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Transcript
BIOLOGICAL OXIDATION Lecture Objectives; At the end of lecture Student will be able to: ► Explain the fundamentals of Cellular Respiration. ► Describe the biochemical mechanisms of generation and utilization of energy. ► Describe the effects of various inhibitors on biological oxidation. ► Study Bioenergetics (Biochemical Thermodynamics) of the energy changes accompanying biochemical reactions. ► Study of generation, storage and utilization of energy in living system. PRODUCTION OF ENERGY IN A LIVING S Y S TE M • In living system energy is generated by precise chemical methods which: Is Precisely controlled and regulated according to requirements Can be stored for use at a proper time Do not require drastic conditions of Temperature, Pressure and pH. ► Medical Biomedical importance problems due to energy imbalance: Starvation Obesity Marasmus Diseases of Thyroid Sources of energy in living system ► The overall process of energy generation by breakdown of food is called Cellular Respiration ► It is the process by which the chemical energy of "food“ molecules is released and captured in the form of ATP. ► Carbohydrates, fats, and proteins can all be used as fuels in cellular respiration. ► Process involves oxidation of energy-rich organic compounds coupled with reduction of other compounds. ► Direct At Substrate Level. ► Indirect Through Biological Oxidation. Storage of energy in living system ► Free or useful energy is released during catabolic reactions. ► This energy is stored as high energy phosphate bonds of various molecules. ► Such molecules are called high-energy compounds. Adenosine Triphosphate (ATP) is the most commonly used Energy Storing Molecule ► Adenosine + ribose + P ___P___P (High Energy Bonds) Hydrolysis of terminal “P” generates 7300 calories ATP is converted to ADP. Reduced Coenzymes (NADH & FADH) are oxidized to generate Energy ► NADH & FADH are generated during Glycolysis, Oxidation of Fatty Acids, Catabolism of Amino Acids and TCA cycle. ► Oxidized in mitochondria to generate ATP. Two types of Cellular Respiration ► Aerobic Respiration. ► Anaerobic Respiration. Aerobic Respiration ► Final Oxidizing agent (Electron Acceptor) is Oxygen ► The most Important Metabolic Source of Energy in Living cells ► Contributes approximately 90% of total energy generated in cell. ► Net result is CO2, H2O and Energy (ATP & Heat) Anaerobic Respiration ► Final Oxidizing agent (Electron Acceptor) is Other than Oxygen. ► Important Source of Energy in: Cells Not Having Mitochondria (RBC). Cells Deprived of Oxygen (Exerting Muscles & Ischemic Tissues) Metabolic Processes Involved In Cell Respiration ► Glycolysis; occurs in cytosol. ► Oxidation of Fatty acids and Krebs Citric acid Cycle occur in Matrix of Mitochondria. ► Biological Oxidation occurs in Inner Membrane of Mitochondria. Carbon skeleton of Glucose, Fatty acids and Amino acids are converted to CO2 along with generation of NADH2 and FADH molecules. ► Final stage of cellular respiration ► It is the oxidation of NADH2 & FADH to generate ATP ► Generates 90% of total energy generated by Cellular Respiration Glucose Metabolism Glycolysis HIGH ENERGY COMPOUNDS Glucose Glyceraldehyde 3-P 1,3 DPG 3, Phosphoglycerate PEP Pyruvic acid. NAD →NADH2 ADP→ATP Fatty Acid Metabolism LIPOLYSIS Fatty acid Acyl~CoA Unsaturated Acyl~CoA -Keto Acyl~CoA Acetyl~CoA HIGH ENERGY COMPOUNDS FAD→FADH2 NAD→NADH2 Amino Acid Metabolism ► Amino Acids are catabolized, after removal of amino group, to generate Intermediates of TCA Cycle Glutamic acid-Ketoglutaric Acid Aspartic AcidOxaloacetic Acid PhenylalanineAcetyl CoA ► These Intermediates generate NADH & FADH through Citric Acid Cycle. Mechanism of Biologic Oxidation ► Includes – – two integrated mechanisms Respiratory Chain: extracts energy from electrons of Hydrogen. Oxidative Phosphorylation: utilizes extracted energy for the formation of high-energy bond. Respiratory Chain; Electron Transport Chain (ETC) ► Electrons carried by reduced NAD and FAD are transported finally to Oxygen (for oxidative phosphorylation) through a gradual downward movement, from high energy level to low energy level. ► A