Introduction to Metabolism 2022 PDF

Royal College of Surgeons in Ireland Medical University of Bahrain Biochem: Introduction to Metabolism - FFP1-22 Salim Fredericks LEARNING OBJECTIVES Define metabolism Explain basic concepts of cellular metabolism Explain anabolism, catabolism, chemical reactions, metabolic pathways and...

Royal College of Surgeons in Ireland Medical University of Bahrain Biochem: Introduction to Metabolism - FFP1-22 Salim Fredericks LEARNING OBJECTIVES Define metabolism Explain basic concepts of cellular metabolism Explain anabolism, catabolism, chemical reactions, metabolic pathways and energy transfer Outline the metabolic map that inter-relates carbohydrate, amino-acid and lipid metabolism; Describe the capture of energy in catabolic processes Describe the use of energy in anabolic processes Identify the common mechanisms of regulation in metabolism Outline the basis of inherited errors of metabolism and consequences of impaired enzyme activity Metabolism Metabolism is the sum of the chemical processes within an organism that are necessary to sustain life Metabolism involves a highly integrated network of chemical reactions. Many of the reactions of metabolism are concerned with generating or using energy What do organisms use energy for? Active transport of ions and molecules The performance of mechanical work in muscle contraction and other cellular movements Synthesis of macromolecules and other biomolecules from simple precursors Waste removal ATP is the common currency in the energy exchange economy Some reactions require the input of energy and other reactions release energy : energy can be transferred from one reaction to another Reactions need a common currency for them to exchange with one another. ATP is the common currency Adenosine triphosphate (ATP) is formed from the oxidation of food fuel. – The energy released from fuel compounds is captured in ATP This small and accessible molecule acts as the free- energy donor in most energy-requiring processes Much of metabolism is geared to generating ATP and NADH (…or using them) Carbohydrate, fatty acids and protein food stuffs are directly or indirectly metabolised to generate ATP and NADH through several pathways. Glycolysis β-oxidation TCA cycle Electron transport coupled to oxidative phosphorylation Hydrolysis and synthesis of ATP ATP + H20↔ ADP + Pi (-30.5 kJ/mol) The forward reaction liberates energy that can be used to drive other reactions The reverse reaction captures energy released from fuel compounds This ATP-ADP cycle is the fundamental mode of energy exchange in biology Generally, most energy-requiring reactions are coupled to ATP hydrolysis. A coupled reaction Glucose + Pi Glucose-6-Phosphate + H2O ΔG = +13.8 kJ/mol ATP + H20 ADP + Pi ΔG = -30.5 kJ/mol Glucose + ATP Glucose-6-Phosphate + ADP ΔG = -16.7 kJ/mol Many cellular reactions involve the exchange of electrons. NADH is a common currency in such Redox Reactions NAD+ Nicotinamide Adenine Dinucleotide You do not need to be able to draw these structures Coupled REDOX reactions During catabolism, hydrogen of substrate transferred to NAD+ & FAD NADH, FADH2 reoxidised to NAD+ and FAD by O2 in electron transport chain located at inner mitochondrial membrane Intermediary metabolism: The metabolic processes involved in the conversion of food to energy, structural and functional components of cells, energy storage and wastes. It includes the interconversion of carbohydrates, proteins and lipids. Intermediary metabolism: Lippencott’s 8.2 The metabolic processes involved in the conversion of food to energy, structural and functional components of cells, energy storage and wastes. It includes the interconversion of carbohydrates, proteins and lipids. Metabolism: Classification and characteristics of major metabolic pathways Metabolic pathways can be: CATABOLIC degradation of molecules; Complex  simple; exergonic (energy releasing) or ANABOLIC synthesis of molecules; simple  complex; Endergonic (energy requiring) ATP and NADH generated in catabolism can be used for anabolic reactions Monomers released from polymeric precursors provide building blocks for synthesis other macromolecules. Three types of metabolic pathways (a) Converging - catabolic; (b) diverging - anabolic; and (c) cyclic Interdependence and independence of anabolic and catabolic pathways CELLULAR MACROMOLECULES Generally, synthetic and degradative FOOD AND CELLULAR ENERGY RICH pathways are distinct. MACROMOLECULES cell membrane, cytoskeleton, organelles, ENERGY RICH enzymes, DNA, RNA, ribosomes, glycogen, starch, glycogen, fats fats The distinction allows for better control. ANABOLIC