Metabolism Lecture Notes - Cellular Respiration PDF

Chapter 25 METABOLISM Part 1 Lecture Outline Metabolism Review/Preview Cellular Respiration of Glucose Glycolysis Formation of Acetyl Coenzyme A Citric Acid Cycle Electron...

Chapter 25 METABOLISM Part 1 Lecture Outline Metabolism Review/Preview Cellular Respiration of Glucose Glycolysis Formation of Acetyl Coenzyme A Citric Acid Cycle Electron Transport Chain (ETC) Dr. Kevin Tipper, ND REVIEW & INTRODUCTION REVIEW: Metabolism Metabolism is all chemical reaction occurring in body Metabolism is the sum of: Catabolism break down complex molecules into simpler ones Exergonic: reactions release energy stored in the molecules Anabolism combine simple molecules into complex ones Endergonic: requires energy Metabolism Cellular catabolism or aerobic metabolism or cellular respiration Requires oxygen Occurs in the mitochondria 40 percent of energy is captured Used to convert adenosine diphosphate (ADP) to adenosine triphosphate (ATP) ATP is used for anabolism and other cellular functions 60 percent of energy escapes as heat Warms the interior of the cell and the surrounding tissue REVIEW: ATP Adenosine Triphosphate (ATP) “energy currency” of the body The energy stored in this molecule is found within the bonds between each phosphate group ATP is created in exergonic reactions and used in endergonic reactions ADP + P + energy ↔ ATP Role of ATP in Linking Anabolic & Catabolic Reactions Catabolic reactions created ATP: Example: glycolysis Anabolicreactions require energy: Example: glycogenesis Metabolism Nutrient pool Source for organic substrates (molecules) for both catabolism and anabolism Anabolism in the cell required for: Replacing membranes, organelles, enzymes, and structural proteins Catabolism in the cell required for: Converting substrates to a 2-carbon molecule Utilized by mitochondria to produce A T P Metabolism Utilization of nutrients Comes from the diet and from reserves Reserves are mobilized when absorption across the digestive tract is insufficient to maintain normal nutrient levels Liver cells break down triglycerides and glycogen Fatty acids and glucose can be released Adipocytes break down triglycerides Fatty acids can be released Skeletal muscle cells break down contractile proteins Amino acids can be released We can use all of these reserves to create ATP Metabolism Restoration of nutrient reserves Reserves are stocked when absorption by the digestive tract is greater than immediate nutrient needs Liver cells store triglycerides and glycogen Adipocytes convert excess fatty acids to triglycerides Skeletal muscles build glycogen reserves and use amino acids to increase numbers of myofibrils Metabolism Utilization of resources Cells in most tissues continuously absorb and catabolize glucose Nervous tissue must have a continuous supply of glucose During starvation, other tissues can shift to fatty acid or amino acid catabolism Conserves body’s glucose for nervous tissue Can also uses ketones (more later) Metabolism Nutrient pool REVIEW: REDOX Reactions Oxidation = removal of electrons from a molecule Decrease in potential energy Typically involves a loss of hydrogen atoms, also called dehydrogenation reactions Reduction = addition of electrons to a molecule Increase in potential energy These two reactions are ALWAYS paired REVIEW: REDOX Reactions So when a molecule is oxidized, it often loses electrons (in the form of hydrogen atoms) These liberated hydrogen atoms have to go somewhere (something must be reduced) 2 common coenzymes used are: Nicotinamide adenine dinucleotide (NAD) NAD+ is reduced to NADH + H+ Flavin adenine dinucleotide (FAD) FAD is reduced to FADH2 When we start talking about glucose metabolism, the process involves the oxidation of glucose REVIEW: REDOX Reactions Glucose is C6H12O6 During glycolysis it is split into 2 