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Transcript
Why Study Metabolism? • Classification of bacteria – Oxygen Tolerance – Biochemical reactions • Acids, Ammonia, Gases • Fermentation Products – Food Products • Yogurt, Sour Cream, Bread, Alcohol – Commercial Products • Citric Acid, Plastics • Environmental Cleanup Metabolism? ● Metabolism Is the Sum of Cellular Reactions - the entire network of chemical reactions carried out by living cells ● Arises from interactions between molecules ● Metabolism = Anabolism + Catabolism ● Catabolic reactions - degrade molecules to create smaller molecules and energy ● Anabolic reactions - synthesize molecules for cell maintenance, growth and reproduction ● Metabolites - small molecule intermediates in the degradation and synthesis of polymers 4 Organization of the Chemistry of Life into Metabolic Pathways • A metabolic pathway has many steps – That begin with a specific molecule and end with a product – That are each catalyzed by a specific enzyme Enzyme 1 A Enzyme 3 D C B Reaction 1 Starting molecule Enzyme 2 Reaction 2 Reaction 3 Product Organization of the Chemistry of Life into Metabolic Pathways • Catabolic pathways – Break down complex molecules into simpler compounds – Release energy • Anabolic pathways – Build complicated molecules from simpler ones – Consume energy Metabolism Breakdown Proteins to Amino Acids, Starch to Glucose Synthesis Amino Acids to Proteins, Glucose to Starch Overview of Metabolism Source of Energy (Photo- vs. Chemotroph) Source of Electrons Carrier of Electrons Final Electron Acceptor Source of Carbon (Auto- vs. Heterotroph) Auto- : Carbon Dioxide Hetero- : Organic Compounds Classification based on Metabolism Where microbes get their energy? ◊ Sunlight vs. Chemical ◊ Photo- vs. Chemo- trophs How do they obtain carbon? ◊ Carbon Dioxide (or inorganic compounds) vs. Organic Compounds (sugars, amino acids) ◊ Auto- vs. Hetero- trophs Examples ◊ Photoautotrophs vs. Photoheterotrophs ◊ Chemoautotrophs vs. Chemoheterotrophs Types of -trophs Type PhotoautoPhotoheteroChemoauto- Energy C-Source Example Purple & Green sulfur bacteria Sun CO2 Sun Organic Purple & Green compounds Non-sulfur bacteria Chemical CO2 bonds H, S, Fe, N bacteria Most bacteria, Chemical Organic Chemoheterofungi, protozoa, bonds Compounds animals Source of Electrons Autotrophs ◊ Photosynthesis ◊ H2O, H2S Chemotrophs ◊ Organic Compounds ◊ Carbohydrates (C H2O) Glucose, Lactose, Sucrose, Mannitol, Citrate ◊ Amino Acids Electron Carriers • Photosynthesis NADP + H to NADPH • Respiration NAD + H to NADH FAD + H to FADH • Contain Niacin and Riboflavin Vitamins, not stable Can’t store these molecules Final Electron Acceptor Photosynthesis CO2 + H’s to CH2O Stores energy Respiration Aerobic ½O2 + H 2 to H2O Anaerobic Fermentation Movement of Electrons • • • • Chemical reactions Oxidation Reactions Reduction Reactions Reactions Coupled – Redox reactions Comparison of oxidation and reduction Oxidation Reduction Loss of electron (A) gain of electrons (B) Gain of oxygen Loss of oxygen Loss of Hydrogen Gain of Hydrogen Loss of energy (Liberates energy) Exothermic; exergonic (gives off heat energy) Gain of energy (stores energy in the reduced compound) Endothermic; endergonic (requires energy, such As heat) Oxidation Reduction Example of Redox Equations Example of Redox Equations Example of Redox Equations Examples • ATP ADP + P ◊ Oxidation, release energy • ADP + P ATP ◊ Reduction, stores energy • NAD + H NADH • FADH FAD + H • NH4 + 1½O2 NO2- +H2O + 2H + ATP • 2H2 + O2 2H2 O Examples Cellular Respiration C6H12 O6 + 6O2 6H2O + 6CO2 + 38 ATP Photosynthesis 6H2O + 6CO2 + light C6H12 O6 + 6O2 Nitrification NH4 NO2 to NO3 • Ammonia to Nitrite to Nitrate Ammonification N2 NH4 Forms of Energy • Energy – Is the capacity to cause change – Exists in various forms, of which some can perform work • Kinetic energy Is the energy associated with motion • Potential energy Is stored in the location of matter Includes chemical energy stored in molecular structure