PATHWAY CATABOLIC PATHWAY SIMPLE ORGANIC MOLECULES This allows for both processes to MONOMERS ENERGY RICH occur at the same time, however this monosaccharides, fatty acids, generally does not occur in the same cell glycerol, amino acids ADP + Pi ATP METABOLIC INTERMEDIATES ENERGY RICH Although distinct, they are linked by glyceraldehyde-P, pyruvate, acetyl CoA, OAA(oxaloacetic acid) - energy coupling reactions ADP + Pi (ATP hydrolysis/synthesis) ATP - shared metabolic intermediates -shared substrates/products INORGANIC MOLECULES ENERGY-DEPLETED -shared enzymes, sometimes CO2, H2O, NH3 REGULATION OF METABOLIC PATHWAYS Each step of a metabolic pathway is catalyzed by a specific enzymes. Enzyme activity may be regulated in several different ways: 1. rate of enzyme synthesis/degradation 2. compartmentalization / subcellular localization 3. modification by another enzyme (eg by phosphorylation and dephosphorylation) 4. allosteric activators/inhibitors Regulation of metabolic pathways Often, metabolic pathways are regulated by allosteric feedback inhibition – that is the end product of the pathway inhibits the activity of an enzyme at or near the start of the pathway. This enzyme usually catalyzes the first, irreversible step (the committed step) in the pathway. Allosteric regulation allows for a rapid response to change. Cellular homeostasis Regulation of metabolic pathways is essential for cellular homeostasis Organisms keep the cells in a steady- state When steady-state is disturbed changes have to be made to return conditions back to normal Metabolic consequences of impaired enzyme activity C Enzyme A X B Metabolic consequences of impaired Enzyme action Accumulation of substrate A Deficiency of product B Diversion to alternate product C Major metabolic pathways and processes glycolysis, glycogenolysis, gluconeogenesis, glycogen synthesis CARBOHYDRATE METABOLISM (glycogenesis), anaerobic glycolysis, hexose monophosphate shunt (pentose phosphate pathway) amino acid synthesis, deamination, PROTEIN METABOLISM transamination, urea cycle, ketogenesis beta-oxidation, ketogenesis, lipolysis, LIPID METABOLISM fatty acid synthesis, triglyceride sythesis citric acid cycle (Krebs cycle, COMMON tricarboxylic acid cycle), oxidative phosphorylation Carbohydrate metabolism glycolysis Glycogen degradation of glucose to pyruvate glycogen glycogenolysis Kreb’s cycle (TCA, CAC) synthesis conversion of acetyl coA into carbon glucose dioxide, water and NADH gluconeogenesis glycolysis oxidative phosphorylation extraction of energy in NADH to pyruvate generate ATP gluconeogenesis synthesis of glucose from non- acetyl coA carbohydrate sources such as carbon skeletons of amino acids glycogenolysis Kreb’s cycle degradation of glycogen into glucose Oxidative phosphorylation glycogen synthesis synthesis of glycogen from glucose (from food sources) Lipid metabolism lipolysis the degradation of triglycerides into glycerol and fatty acids fatty acid oxidation Triglycerides the step-wise degradation of fatty acids into acetyl coA which can lipogenesis lipolysis enter the Kreb’s cycle glucose glycerol + fatty acids fatty acid synthesis glycerol synthesis synthesis of fatty acids from pyruvate fatty acid acetyl coA oxidation fatty acid synthesis glycerol synthesis synthesis from glycolytic acetyl coA intermediates ketone bodies lipogenesis synthesis of triglycerides from glycerol and fatty acids Protein metabolism proteolysis degradation of protein into Protein amino acids protein proteolysis synthesis protein synthesis amino acids glucose synthesis of proteins from gluconeogenesis amino acid glucogenic amino acid metabolism pyruvate amino acid catabolism degradation of amino acids into amino group and carbon ketogenic amino acid metabolism backbone acetyl coA glucogenic & ketogenic gluconeogenesis amino acid synthesis transamination Kreb’s cycle synthesis of amino acids by transamination transamination of metabolic urea cycle intermediates urea Intermediary metabolism Protein Glycogen Triglycerides protein glycogen glycogenolysis proteolysis synthesis synthesis lipogenesis lipolysis amino acids glucose gluconeogenesis glycerol + fatty acids glycolysis glucogenic amino acid glycerol synthesis metabolism fatty acid pyruvate fatty acid oxidation synthesis ketogenic amino acid metabolism acetyl coA gluconeogenesis ketone bodies transamination transamination Kreb’s cycle Oxidative phosphorylation urea cycle urea Further resources Reading: Lippincott Illustrated Reviews: Biochemistry, Marks' Basic Medical Biochemistry: A Clinical Approach. By Michael Lieberman, Alisa Peet, Principles of Medical Biochemistry. By Meisenberg and Simmons