pyruvate molecules Pyruvate is C3H4O3 (reminder: there are two of these molecules) Therefore, we have lost 4 hydrogen atoms Where do they go? They are accepted by NAD + which becomes NADH/H+ NAD+ + 2 e- + 2 H+ H/H+ REVIEW: REDOX Reactions LEO the lion says GER Loss of Electrons = Oxidation Gain of Electrons = Reduction OIL RIG Oxidation is Loss Reduction is Gain CELLULAR RESPIRATION OF GLUCOSE Mechanisms of ATP Generation 1. Substrate-level phosphorylation Transferring of a high-energy phosphate group from an intermediate directly to ADP Examples: Glycolysis, citric acid cycle, and phosphocreatine 2. Oxidative phosphorylation Remove electrons and pass them through electron transport chain to oxygen 3. Photophosphorylation Only in chlorophyll-containing plant cells - not going to be discussed here! Carbohydrate Metabolism Remember glucose? Breakdown product of carbohydrates that is absorbed in the small intestine Glucose is the preferred source of energy, most other saccharides are converted to glucose Carbohydrate Metabolism Why is glucose preferred? Glucose is a small, soluble molecule that is easily distributed through body fluids Glucose can provide A TP anaerobically (without oxygen) through glycolysis Glucose can be stored as glycogen, which forms compact, insoluble granules Glucose can be easily mobilized because the breakdown of glycogen (glycogenolysis) occurs very quickly Mobilization of other intracellular reserves involves much more complex pathways and takes considerably more time. Carbohydrate Metabolism GluTtransporters bring glucose into the cell via facilitated diffusion Insulin causes expression of more of these transporters in the plasma membrane, increasing rate of entry into cells Glucose is trapped in cells after being phosphorylated Carbohydrate Metabolism Fate of glucose depends on needs of body cells 1. ATP production if energy is needed immediately 2. Glycogen synthesis combining hundreds to thousands of glucose molecules to form glycogen (stored form of glucose) 3. Synthesis of amino acids used to form proteins 4. Triglyceride synthesis when other body stores are full, the remaining glucose is converted to fats Carbohydrate Metabolism Cellular Respiration There are 4 steps in the complete utilization of a glucose molecule (glucose catabolism) 1. Glycolysis Anaerobic respiration: does not require oxygen Substrate-level phosphorylation 2. Formation of acetyl coenzyme A Aerobic respiration: requires oxygen 3. Citric Acid Cycle reactions (Kreb’s Cycle) Substrate-level phosphorylation 4. Electron transport chain reactions Aerobic respiration: requires oxygen “oxidative phosphorylation” Overview of Cellular Respiration 1 Glucose 2 ATP 1 GLYCOLYSIS 2 NADH + 2 H+ 2 Pyruvic acid 2 FORMATION 2 CO2 OF ACETYL COENZYME A 2 NADH + 2 H+ 4 ELECTRON TRANSPORT 2 Acetyl CHAIN coenzyme A 2 ATP Electrons 32 or 34 ATP e – 4 CO2 e– 3 e– KREBS 6 NADH + 6 H+ CYCLE 2 FADH2 6 O2 6 H2O Glycolysis Overview Cellular respiration begins with glycolysis Splits 6-carbon glucose into two 3-carbon molecules of pyruvic acid Occurs in the cytosol 10 reactions Consumes 2 ATP but generates 4  NET GAIN of 2 ATP First 5 steps uses the ATP and increases the potential energy in the molecules Steps 6-10 is where 4 ATP are generated Glycolysis The 10 Reactions of Glycolysis  H CH2O P C O C O HCOH 6 CH2OH CH2OH CH2O P 5 O H H H Dihydroxyacetone Glyceraldehyde 5 4 1 phosphate 3-phosphate HO OH H OH 2 NAD+ + 2 P 3 2 6 H OH Glucose (1 molecule) 2 NADH + 2H+ CH2O P ATP 1 HCOH ADP C O P 1, 3-Bisphosphoglyceric acid (2 molecules) P OH2C O 2 ADP O 7 H H H 2 ATP OH H CH2O P HO OH OH H HCOH 3-Phosphoglyceric acid OH Glucose 6-phosphate COOH (2 molecules) 2 8 6 P OH2C O CH2OH 1 CH2OH 5 HCO P 2-Phosphoglyceric acid 2 (2 molecules) H H HO COOH OH 4 3 9 OH H Fructose 6-phosphate CH2 ATP Phosphofructokinase 3 C O P Phosphoenolpyruvic acid