Energy Metabolism Past Paper 2022

Energy Metabolism Dr Nick Hopcroft Academic Lead for Cell and Tissue Biomedicine [email protected]  Learning Outcomes Glycolysis Oxidative decarboxylation Krebs cycle β-oxidation of fatty acids Electron transport chain and ATP synthesis Energy sto...

Energy Metabolism Dr Nick Hopcroft Academic Lead for Cell and Tissue Biomedicine [email protected]  Learning Outcomes Glycolysis Oxidative decarboxylation Krebs cycle β-oxidation of fatty acids Electron transport chain and ATP synthesis Energy storage and utilisation of stores Gluconeogenesis Urea cycle Roles of different organs Metabolic Response to Food Blood glucose  Pancreas Insulin (b cells) Glucose uptake by cells  Glucose Transporters Transporter Affinity Specificity Tissue Comments Km (mM) distribution Passive transport GLUT-1 1.5 Glucose, RBCs, brain, Basal uptake galactose, ubiquitous (high mannose affinity) GLUT-2 15.0 Glucose, Liver, Glucose fructose pancreatic -cell sensing (low affinity) GLUT-3 1.8 Glucose Brain, intestine, placenta GLUT-4 5.0 Glucose Muscle (Sk, Insulin Card), sensitive adipose GLUT-5 10.0 Fructose Intestine Active transport SGLT-1 0.3 2 glucose, Intestine Na+, Kidney galactose  Glycolysis Glucose ATP Hexokinase ADP Glucose-6-P Isomerase ATP Fructose-6-P Phosphofructokinase ADP Fructose-1,6-bis-P Aldolase Nicotinamide adenine dinucleotide Dihydroxyacetone-P Glyceraldehyde-3-P + Isomerase NAD Pi Dehydrogenase NADH 1,3-bisphosphoglycerate ADP Phosphoglycerate kinase ATP 3-phosphoglycerate Mutase 2-phosphoglycerate Enolase + NAD NADH Phosphoenolpyruvate ADP Pyruvate kinase Lactic ATP acid Pyruvate Lactate dehydrogenase  Mitochondria – Oxidative Phosphorylation Most ATP formation takes place in the mitochondria and requires O2 The Krebs cycle occurs in the mitochondrial matrix The electron transport chain is on the inner mitochondrial membrane Inner membrane Outer membrane Strictly controls Permeable to small molecule movement across it through the presence of specific carriers  Oxidative Decarboxylation Import of pyruvate from glycolysis into the mitochondria involves oxidative decarboxylation This produces acetyl-CoA and NADH inside the mitochondria 7  Oxidative Phosphorylation NADH from glycolysis and oxidative decarboxylation carries electrons that can be used in the presence of O2 to make more ATP In the mitochondria, NADH is oxidised using the electron transport chain and the energy released used to make ATP Acetyl-CoA from glycolysis, followed by oxidative decarboxylation, can be used in the Krebs cycle, in the presence of O2, to make more NADH, plus FADH2, for use in the electron transport chain  Krebs Cycle Oxidation of Acetyl-CoA to Acetyl-CoA Also known as: produce NADH and FADH2 2C Citric acid CoA cycle NADH Oxaloacetate Tricarboxylic 4C Citrate acid cycle NAD 6C Malate 4C Isocitrate 6C NAD NADH 4C Fumarate CO2 Ketoglutarate FADH2 5C Flavin adenine CoA dinucleotide FAD 4C Succinate NAD 4C Succinyl-CoA NADH CoA CO2 GTP GDP  β-oxidation of Fatty Acids O C C C C Flavin adenine * CoA dinucleotide FAD H2 O C C C C * CoA OH O C C C C * CoA Nicotinamide adenine dinucleotide NADH H O O H C C H CoA C C C C * CoA Acetyl-CoA Production of NADH and FADH2 Triglycerid es β-oxidation FADH2 + NADH Oxidative Glycolysis decarboxylation Krebs cycle ATP NADH NADH FADH2 + NADH Electron transport chain ATP  Electron Transport Chain O2 is the ultimate electron acceptor Energy from oxidation (removing electrons) of NADH and FADH 2 is used to pump H+ across the mitochondrial inner membrane against their concentration gradient As H+ moves back