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London South Bank University

Dr. Mohammed Mansour

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carbohydrates metabolism biochemistry metabolic pathways London South Bank University

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These lecture notes cover carbohydrates metabolism 2, a biochemistry module from London South Bank University. The notes discuss learning outcomes, a quick recap of glycolysis and the TCA cycle, the site of synthesis, the major functional compartments of mitochondria, and the mechanisms of action of enzymes such as pyruvate dehydrogenase. They also discuss the catabolic and anabolic roles of the TCA cycle, its regulation, the electron transport chain, and gluconeogenesis.

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Module: Biochemistry Carbohydrates metabolism 2 Dr Mohammed Mansour Senior Lecturer in Biomedical Science, London South Bank University, UK E: [email protected] Learning outcomes 1) Identify key carbohydrate metabolic pathways including Krebs cycle, and gluconeoge...

Module: Biochemistry Carbohydrates metabolism 2 Dr Mohammed Mansour Senior Lecturer in Biomedical Science, London South Bank University, UK E: [email protected] Learning outcomes 1) Identify key carbohydrate metabolic pathways including Krebs cycle, and gluconeogenesis. 2) Demonstrate the ability to describe the metabolic regulation. 3) Explain interconnection between metabolic pathways. A quick recap.... In earlier lectures, we saw that glucose is degraded to pyruvate by glycolysis Pyruvate is taken into the mitochondria and converted into acetyl-CoA, which is metabolised by the TCA cycle The TCA cycle yields energy-rich NADH and FADH2 molecules We need to convert the energy in NADH and FADH2 into ATP 3/56 Tricarboxylic acid cycle Introduction: The citric acid cycle, Krebs cycle, or tricarboxylic acid cycle is the pathway that occurs in mitochondria that oxidises acetyl-CoA and reduces the coenzymes NADH+ and FADH2 reoxidised through the electron transport chain. The third phase of metabolism is the citric acid cycle. The carbohydrate, lipid and protein finally meet in this pathway, because glucose, fatty acids and most amino acids are catabolised to acetyl-CoA or any of the intermediates of this pathway. Site of synthesis Tricarboxylic acid (TCA) cycle takes place in most of the tissues, but liver is the only tissue where it occurs to a significant extent. The enzymes of the citric acid cycle are located in the mitochondrial matrix, either free or attached to the inner mitochondrial membrane and the crista membrane, where the enzymes of the respiratory chain are also found. The major functional compartments of mitochondria The main functional compartments are: (i) the outer membrane (ii) the intermembrane space (iii) the inner membrane (iv) the cristae (v) the matrix (central space) 4/56 Pyruvate dehydrogenase How much ATPs is produced by 1 molecule glucose metabolism?? N.B. 1 NADH+=3 ATP 1FADH2=2 ATP GTP=ATP Catabolic process: The cycle helps in the degradation of acetyl residues, which are derived from carbohydrates, fats, proteins, and so on. Anabolic process: The intermediates of TCA cycle are used as precursors in the biosynthesis of many compounds. Amphibolic Role of TCA Cycle The word ‘amphi’ means both—the anabolic and catabolic reactions occur in the same pathway or cycle and hence TCA cycle is regarded as ‘amphibolic’. Anabolic Role 1) Amino Acid Metabolism A number of glycogenic amino acids enters the TCA cycle via transamination reactions. 2) Lipid Metabolism: Acetyl-CoA and glycerol are needed for the synthesis of steroids and fatty acids. For porphyrin synthesis, succinyl-CoA and glycerol are required as precursors. TCA cycle is thus involved in synthesis of haemoglobin, cytochromes and haemoproteins. 3) Nitrogen Metabolism Aspartate, which is formed from oxaloacetate through transamination reaction, is used for the synthesis of argininosuccinate and purines. The final product of this process is fumarate, which enters the TCA cycle. Catabolic Role The oxidation of acetyl-CoA of TCA cycle produces energy, CO2, and water. Regulation of TCA cycle The cellular demands of ATP are crucial in controlling the rate of citric acid cycle. The regulation is brought about either by enzymes or the levels of ADP. Three enzymes, namely citrate synthase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase, regulate citric acid cycle. Regulatory enzymes of the TCA cycle include citrate synthase, isocitrate dehydrogenase, and α- ketoglutarate dehydrogenase complex. High accumulation of ATP:ADP, so high concentration of acetyl-CoA and NADH : NAD+ ratio inhibit the TCA cycle at the respective steps. The mitochondrial inner membrane Inner membrane Unlike the outer membrane, the inner membrane has no porins, so is highly impermeable to almost all molecules The barrier is strengthened by incorporating a high