Unit 6 - 7 Carbohydrate Metabolism PDF

CHY2026: General Biochemistry UNIT 7& 8: CARBOHYDRATE METABOLISM  Metabolism ❖ Bioenergetics is the transfer and utilization of energy in biological systems ❖ The direction and extent to which a chemical reaction proceeds is determined by the degre...

CHY2026: General Biochemistry UNIT 7& 8: CARBOHYDRATE METABOLISM  Metabolism ❖ Bioenergetics is the transfer and utilization of energy in biological systems ❖ The direction and extent to which a chemical reaction proceeds is determined by the degree to which two factors (enthalpy and entropy) change during the reaction ❖ Enthalpy (∆H) is a measure of the change in the heat content of reactants And products ❖ Entropy (∆S) is a measure of the change of randomness or disorder of reactants and products ❖ Changes in free energy (∆G) provide a measure of the energetic feasibility of a chemical reaction ❖ -∆G = there is a net loss of energy and reaction goes spontaneously ❖ + ∆G = there is a net gain of energy and the reaction does not go spontaneously ❖ ∆G = 0 the reactants are in equilibrium  Free Energy (∆G)  The free energy of the forward reaction is equal in magnitude but opposite in sign to the reversed reaction Fructose-6-phosphate to glucose 6-phosphate = -1.7 kJ/mol  The free energy of a reaction depends on the concentration of reactants and products at constant temp and pressure: Standard Free Energy (∆G°)  The ∆G°/ ∆G of two consecutive reactions are additive glucose + ATP glucose-6-phosphate + ADP ∆G° = -4000 cal mol-1 glucose – 6 – phosphate fructose – 6 – phosphate ∆G° = 400 cal mol-1 glucose + ATP fructose – 6 - phosphate ∆G° = -3600 cal mol-1 A thermodynamically unfavourable reaction can be driven by a thermodynamically favourable reaction that is coupled to it  The ∆G of a pathway are additive. This property becomes very important in biochemical pathways  As long as the sum of the ∆G of individual reactions is negative, the reaction can proceed as written, even if some of the individual reactions have a positive ∆G  Metabolism ❖ ATP is a high energy phosphate compound ❖ The ∆G° is approximately -7.3 kcalmol-1 for each of the two terminal phosphate groups Hydrolysis of some ATP related Compounds Source: Chemistry for Today by Seager and Slabaugh Metabolism – Coupling Reactions ❖ Some reactions need energy and some produce energy ❖ The strategy for making the ones that need energy to occur is to couple them with those that yield energy 1. ATP → ADP - 7.3 kcal/mol Glucose → Glu-6-phosphate +3.3 kcal/mol - 4 kcal/mol → HEAT) 2. Phosphoenolpyruvate → Pyruvate -14.8 kcal/mol ADP → ATP +7.3 kcal/mol - 7.5 kcal/mol → HEAT  Metabolism ❖ Metabolism is the assembly of biochemical reactions used by an organism for the synthesis of cell materials and the utilization of energy from the environment ❖ Metabolism → Anabolic (assimilation) or Catabolic (dissimilation)  Metabolism ❖ Anabolic reactions are the synthesis of large molecules from simple or smaller molecules ❖ Energy is used in the process → Endergonic A + B → AB [+∆G] ❖ Example, Photosynthesis sunlight; chlorophyll carbon dioxide + water → carbohydrate + oxygen ❖ Anabolic reactions are involved in chemical reduction  Metabolism ❖ Catabolic reactions are the breakdown of large molecules to smaller or simpler molecules ❖ Energy is released in this process → Exergonic AB → A + B [- ∆G] E.g. Digestion ❖ Catabolic reactions are typically oxidative and require the coenzymes NAD+ Metabolism http://web.virginia.edu/Heidi/chapter18/Images/8883n18_04.jpg Carbohydrate Metabolism  Carbohydrate Metabolism Catabolic Reactions Anabolic Reactions Glycolysis Gluconeogenesis Glycogenolysis ❖ Other reactions include TCA Cycle, Oxidative phosphorylation and electron transport  Carbohydrate Metabolism ❖ Carbohydrates are metabolized to yield a vast array of other organic compounds ❖ Animals ingest large quantities of carb. that can either be stored, oxidized to obtain energy, converted to lipid for more efficient energy storage or use for the synthesis of many cellular constituents ❖ Major function is to be oxidized and provide energy for