series of Proteins & enzymes Complexes, cytochromes, present in inner membrane of mitochondria, act as temporary electron carriers during downward movement of electron. ► Movement from high to low level librates energy that is utilized to generate ATP. Cytochromes ► Membrane bound hemoproteins. ► Act as electron carrriers. ► Contain heme (iron porphyrin) as Prosthetic Group. ► In Types of Cytochromes Human Mitochondria Cytochromes Related to Respiration are Distinguished As: Cytochrome b Cytochrome c Cytochrome c1 Cytochrome a and Cytochrome a3 Two Categories of electron carriers (Components Of ETC) 1. Large, immobile Protein complexes. Complex I Complex II Complex III Complex IV 2. Mobile electron carriers. Coenzyme Q cytochrome C Oxygen Large, Immobile Protein Complexes of Respiratory Chain ► E m b ed d ed in Inner Mitochondrial Membrane: Complex I; NADH dehydrogenase. Complex II; Succinate-ubiquinone oxidoreductase. Complex III; the bc1 complex or ubiquinol-cytochrome c reductase. Complex IV; Cytochrome Oxidase. Mobile electron carriers of Respiratory Chain ►Shuttles electrons between Complexes. ►Serve as links between ETC complexes: Ubiquinone (Coenzyme Q). Cytochrome c. Cytochromes Found in two different environments 1. The mobile cytochrome electron carriers (Such as Cytochrome c). 2. Subunits of bigger enzymatic complexes such as Cyt. b in Complex III. and Cyt. a, a3 in Complex IV. ► Step #1: Steps of Electron Transport Transfer of Electron to complex I and complex II. ► Step #2 : ► Step #3 : ► Step #4 : Transfer of Electron to Coenzyme Q. Coenzyme Q shuttles electrons and pass them to complex III. Transfer of Electron to Cytochrome c. ► Step #5 ► Step #6 : Cytochrome c shuttles electrons and pass them to complex IV. Transfer of Electron to Oxygen. Net result of ETC ► Recovery of Free NAD & FAD: Oxidized (Free) NAD & FAD are recovered to Continue dehydrogenation reactions of catabolism. ► Formation of water: NADH2 + ½ O2 NAD+ + H2O FADH2 + ½ O2 FAD+ + H2O ► Energy which is captured as ATP by process of Proton Pump. Flow Of Electrons through Complexes I, III and IV release energy which is used to pump protons across the IMM and from a "Proton Gradient” High Proton Gradient In Inter-membrane space [H+] NADH FMNH2 [H+] QH2 Cyt. b Cyt. c Cyt. a-a3 [H+] O- Mitchell’s Hypothesis The Chemiosmotic Hypothesis for oxidative phophorylationElectron transport through the ETC generates a proton concentration gradient (Proton motive force; PMF). ► PMF serves as the energy reservoir for driving ATP formation. ► This energy is utilized for the synthesis of ATP, when Protons flow back into the matrix via ATP synthase (Complex V). ► Chemiosmotic Potential or Proton-Motive Force (PMF) The electrochemical potential difference between the two sides of the IMM, that engage in active transport of Protons is called Proton-Motive Force (PMF). ► Proton motive force is the energy of the proton concentration gradient for OXIDATIVE PHOSPHORYLATION. ► Proton flow back to matrix “Proton Channel” & Release energy for synthesis of ATP ► ATP Synthase (Complex V) has 2 components: F1 and F0 Mitochondrial Chemiosmosis; H+ flow forms a circuit (similar to an electrical circuit) Estimation Of ATP Synthesis ► According to most textbooks: 3 ATPs for NADH and 2 ATPs for FADH. ► According to recent research: 10 protons are pumped by NADH. 6 protons are pumped by FADH. 4 Protons are needed by ATP synthase to make one ATP molecule. This means that each NADH can make 2.5 ATPs (10/4) and each FADH can make 1.5 ATPs (6/4). FORMATION OF SUPEROXIDE Complex I & III are the main sites of premature electron leakage to oxygen, producing free radical superoxide, which contributes to pathology of different diseases and aging UNCOUPLERS In some special cases, Uncouplers stimulate the oxidation of substrates in the absence of ADP so that large amounts of O2 are consumed but no ATP is produced. ► Do NOT affect electron transport Agents that Interfere With ATP Synthesis ► GENETIC DEFECTS ► Respiratory Chain Inhibitors: CN, CO, Antimycin A etc. ► ATP Synthase Inhibitors: Oligomycin. ► Uncouplers: DNP (synthetic) and Thermogenin(natural). ATP-ADP Exchange Inhibitors: Atractyloside.