proportion of the specialised phospholipid cardiolipin It has a very high protein content (76%), and is folded into many cristae 6/56 Role of the electron transport chain Complex Complex Complex Complex I II III IV Inter-membrane space Mitochondrial matrix The electron transport chain (also called the respiratory chain) is used to convert the energy from the high energy electrons stored in NADH and FADH2 molecules, into useful ATP energy The electrons from NADH and FADH2 are passed through 4 complexes (I-IV) in order to achieve this 7/56 A hydrogen ion gradient is generated A small fraction of the water molecules in a solution will spontaneously split to yield a hydroxyl ion (OH-) and a hydrogen ion (H+) A hydrogen ion is simply a proton These readily recombine to produce water (H2O, neutral) 8/56 The ETC pumps hydrogen ions out of the matrix H+ H+ H+ H+ H+ H+ H+ H+ H+ H+ H+ H+ H+ H+ H+ H+ H+ H+ Inter-membrane H+ H+ H+ H+ H+ H+ space H+ H+ H+ I II III IV H+ Mitochondrial H+ H+ matrix H+ Together, the 4 multi-protein complexes of the electron transport chain use the energy from electrons in NADH and FADH2 to pump hydrogen ions across the inner 9/56 membrane, out of the matrix A proton motive force is generated H+ [High concentration H of H +] + H+ H+ H+ H+ H+ H+ H+ H+ H+ H+ H+ Inter-membrane + H+ H+ H+ H+ H+ H+ H+ H+ space H+ H+ -160 mV I II III IV - H+ H+ Mitochondrial H+ [Low concentration of H +] matrix The proton motive force derives both from the H+ ion concentration gradient AND the voltage across the membrane The hydrogen ions experience a strong “pull” back into 10/56 the matrix - this is called the proton motive force This hydrogen ion gradient is used by ATP synthase to generate ATP The ATP synthase complex uses the force from the returning H+ ions to force a phosphate group onto ADP, so forming ATP The proton motive force, together with the voltage across the membrane, drives this return of hydrogen ions 11/56 The routes taken by the electrons NADH 2 e- Complex I Complex II 2 e- FADH2 Redox potential (mV) Coenzyme Q Complex III Cytochrome c Complex IV Tip! Remember this order O2 H2O 12/56 The overall picture of the electron transport chain Electrons from NADH and FADH2 travel through complex I or II respectively, then to CoQ, then through complex III, Cyt C and complex IV, then finally to oxygen 23/56 Thank you Dr. Mohammed Mansour E: [email protected] Quiz 1 Reactions of TCA cycle occur in: 1) Cytosol 2) Mitochondria 3) Both of them Quiz 2 Pyruvate is converted to Acetyl CoA by the enzyme: 1) Pyruvate dehydrogenase 2) Acetyl CoA synthase 3) Acetyl CoA synthetase Quiz 3 The number of ATPs generated by 1 molecule of Glucose metabolism is……….. Explain your answer. Quiz 4 Citrate synthase is one of the 3 TCA cycle regulatory enzymes. 1) True 2) False Quiz 5 Malate dehydrogenase is one of the 3 TCA cycle regulatory enzymes. 1) True 2) False Gluconeogenesis Introduction: The synthesis of glucose of glycogen from a non- carbohydrate compounds is known as gluconeogenesis. The major substrates precursors for gluconeogenesis are lactate and pyruvate, glucogenic amino acids, propionate, and glycerol. Biomedical importance Liver and kidney are the major gluconeogenic tissues. Gluconeogenesis meets the glucose requirement of the body when carbohydrate is not available in the required amount from the diet or from glycogen reserves. Erythrocytes and nervous systems especially require glucose as energy fuel, so supply of glucose is a must for these tissues. Failure of gluconeogenesis is usually fatal. Location Gluconeogenesis mainly occurs in the cytosol. Gluconeogenesis mostly takes place in the liver and, to some extent, in the kidney matrix. Reactions of gluconeogenesis Gluconeogenesis closely resembles the reversed pathway of glycolysis, the citric acid cycle, and some special reactions. The three stages bypassed by alternate enzymes specific to gluconeogenesis are discussed here: 1) Conversion of Pyruvate to Phosphoenol Pyruvate This takes place in two steps. Pyruvate carboxylase is a biotin-dependent mitochondrial enzyme that converts pyruvate to oxaloacetate in the presence of ATP and CO2. This enzyme regulates gluconeogenesis. Oxaloacetate is synthesised in the mitochondrial matrix. It has to be transported to cytosol to be used in gluconeogenesis, where the rest of the pathway occurs. In the cytosol, phosphoenol pyruvate carboxylase converts oxaloacetate to phosphoenol pyruvate. 2) Conversion of Fructose 1,6-bisphosphate to Fructose 6- Phosphate -Phosphoenol pyruvate undergoes the reversal of glycolysis until fructose 1,6-bisphosphate is produced. The enzyme fructose 1,6-bisphosphatase converts fructose 1,6 bisphosphate to fructose 6-phosphate. 3) Conversion of Glucose 6-phosphate to Glucose -Glucose 6-phosphatase catalyses the conversion of glucose 6-phosphate to glucose. Thank you Dr. Mohammed Mansour E: [email protected]

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