ADP (2 molecules) COOH P OH2C 2 ADP O 10 CH2O P 2 ATP H H HO OH CH3 OH H Fructose 1, 6-bisphosphate C O Pyruvic acid COOH (2 molecules) 4 Glycolysis Important Reactions: Reaction 1 First step is always phosphorylation Addition of phosphate group to glucose Uses the enzyme hexokinase in most cells (glucokinase in the liver) REQUIRES 1 ATP Benefit: phosphorylation of glucose to keep it in the cell GluT transporters do not recognize G- Glycolysis Important Reactions: Reaction 3 Another phosphorylation reaction Addition of phosphate group to F-6-P Uses the enzyme phosphofructokinase REQUIRES 1 ATP Rate-limiting step The rate limiting step is the slowest (irreversible) step in a pathway determines how fast the whole pathway can be carried out Glycolysis Important Reactions: Reaction 4 One 6-carbon molecule is split into two 3-carbon molecules (G-3-P) Glycolysis Important Reactions: Reaction 6 Redox Reaction G-3-P is oxidized, NADH is reduced GENERATES 2 NADH (one from each 3-carbon molecule) Also, each G-3-P is phosphorylated Does not require ATP (exergonic reaction, uses energy to add Pi) Now we have added 4 phosphate groups total Glycolysis Important Reactions: Reaction 7 1 phosphate group from each 3- carbon molecule is removed GENERATES 2 ATP (1 from each 3- carbon molecule) Glycolysis Important Reactions: Reaction 10 1 more phosphate group from each 3-carbon molecule is removed GENERATES 2 ATP (1 from each 3- carbon molecule) Final product is pyruvate Glycolysis End Products from one glucose molecule 2 pyruvate molecules 4 ATP molecules (net 2 ATP) 2 NADH If oxygen is available, will go to ETC to create more ATP Running Tally of Products Per Glucose NADH FADH2 ATP Glycolysis 2 - 2 Formation of Acetyl CoA Citric Acid Cycle TOTAL Review How does glucose enter the cell? Through GLUT transporters via facilitated diffusion What happens once glucose enters the cell? It is phosphorylated right away, which traps it in the cell What is the starting molecule in glycolysis? ONE molecule of glucose What is the end product of glycolysis? TWO molecules of pyruvic acid What is the net gain of ATP?  2 ATP Produces 4 but uses 2 What Happens to Pyruvate? Fate of pyruvic acid depends on oxygen availability If oxygen is scarce (anaerobic), it is reduced to lactic acid More soon If oxygen is plentiful (aerobic), pyruvic acid is converted to acetyl coenzyme A and it enters the Citric Acid Cycle Overview of Cellular Respiration 1 Glucose 2 ATP 1 GLYCOLYSIS 2 NADH + 2 H+ 2 Pyruvic acid 2 FORMATION 2 CO2 OF ACETYL COENZYME A 2 NADH + 2 H+ 4 ELECTRON TRANSPORT 2 Acetyl CHAIN coenzyme A 2 ATP Electrons 32 or 34 ATP e – 4 CO2 e– 3 e– KREBS 6 NADH + 6 H+ CYCLE 2 FADH2 6 O2 6 H2O Formation of Acetyl coenzyme A The second step in cellular respiration Transitional step between glycolysis and Krebs cycle Each pyruvic acid is converted to 2-carbon acetyl group Remove one molecule of CO2 as a waste product Pyruvic acid enters the mitochondria first and then is converted to acetyl coenzyme A Each pyruvic acid also loses 2 hydrogen atoms NAD+ reduced to NADH/H+ Formation of Acetyl coenzyme A Occurs in mitochondrial matrix Endproducts per glucose molecule: 2 CO2 (waste product) 2 NADH will go to ETC to create more ATP What Happens to Pyruvate? If oxygen is scarce (anaerobic), it is reduced to lactic acid 2 pyruvic acid + 2NADH + 2H+  2 lactic acid and 2 NAD+ Cori Cycle: Once lactic acid is produced, it quickly diffuses out of the cell and enters the blood Hepatocytes can convert lactic acid to glucose Other oxygenated tissue can reduce the lactic acid back into pyruvate, where it will then be used What Happens to Pyruvate? The Cori Cycle In anaerobic conditions Can replenish glucose to be used for substrate level phosphorylation Why is this not sustainable? Running Tally of Products Per Glucose NADH FADH2 ATP Glycolysis 2 - 2 Formation