metabolic processes ❖ Carbohydrate is utilized by the cells mainly as glucose ❖ Fructose and galactose are easily converted to glucose in the liver  Abnormal Lactose Metabolism ❖ More than ¾ of the world’s adult are lactose intolerant ❖ Up to 90 % of adults of African and Asian descent are lactase deficient  Glycolysis ❖ It is the central pathway of glucose catabolism ❖ This is a process by which glucose is broken down to produce energy to all cells Glucose 2 Pyruvate + 2 ATP + 2H+ (6 C) (3 C) ❖ It occurs in the cytoplasm of the cell …transporters carry glucose molecules to the cells ❖ It is a hub of carbohydrate metabolism because all sugars (whether from diet or via catabolic reactions) can be converted to glucose Glycolysis Total Input Total Output 1 molecule of glucose (6 C) 2 molecules pyruvate (3 C) 2 ATP 4 ATP 4 ADP 2 ADP 2 NAD 2 NADH 2 Pi 2 H2O Net gain = 2 ATP  Glycolysis ❖ The fate of pyruvate depends on the availability of oxygen ❖ If oxygen is present, pyruvate enters the mitochondria and will be oxidized to carbon dioxide and water (aerobic respiration) ❖ If oxygen is absent then pyruvate is converted into alcohol or lactate (anaerobic respiration) ❖ Supplemental info: http://www.bioinfo.org.cn/book/biochemistry/chapt14/sim1.htm - http://www.bioinfo.org.cn/book/biochemistry/chapt14/403.jpg  Aerobic Respiration ❖ This involves two phases 1. Oxidative decarboxylation of pyruvate – removal of CO2 and oxidation (removal of hydrogen) 2. TCA  Oxidative Decarboxylation of Pyruvate ❖ Occurs in the mitochondria (matrix) ❖ Pyruvate + coenzyme A (CoASH) + NAD+ pyruvate dehydrogenase acetyl CoA + CO2 + NADH + H+ ❖ Acetyl CoA TCA cycle ❖ NADH + H+ respiratory chain in the mitochondria  Oxidative Decarboxylation of Pyruvate ❖ A deficiency in pyruvate dehydrogenase leads to lactic acidosis ❖ Due to the prevention of acetyl CoA formation from pyruvate, the pyruvate therefore forms lactic acid ❖ TCA cycle provides most of the energy needed for the brain ❖ Since the TCA process is hindered, this deficiency can lead the developmental defects of the brain and nervous system  Tricarboxylic Acid Cycle  Tricarboxylic acid (TCA) cycle/ Krebs cycle/ citric acid cycle  Acetyl CoA is hydrolyzed to form acetyl  A series of reactions then follows which results in the formation of 2  molecules of CO2 and 1 molecule of ATP  Energy from Acetyl CoA Energy Producing Reaction Number of ATP Produced 3 NADH 3 NAD+ 3 x 2.5 = 7.5 FADH2 FAD 1 x 1.5 = 1.5 GDP + Pi GTP 1 x 1 = 1.0 10 ATP/acetyl CoA oxidized  Energy from NADH ❖ NADH produced in the cytoplasm do not pass through the mitochondrial membrane to the site of electron transport chain. ❖ Brain and muscle cells employ a transport mechanism that passes electrons from the cytoplasmic NADH through the membrane to FAD inside the mitochondria, forming FADH2 1 cytoplasmic NADH = 1.5 ATP molecules (glycerol phosphate shuttle) ❖ Liver, heart and kidney cells employ a different mechanism by which electrons are passed from NADH 1 mitochondrial NADH = 2.5 ATP molecules (malate-aspartate shuttle)  Carboxylation of Pyruvate ❖ Since the oxidation of 1 molecule glucose ↓ 2 molecules of acetyl CoA ❖ The TCA cycle occurs twice for every molecule of glucose oxidized ❖ The net result is 2 ATP and 4 CO2 ❖ The overall reaction for glycolysis, acetyl CoA formation and TCA cycle is C6H12O6 + 6 H2O 6CO2 + 4 ATP + 12 H+  Electron Transport Chain  The reaction occurs in the inner mitochondrial membrane  Electrons from intermediates in Glycolysis and the TCA cycle are donated to specific coenzymes (NAD+ and FAD) to form energy-rich reduced co- enzymes (NADH and FADH2)  Each reduced co-enzyme donate a pair of electrons to electron carriers (NADH dehydrogenase (Complex 1), flavoprotein (Complex II), coenzyme Q (ubiquinone), cytochrome bc1 (Complex III), cytochrome c (Complex IV) and cytochrome a+a3 (Complex V)  As electrons are passed down the chain they lose some of their free energy. At the end of the chain, hydrogen combines with oxygen to form water  Oxidative Phosphorylation ❖ Oxidative phosphorylation is the process by which ATP is formed as a result of the