Energy can be converted From one form to another Concept : The free-energy change of a reaction tells us whether the reaction occurs spontaneously Free-Energy Change, DG The change in free energy, ∆G during a biological process is related directly to the enthalpy change (∆H) and the change in entropy (DS) ∆G = ∆H – T∆S Free-Energy Change, DG Free-Energy Change ● A living system’s free energy = energy that can do work under cellular conditions ● Free-energy change (G) is a measure of the chemical energy available from a reaction G = Gproducts - Greactants ● The free energy change (G) of a reaction determines its spontaneity ● A reaction is spontaneous if ∆G is negative (if the free energy of products is less than that of reactants). Bioenergetics and Thermodynamics Enthalphy ● A thermodynamic function of a system ● The heat content of a chemical system = sum of the internal energy of the system + the product of its volume multiplied by the pressure exerted on it by its surroundings Bioenergetics and Thermodynamics Entrophy ● Entropy is the quantitative measure of disorder in a system ● In any closed system, the entropy of the system will either remain constant or increase ● E.g. adding heat to a system causes the molecules and atoms to speed up Relationship between energy and entropy ● The change in free energy, ∆G during a biological process Is related directly to the enthalpy change (∆H) and the change in entropy ∆G = ∆H – T∆S DH = change in enthalpy DS = change in entropy ; T = degree Kelvin ◘ -DG = a spontaneous reaction in the direction written ◘ +DG = the reaction is not spontaneous ◘ DG = 0 the reaction is at equilibrium Standard Free-Energy Change (DGo) Reaction free-energy depends upon conditions Standard state (DGo) - defined reference conditions Standard Temperature = 298K (25oC) Standard Pressure = 1 atmosphere Standard Solute Concentration = 1.0M Standard transformed constant = DGo’ Standard H+ concentration = 10-7 (pH = 7.0) H2O concentration = 55.5 M Mg2+ concentration = 1 mM For a reaction A + B C + D G = Go' + RT ln [C] [D] [A] [B] DGo' = standard free energy change (at pH 7, 1M reactants & products); R = gas constant; T = temp) At equilibrium DG = 0. K'eq, the ratio [C][D]/[A][B] at equilibrium, is the equilibrium constant. An equilibrium constant (K'eq) greater than one indicates a spontaneous reaction (negative DG'). [C] [D] [A] [B] G = Gº' + RT ln = Gº' + RT ln Gº' = - RTln [C] [D] [A] [B] [C] [D] [A] [B] [C] [D] defining K'eq = [A] [B] Gº' = - RT ln K'eq DGo' = - RT ln K'eq Variation of equilibrium constant with DGo‘ (25 oC) K'eq G º' kJ/mol 104 - 23 proceeds forward (spontaneous) 102 - 11 proceeds forward (spontaneous) 100 = 1 0 Starting with 1 M reactants & products, the reaction: is at equilibrium 10-2 + 11 reverses to form “reactants” 10-4 + 23 reverses to form “reactants” • ATP hydrolysis – Can be coupled to other reactions Endergonic reaction: ∆G is positive, reaction is not spontaneous NH2 Glu NH3 + Glutamic acid Ammonia ∆G = +3.4 kcal/mol Glu Glutamine Exergonic reaction: ∆ G is negative, reaction is spontaneous ATP + H2O ADP + Coupled reactions: Overall ∆G is negative; together, reactions are spontaneous P ∆G = - 7.3 kcal/mol ∆G = –3.9 kcal/mol Other examples of high energy compounds Phosphocreatine Other examples of high energy compounds Phosphoenolpyruvate (PEP) Other examples of high energy compounds 1, 3-bisphosphoglycerate • At maximum stability – The system is at equilibrium • More free energy (higher G) • Less stable • Greater work capacity In a spontaneously change • The free energy of the system decreases (∆G<0) • The system becomes more stable • The released free energy can be harnessed to do work . • Less free energy (lower G) • More stable • Less work capacity (a) Gravitational motion. Objects move spontaneously from a higher altitude to a lower one. (b) Diffusion. Molecules in a drop of dye diffuse until they are randomly dispersed. (c) Chemical reaction. In a cell, a sugar molecule is broken down into simpler molecules. Free Energy