of 2 - - Acetyl CoA Citric Acid Cycle TOTAL The Citric Acid Cycle (CAC) Also known as Kreb’s Cycle or TCA Cycle (Tricarboxylic Acid Cycle) The third step of cellular respiration Requires oxygen (aerobic respiration) Occurs in matrix of mitochondria Series of redox reactions that transfer energy to coenzymes Overall function is to remove hydrogen atoms from specific organic molecules and transfer them to coenzymes The Citric Acid Cycle (CAC) The Eight Reactions of the Citric Acid Cycle (FYI)  CO2 CH3 CoA C O C O COOH CH3 NADH + H+ Pyruvic NAD + Acetyl acid coenzyme A To electron transport chain Oxaloacetic acid CoA COOH NADH + H+ C O CH2 H2C COOH NAD+ COOH 1 HOC COOH H2O H2C COOH Citric acid COOH HCOH 8 CH2 2 To electron transport Malic acid COOH chain H2O 7 H2C COOH COOH HC COOH Fumaric acid CH HC KREBS HOC COOH H Isocitric acid COOH CYCLE 3 FADH2 6 FAD H2C COOH NAD+ CoA CO2 H2C COOH NADH + H+ Succinic acid 5 H2C COOH GTP CO2 H2C COOH 4 HCH ADP GDP CH2 O C COOH O C S CoA Alpha-ketoglutaric acid ATP Succinyl CoA NAD+ To electron NADH + H+ transport chain The Citric Acid Cycle (CAC) 2 decarboxylation reactions release CO 2 CO2 will diffuse out of cell and will be carried to the lungs Reduced coenzymes (NADH and FADH2) are the most important outcome For every ONE acetyl CoA that enters the Krebs cycle, 3 NADH + 3H+, and 1 FADH2 is produced Onemolecule of ATP generated by substrate-level phosphorylation The Citric Acid Cycle (CAC) End products of the CAC Per acetyl CoA molecule (per glucose molecule in brackets) 2 CO2 (4 CO2 per glucose molecule) Waste product 3 NADH (6 NADH per glucose molecule) will go to ETC to create more ATP 1 FADH2 (2 FADH2 per glucose molecule) will go to ETC to create more ATP 1 ATP (2 ATP per glucose molecule) Running Tally of Products Per Glucose NADH FADH2 ATP Glycolysis 2 - 2 Formation of 2 - - Acetyl CoA Citric Acid Cycle 6 2 2 TOTAL 10 2 4 Review What happens to pyruvic acid in an anaerobic environment? Reduced to form lactic acid which diffuses into the blood where it travels to liver What happens to pyruvic acid in an aerobic state? Converted to Acetyl CoA to enter the CAC Where is Acetyl CoA formed? Mitochondrial matrix What is the overall purpose of the Citric Acid Cycle? The reduced coenzymes that carry potential energy (NADH and FADH2) What happens to the CO2 produced in the Citric Acid Cycle? Diffuse out of mitochondria, out of the plasma membrane, into the blood where it is transported to the lungs to be exhaled Electron Transport Chain (ETC) Series of electron carriers called cytochromes in inner mitochondrial membrane Receive electrons from NADH and FADH2 Each electron carrier is reduced or oxidized as it passes along electrons down the chain O2 is the final electron acceptor The site of oxidative phosphorylation Electron Transport Chain (ETC) Electron Transport Chain (ETC) Oxidative Phosphorylation Overview Each electron carrier has an increased infinity for electrons as we move down the chain As electrons are passed from one carrier to another, energy is released Energy is used to pump H+ ions into intermembrane space Energy stored in electrochemical gradient is used to create ATP Final electron acceptor is O and water is formed 2 Produces more than 90% of ATP used in the body Electron Transport Chain (ETC) Oxidative Phosphorylation Overview Lack of oxygen stops the ETC Blocking cytochromes also stops the ETC Example: poisons such as cyanide With no functioning ETC, the citric acid cycle stops Cells die from lack of ATP Electron Transport Chain (ETC) Steps in Oxidative Phosphorylation 1. NADH/FADH2 deliver hydrogen atoms from the citric acid cycle to the ETC The hydrogen atom is composed of: A high-energy electron (e-) Given to the ETC A hydrogen ion or proton (H+) Released into the mitochondrial matrix Electron Transport Chain (ETC) Steps in Oxidative Phosphorylation 