transfer of electrons from NADH and FADH2 ❖ The reaction occurs in the inner mitochondrial membrane http://files.cellularenergytextbook.webnode.com/200000006-39b4c3aaf1/pic9.jpg  Anaerobic Respiration In Plants Pyruvate + NADH + H+ → Ethanol + CO2 + NAD+  This occurs in yeast cells and other microorganisms  Anaerobic Respiration ❖ In Animals … Pyruvate is converted to lactate ❖ The reaction is catalysed by lactase dehydrogenase ❖ This occurs in the red blood cells, exercising muscles and anoxic tissues  Glycogenolysis ❖ This is the breakdown of glycogen in the liver and skeletal muscle to produce glucose ❖ It is not the reversal of glycogen synthesis (glycogenesis) http://chemistry.gravitywaves.com/CHE452/images/Glycogenolysis.GIF  In-borne Errors of Carbohydrate Metabolism ❖ Skeletal muscle - glycogen phosphorylase deficiency results in McArdle syndrome (Cori Type V) ❖ Symptoms include – (a) temporary weakness and cramping of skeletal muscle after exercise (b) no rise in blood lactate after strenuous exercise (c) High levels of glycogen  In-borne Errors of Cabohydrate Metabolism ❖ Glucose-6-phosphatase deficiency results in Von Gierke disease (Cori Type 1a) ❖ Symptoms include – (a) severe fasting hypoglycaemia (b) progressive renal disease (c) increased stored glycogen  Glycogen Metabolism ❖ Glycogen metabolism is regulated by the hormones insulin, glucagon and epinephrine ❖ Insulin (β-cells pancreas) induces the synthesis of glycogen when the blood glucose concentration is high ❖ Glucagon and epinephrine induces the breakdown of glycogen when the blood glucose concentration is low ❖ Epinephrine (adrenal medulla) stimulates glycogen breakdown in the muscle ❖ Glucagon (α-cells pancreas) stimulates glycogen breakdown in the liver  Pentose Phosphate Pathway ❖Also called the hexose monophosphate shunt or 6- phosphogluconate pathway ❖ The reaction occurs in the cytosol of the cell ❖ The reaction produces NADPH and 5-C sugars The pathway is divided into two portions (a) Irreversible oxidative reactions (b) Reversible non oxidative reactions  Irreversible Oxidative Reactions ❖ This portion results in the formation of ribulose-5-phosphate, CO2 and NADPH per molecule of glucose-6-phosphate oxidized ❖ NADPH needed for the synthesis of steroids, fatty acid synthesis, drug metabolism and to keep glutathione in the reduced form in the erythrocytes  Reversible Non oxidative Reactions ❖ This set of reaction occurs in all cell types Ribose-5-phosphate nucleotide synthesis Glyceraldehyde-3-phosphate and fructose-6-phosphate intermediate for glycolysis  G6PD Deficiency ❖ Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a hereditary disease characterized by haemolytic anaemia ❖ This occurs due to the reduction of NADPH formation and thus a decrease in [reduced decrease glutathione] in [reduced leading glutathione] to atoreduction leading in the a reduction in the detoxification of free radicals ❖ Reduced glutathione helps to prevent the formation of denatured proteins that will attach to the red blood cells and damage to the cell wall resulting in haemolysis  Gluconeogenesis ❖ This is the synthesis of glucose from non carbohydrate precursors ❖ The major non carbohydrate precursors are (1) Lactate – formed from pyruvate under anaerobic conditions (2) Amino acid – digestion of proteins and breakdown of proteins from skeletal muscles during starvation (3) Glycerol – hydrolysis of triglycerides ❖ This process provides a continuous supply of glucose as metabolic fuel ❖ Areas that need this continuous supply include the brain, red blood cells, kidney medulla, lens and cornea of the eye, testes, and exercising muscles  Gluconeogenesis ❖ Stored glycogen can only provide 10 – 18 h of glucose in the absence of carbohydrate intake from the diet (Glycogenolysis) ❖ During prolonged fast, glucose must be formed from non carbohydrate sources ❖ During an overnight fast 90% of gluconeogenesis occurs in liver 10% of gluconeogenesis occurs in kidneys ❖ During prolonged fasting, the kidneys are the major glucose producing organ (40 %) ❖ Gluconeogenesis requires both mitochondrial and cytosolic enzymes