and Metabolism Exergonic and Endergonic Reactions in Metabolism • An exergonic reaction – Proceeds with a net release of free energy and is spontaneous Free energy Reactants Amount of Energy released (∆G <0) Energy Products Progress of the reaction (a) Exergonic reaction: energy released Exergonic and Endergonic Reactions in Metabolism • An endergonic reaction – Is one that absorbs free energy from its surroundings and is nonspontaneous Free energy Products Energy Reactants Progress of the reaction (b) Endergonic reaction: energy required Amount of Energy released (∆G>0) Equilibrium and Metabolism • Reactions in a closed system – Eventually reach equilibrium ∆G < 0 ∆G = 0 (a) A closed hydroelectric system. Water flowing downhill turns a turbine that drives a generator providing electricity to a light bulb, but only until the system reaches equilibrium. Cells in our body – Experience a constant flow of materials in and out, preventing metabolic pathways from reaching equilibrium (b) An open hydroelectric system. Flowing water keeps driving the generator because intake and outflow of water keep the system from reaching equlibrium. ∆G < 0 • An analogy for cellular respiration ∆G < 0 ∆G < 0 ∆G < 0 (c) A multistep open hydroelectric system. Cellular respiration is analogous to this system: Glucoce is broken down in a series of exergonic reactions that power the work of the cell. The product of each reaction becomes the reactant for the next, so no reaction reaches equilibrium. • Concept :ATP powers cellular work by coupling exergonic reactions to endergonic reactions • A cell does three main kinds of work – Mechanical – Transport – Chemical • Energy coupling – Is a key feature in the way cells manage their energy resources to do this work 49 OBJECTIVE –Learning outcome 1. learn essentially all of the reactions in the glycolytic pathway (substrates and products) 2. understand where the free energy changes come from which allow production of ATP in glycolysis 3. Know the activators and inhibitors of the major regulated enzymes in glycolysis and understand the metabolic logic of their function. 4. What is "substrate level" phosphorylation? 5. Understand the connection between glycolysis and glycogen synthesis & gluconeogenesis 6. relationship between glycolysis, gluconeogenesis and the pentose pathway. 50 METABOLISM ● Summation of all chemical reactions in an organism in order to maintain life ● These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments ● Metabolism is usually divided into two categories. a. Catabolism breaks down large molecules, for example to harvest energy in cellular respiration. b. Anabolism, uses energy to construct components of cells such as proteins and nucleic acids. 51 METABOLISM ● The chemical reactions of metabolism are organized into metabolic pathways, in which one chemical is transformed into another by a sequence of enzymes. ● Enzymes are crucial to metabolism because they allow organisms to drive desirable but thermodynamically unfavorable reactions by coupling them to favorable ones. ● Enzymes also allow the regulation of metabolic pathways in response to changes in the cell's environment or signals from other cells. 52 CARBOHYDRATE METABOLISM ● All organisms obtain energy from the oxidation of glucose and other carbohydrates ● In some cells and organisms, glucose is the major or sole source of energy Brain Erythrocytes Many bacteria 53 CARBOHYDRATE METABOLISM Major pathways 1. Glycolysis ● Main pathway for glucose oxidation ● Forms pyruvate anaerobically 2. Phosphogluconate pathway ● an auxillary route for glucose oxidation in animals ● Produces ribose-5-phosphate 3. Gluconeogenesis ● Pathway for the synthesis from pyruvate 54 Energy metabolism of glucose 55 56 GLYCOLYSIS ● First stage of CHO metabolism ● Simple sugars are broken down to pyruvate ● Anaerobic process – no oxygen required ● All life use this process ● Requires Glucose 2ADP 2ATP 2NAD+ 2PO4= 10 different enzymes 57 Overall Glycolysis ● Net energy produced is 2ATP ● The two pyruvate can go on the citric acid cycle to produce more energy 58 Glycolysis = two phases 1. a preparatory phase 2. payoff or energy-yielding phase. 