2. Cytochromes pass electrons sequentially down the chain of electron carriers 3. Released energy is used to pump hydrogen ions into the intermembrane space creating an electrochemical gradient Stored energy is called proton-motive force Electron Transport Chain (ETC) Outer membrane Steps in Oxidative Phosphorylation Inner membrane Matrix High H+ concentration H+ between inner and channel 4. Hydrogen ions can diffuse down outer mitochondrial membranes 2 H+ H+ electrochemical gradient back into the matrix only through specific hydrogen Electron ion channels Inner transport mitochondrial membrane chain (includes As H+ flows back into matrix through the proton pumps) membrane, an enzyme called ATP 1Energy from 3 synthase uses the movement of energy to NADH + H+ ADP + P generate ATP ATP The movement of H+ back into the matrix is ATP synthase Low H+ concentration in called chemiosmosis matrix of mitochondrion Electron Transport Chain (ETC) Steps in Oxidative Phosphorylation 5. O2 is the final electron acceptor Reacts with 2 hydrogen atoms to form H2O Electron Transport Chain (ETC) ETC in Action: Video Electron Transport Chain (ETC) Yield from the ETC Each NADH will yield 2.5 ATP Each FADH2 will yield 1.5 ATP *these are theoretical yields ATP Produced By One Molecule of Glucose NADH FADH2 ATP Glycolysis 2 - 2 Formation of 2 - - Acetyl CoA Citric Acid Cycle 6 2 2 TOTAL 10 2 4 10 NADH x 2.5 ATP/NADH = 25 ATP 2 FADH2 x 1.5 ATP/FADH2 = 3 ATP 4 ATP 32 ATP per glucose molecule Review In the electron transport chain, how many ATP will a molecule of NADH produce? 2.5 In the electron transport chain, how many ATP will a molecule of FADH2 produce? 1.5 Where is the electron transport chain located? Inner mitochondrial membrane What is the pumping of H+ into the space between the membranes creating? Concentration and electrical gradient Summary of Cellular Respiration ATP YIELD PER GLUCOSE SOURCE LOCATION MOLECULE GLYCOLYSIS Oxidation of one glucose 2 ATP (substrate-level molecule to two pyruvic Cytosol phosphorylation) acid molecules Production of 2 NADH + 3 or 5 ATP (oxidative Cytosol H+ phosphorylation) FORMATION OF TWO MOLECULES OF ACETYL COENZYME A 5 ATP (oxidative 2 NADH + 2 H+ Mitochondrial Matrix phosphorylation) KREBS CYCLE AND ELECTRON TRANSPORT CHAIN 2 GTP that are converted to Oxidation of succinyl-CoA Mitochondrial Matrix 2 ATP (substrate-level to succinic acid phosphorylation). Production of 6 NADH + 6 Mitochondrial Matrix 15 ATP (oxidative H+ phosphorylation) Mitochondrial Matrix 3 ATP (oxidative Production of 2 FADH2 phosphorylation) 30 or 32 ATP per glucose Total molecule Summary of Cellular Respiration Glucose Metabolism Glucose storage: glycogenesis Polysaccharide that is the only stored carbohydrate in humans If glucose is not needed, many glucose molecules will combine to form glycogen Insulin stimulates hepatocytes and skeletal muscle cells to synthesize glycogen The body can store about 500g of glycogen (75% of that is in skeletal muscle) Glucose Metabolism Glucose release: glycogenolysis Glycogen stored in hepatocytes is broken down into glucose and released into blood Glycogen stored in muscle will be converted to glucose-6-phosphate and then will enter glycolysis Skeletal muscle lacks the enzyme to cleave the final phosphate Stimulated by glucagon and epinephrine Glycogenesis and Glycogenolysis Glucose Metabolism Gluconeogenesis Glucose formed from noncarbohydrate sources Substances that can be used: Glycerol part of triglycerides lactic acid most amino acids Occurs in the liver Stimulated by cortisol and glucagon What is glycogenesis? The process of making glycogen. Occurs in the liver and skeletal muscle What is glycogenolysis? The breakdown of glycogen if ATP is required What is gluconeogenesis? Formation of glucose from non-carbohydrate sources (glycerol, amino acids, and lactic acid)