4 CO2 C. Electron Transport & Oxidative Phosphorylation 1. In the folds or 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. 2. 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 energy produced is used to make ATP from ADP. 1) ADP is phosphorylated. 2) This process is called oxidative phosphorylation. c. 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 D. Coupling of electron transport to ATP production 1. 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 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 2. The Function of Oxygen a. Final electron acceptor. Without a final acceptor, the whole process would come to a halt. b. The citric acid cycle and electron transport require oxygen to continue. c. Water is formed in the following reaction: O2 + 4 e- + 4 H+ 2 H2O E. ATP Balance Sheet 1. Direct (substrate-level) phosphorylation in glycolysis and the citric acidcycle yields 4 ATP. a. These numbers are constant. 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. Theoretical ATP yield is 36-38 per glucose. 3. Actual ATP yield a. NADH yields 2.5 ATP and FADH2 yields 1.5 ATP b. Energy is needed to move the ATP out of the mitochondria into the cell cytoplasm c. One glucose will actually yield 30-32 ATP Detailed Accounting III. Interconversion of Glucose, Lactic Acid, and Glycogen A. Glycogenesis and Glycogenolysis 1. 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 2) Glycogen synthase removes the phosphate and joins glucose together 2. Glycogenolysis a. When the cell needs glucose, it breaks glycogen down again. b. Produces glucose 1-phosphate (see Fig 5.10) c. Glycogen phosphorylase is the catalyst 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) d. Glycogenolysis in the Liver 1) Glucose from glycogen is in the form glucose 1phosphate, so cannot leave muscle or heart cells. 2) The liver has an enzyme called glucose 6phosphatase that removes the phosphate so glucose can reenter the bloodstream. C. Cori Cycle 1. Some lactic acid can be used in cellular respiration to produce carbon dioxide and water. Skeletal muscles make too much, so it is shipped to the liver. 2. The liver has the enzyme lactic acid dehydrogenase, which converts lactic acid to pyruvic acid and NADH. The Cori Cycle, cont 3. The liver can convert pyruvic acid to glucose 6phosphate. a. This can be used to make glycogen or glucose in a reverse of glycolysis. b. Pyruvic acid Glucose = gluconeogenesis (making “new” glucose from noncarbohydrate molecules) c. The glucose can return 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 A. Introduction 1. Lipids and proteins can also be used for energy via the same pathways used for the metabolism of pyruvic acid. 2. 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 B. Lipid Metabolism 1. 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 2. 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 d. Fatty Acids as an Energy Source 1) β-oxidation: Enzymes remove acetic acid molecules from fatty acids to form acetyl CoA. a) For every 2 carbons on the fatty acid chain, 1 acetyl CoA can be formed. b) A 16-carbon fatty acid 8 acetyl CoA c) Each acetyl CoA 10 ATP + 1 NADH + 1 FADH2 d) A 16-carbon fatty acid 80 ATP + 28 in electron transport = 108 ATP!!! 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 3. 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 4. Ketone Bodies a. 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. b. Liver cells convert the fatty acids into acetyl CoA and then into ketone bodies. c. These are water-soluble molecules that circulate in the blood. d. Build-up in the blood can cause ketosis C. 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 5. Transamination a. Pyruvic acid and several citric acid cycle intermediates (called keto acids) can be converted to amino acids by adding an amine group (NH2). 1) Usually obtained from other amino acids 2) Called transamination 3) Requires vitamin B6 as a coenzyme 4) 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 6. Oxidative Deamination a. If there are more amino acids than needed, the amine group from glutamic acid can be stripped and excreted as urea in the urine. b. Oxidative deamination sometimes forms pyruvic acid or another citric acid cycle intermediates. 1) These can be used to make energy or converted to glucose or fat. 2) The formation of glucose from amino acids is called gluconeogenesis and occurs in the Cori cycle. 3) The main substrates are 3-carbon molecules – alanine, lactic acid, and glycerol Oxidative Deamination 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 D. Uses of different energy sources 1. Glucose and ketone bodies come from the liver 2. Fatty acids come from adipose tissue 3. 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