59 Preparatory phase Energy-yielding phase Overall Glycolysis 60 6-Carbon Stage Requires Energy GLUCOSE ADP ATP Glucose-6-phosphate Fructose-6-phosphate ADP ATP Fructose-1,6-diphosphate Glyceraldehyde-3-P Dihydroxyacetone -P 61 62 Glyceraldehyde -3-phosphate NAD Pi NADH + H 1-3-Dihosphoglycerate ADP ATP 3-Carbon Stage – Double this because 2piruvate are produced 3-phosphoglycerate 2-dihosphoglycerate 3-phosphoenolpyruvgate ADP ATP PYRUVATE 63 64 Overall Glycolysis Glucose + 2ATP + 2ADP + 2PO42- + 2NAD+ 10 enzymes 2 Pyruvate + 2NADH + 2H2O + 4ATP 65 Regulation of Glycolysis AS with all metabolic pathways, glycolysis is under constant control by the body Glycolysis is regulated by 3 enzymes 1. Hexokinase Inhibited by glucose-6-phosphate 2. Phosphofructokinase Inhibited by glucose-6-phosphate 3. Pyruvate kinase Inhibited by ATP 66 Feedback inhibition GLUCOSE Hexokinase Glucose-6-phosphate Fructose-6-phosphate Phosphofructokinase Fructose-1,6-diphosphate Phosphophenolpyruvate Pyruvate kinase PYRUVATE 67 OVERVIEW OF GLYCOLYSIS 68 Glycolysis pathway is similar in all organisms What happens to pyruvate? What happens to pyruvate will vary significantly 1. In animal, plant and many microbial cells, under aerobic conditions – pyruvate is converted to acetylCoA in mitochondria 2. Under anaerobic conditions – fermentation to produce lactate/ethanol 69 FERMENTATION Processing of pyruvate under anaerobic conditions 2 types – lactate and alcohol fermentations 70 Lactate fermentation Lactate produced by muscles when the body cannot supply enough O2 Anaerobic conversion of pyruvate to lactate permits regeneration of NAD+ Body can then make more ATP – but at a cost- creates an oxygen debt Must use extra O2 to oxidise lactate later 71 Lactate fermentation 72 Alcohol fermentation 73 Alcohol fermentation 74 75 What happens to Pyruvate? Pyruvate is the final product of the 10 step pathway of glycolysis. The next step in the oxidation of glucose is the conversion of pyruvate to acetyl-CoA, and the subsequent oxidation of this two carbon compound to CO2 The metabolic pathway in which this occurs is a cyclic one known as the Citric Acid Cycle (CAC) or Krebs Cycle or TCA Cycle Acetyl CoA comes from multiple sources including carbohydrates, fats and many amino acids 76 The citric acid cycle Also known as Krebs cycle after the founder, Hans Kreb Final stage for the metabolism of carbohydrates Requires oxygen – aerobic process 77 Conversion of pyruvate to acetyl-CoA 78 79 80 81 82 83 84 How? Where? Energy extracted??? How much OXIDATIVE PHOSPHORYLATION 85 OXIDATIVE PHOSPHORYLATION Oxidative phosphorylation is the process in which ATP is formed as a result of the transfer of electrons from NADH or FADH2 to O2 by a series of electron carriers – Electron transport system The NADH and FADH2 formed in glycolysis, fatty acid oxidation, and the citric acid cycle are energy-rich molecules because each contains a pair of electrons having a high transfer potential takes place in mitochondria the major source of ATP in aerobic organisms 86 Electron Transport Schematic 87 Electron Transport Schematic 1. Citric acid cycle NADH and FADH2 - energy-rich molecules because each contains a pair of electrons having a high transfer potential = electron motive force 2. The flow of electrons from NADH or FADH2 to O2 through protein complexes located in the mitochondrial inner membrane leads to the pumping of protons out of the mitochondrial oxidoreductase, Q-cytochrome c oxidoreductase, and cytochrome c oxidase 3. These large transmembrane complexes contain multiple oxidation-reduction centers, including quinones, flavins, iron-sulfur clusters, hemes, and copper ions 88 Flavin adenine dinucleotide 89 Electron Transport Schematic 90 Electron Transport Schematic 4. The final phase of oxidative phosphorylation is carried out by ATP synthase, an ATP-synthesizing assembly that is driven by