across the membrane through ATP synthase, ATP is produced from ADP Total ATP Yield from Glucose ATP equivalents Glycolysis 2 ATP 2 2 NADH 6 Oxidative decarboxylation (link reaction) 2 NADH 6 Krebs cycle 6 NADH 18 2 FADH2 4 2 GTP 2  Metabolic Response to Food Blood glucose  Pancreas Insulin (b cells) Glycogenesis Lipogenesis Protein synthesis Anabolic reactions – large molecules made from smaller parts  Energy Storage Glucose Glycogen Glycogen esis Glucose-6-P (liver, skeletal muscle) Fructose-6-P Fructose-1,6-bis-P Dihydroxyacetone-P Glyceraldehyde-3-P Glycoly sis Glycerol-3- P Triglycerides Fatty Phospholipids acids ketone (β-oxidation, Lipogenesis bodies produced by liver) Protein Lactate Pyruva Amino acidssynthesis Protein te Metabolic Response to Starvation Blood glucose  Glucagon Pancreas (α cells) Lipolysis Glycogenolysis Gluconeogenesis Free fatty acids Ketone bodies Glucose  Utilisation of Energy Stores Glucose Glycogen Glycogen esis Glucose-6-P (liver, skeletal Glycogenol muscle) ysis Fructose-6-P Fructose-1,6-bis-P Dihydroxyacetone-P Glyceraldehyde-3-P Glycoly sis Glycerol-3- P Gluconeogenesis Triglycerides Fatty Lipolysis Phospholipids acids (β-oxidation, ketone Lipogenesis bodies produced by liver) Lactate Pyruva Amino acids Protein te  Gluconeogenesis Gluconeogenesis is the formation of ‘new’ glucose from non-carbohydrate sources Virtually all gluconeogenesis takes place in the liver and the process requires energy The three sources are glycerol from triglycerides, lactate from anaerobic glycolysis and amino acids from proteins  The regenerated glucose is available for further glycolysis in other tissues Glucose Glucose This is known Pyruvate as the Cori Pyruvate cycle Lactate Lactate The lactate is transported to During vigorous exercise, the liver, where it is muscle metabolism switches converted to glucose by to anaerobic glycolysis, gluconeogenesis, albeit generating lactate requiring energy to do so  Biosynthetic Roles of the Krebs Cycle Alanine, Cysteine Glycine, Serine, Threonine Leucine Tryptophan Synthesis of glucose Lysine Isoleucine Phenylalanine (Gluconeogenesis) Leucine Tryptophan Tryptophan Tyrosine pyruvate acetyl-CoA Acetoacetyl-CoA Ketone bodies Arginine Oxaloace Aspartate tate Citrate Malat Isocitra e te Aspartate Krebs cycle Glutamate Phenylalanine Fumar (liver) Glutamine Tyrosine ate Ketogluta Arginine rate Histidine Proline Isoleucine Succina Methionine Threonine te Succinyl- Valine CoA  Amino Acid Metabolism Amino acids require deamination (removal of the amino group, -NH2) before they can be used for glucose/lipid synthesis This is achieved through a series of transamination reactions before urea formation Urea is produced in the liver via the urea cycle and released into the bloodstream Urea is the main nitrogen-containing compound that is excreted through the kidneys, as it is less toxic than ammonia Urea Urea Cycle and Krebs Cycle (Amino acid) (Amino acid) (Amino acid) Urea Kreb cycle s cycle Argini neacid) (Amino Tissue Variations in Energy Source Glucose for most tissues, obligatory for brain and RBCs Fatty acids for most tissues, but minimal in neurons as a source of energy Ketones can be used by most tissues, but not the liver (where they are synthesised); important for the brain as a partial substitute for glucose when this is less available Amino acids not used as fuels by many cell types, but are used (particularly glutamine) in fast-dividing cells e.g. cancer cells  Glucose Glycogen Glucose Glucose Glycogen Lactate Glucose  Recommended Reading Medical Sciences, Naish and Syndercombe Court, Chapter 3