the flow of protons back into the mitochondrial matrix 91 ELECTRON TRANSPORT CHAIN NADH and FADH2 carry protons (H+) and electrons (e-) to the electron transport chain located in the membrane The energy from the transfer of electrons along the chain transports protons across the membrane and creates an electrochemical gradient. As the accumulating protons follow the electrochemical gradient back across the membrane through an ATP synthase complex, the movement of the protons provides energy for synthesizing ATP from ADP and phosphate At the end of the electron transport system, two protons, two electrons, and half of an oxygen molecule combine to form water. 92 93 94 95 ATP synthase and the F1 complex In this step, the H+ concentration difference between the mitochondrial matrix and the intermembrane space is what provides the energy to produce ATP Steps consist of H+ transport – movment of H+ F1 event = production of ATP 96 97 98 GLUCONEOGENESIS Process where glucose is synthesised Occurs primarily in the liver Common materials used as starting materials are o o o Lactate All amino acids except leucine and lysine Glycerol from fats Sometimes referred to as “reverse glycolysis” but not true because glycolysis is not reversible Only used under starvation conditions 99 100 Gluconeogenesis appears to be the exact reverse of glycolysis but why is it not the reverse of glycolysis? Because there 3 reactions in glycolysis that are not reversible 1. Phosphoenol pyruvate to pyruvate – catalysed by piruvate kinase 2. Fructose 6 phosphate to fructose 1,6-biphosphate – catalysed by phospho fructokinase-1 3. Glucose 6-phosphate to glucose 6-phosphate – catalysed by hexokinase 101 102 These 3 reactions must be bypassed in gluconeogenesis By pass 1- Pyruvate to Phosphoenolpyruvate Pyruvate in cytoplasm is transported into the mitochondria where it converted to oxaloacetate by pyruvate carboxylase OAA is transported back to the cytoplasm where it is converted to PEP (phosphoenolpyruvate) by PEP carboxykinase 103 104 105 By pass 2 – Fructose 1,6-Biphosphate to Fructose 6phosphate Reaction catalysed by fructose 1,6-biphosphatase Fructose 1,6-biphosphate + H2O fructose 6phosphate + Pi By pass 3 – Glucose 6-phosphate to glucose Reaction catalysed by glucose 6-phosphatase Glucose 6-phosphate + H2O glucose + Pi 106 107 PENTOSE PHOSPHATE PATHWAY The major catabolic fate of most glucose is oxidation via the TCA cycle. However, some can undergo the pentose pathway. The pentose pathway has several names-the phosphogluconate pathway, or the hexose monophosphate pathway. Importance? 1. yields the five carbon sugars used in biosynthesis of RNA, DNA, and coenzymes such as ATP, NAD+, FAD, and coenzyme A - required by rapidly growing cells such as those of bone marrow, skin and intestinal mucosa. 108 2. To produce NADPH which are required a. for reductive biosynthetic reactions - fatty acid biosynthetic reactions in liver, adipose tissue and lactating mammary glands, cholesterol and steroid hormones b. for protection of tissues from damage due to reactive oxygen species. Erythrocytes and the cells of the cornea are exposed to high concentrations of oxygen and are therefore prone to oxidative damage from a variety of oxygen radicals. NADPH is required to reduce glutathione which is one of the prime defenses from oxidative damage. 109 PENTOSE PHOSPHATE PATHWAY The pentose pathway is logically divided into two components, 1. an oxidative component in which 2 moles of NADPH are produced for each mole of glucose 6-phosphate that enters the pathway. 2. The second portion of the pentose pathway is the nonoxidative phase in which the product of the oxidative phase is reorganized into glucose 6phosphate. 110 111 112 113 114 OVERVIEW OF GLYCOLYSIS 116 Glycolysis –Steps 1-6 117 Glycolysis –Steps 6-10 118 Pyruvate Pathways 119 Pyruvate Oxidation 120 Krebs Cycle Overview 121 Krebs Cycle begins 122 ELECTRON TRANSPORT CHAIN Chemiosmosis Overview of ATP Synthesis ATP Theoretical Yield Catabolism of other Organic Molecules