Lecture 16 Chapters 17 26 Gluconeogenesis and the Pentose Phosphate Pathway Gluconeogenesis is an important metabolic pathway during 6mes of fas6ng Outline Glucose can be synthesized from noncarbohydrate precursors Gluconeogenesis and glycolysis are reciprocally regulated The Cori cycle Purpose of the Pentose Phosphate Pathway PPP Oxida6ve phase Nonoxida6ve phase Balancing the cellular needs for ATP NADPH and ribose 5 P The Liver Regulates Blood Sugar Levels Amino Lactate glycerol acids Gluconeogenesis Glycogenolysis Converted to glucose Lactate To the liver hOp dtc ucsf edu types of diabetes type1 understanding type 1 diabetes how the body processes sugar the liver blood sugar In some ways Gluconeogenesis is the reverse of Glycolysis Glycolysis Gluconeogenesis Glucose is catabolized Glucose is synthesized ATP is produced ATP is consumed NAD is reduced to NADH NADH is oxidized to NAD However the reac6ons in the Gluconeogenesis pathway CANNOT be the exact reverse of the reac6ons in the Glycolysis pathway WHY Gluconeogenesis is not exactly the reverse of Glycolysis Hexokinase Glucose 6 Phosphatase G 33 kJ mol 1 Phosphofructokinase PFK 2 Fructose 1 6 bisphosphatase F 1 6 BPase G 22 kJ mol 1 Pyruvate Kinase G 17 kJ mol 1 G 84 kJ mol 1 2 ATP Pyruvate Carboxylase PEP Carboxykinase G 38 kJ mol 1 6 ATP equivalent Glycolysis Reac6on 10 G 31 7 kJ mol after removing the energy used to phosphorylate ADP Pyruvate kinase Gluconeogenesis Reac6ons 1 2 Pyruvate carboxylase ATP CO2 ADP PEP Carboxykinase GTP ADP CO2 7 Pyruvate is Converted to Oxaloacetate in Mitochondria In Mitochondria Citric acid cycle Pyruvate carboxylase requires the vitamin bio6n vit B7 as a coenzyme proesthe6c group Acetyl CoA CO2 Carboxybio6n In Mitochondria Citric acid cycle Carboxyla6on of Pyruvate Pyruvate Carboxylate carboxyphosphate Carboxylated bio6n G for the last step is 20 kJ mol 1 Oxaloacetate must move out to the cytoplasm to be converted to PEP mitochondria mitochondria Oxalacetate can then be converted to Phosphophenolpyruvate kinase PEP Need two molecules of pyruvate to generate one glucose Pyruvate PEP Gluconeogenic speci c enzymes aldolase F1 6P GAP Gluconeogenesis is not merely exactly the reverse of Glycolysis Hexokinase Glucose 6 Phosphatase G 33 kJ mol 1 Phosphofructokinase PFK 2 Fructose 1 6 bisphosphatase F 1 6 Bpase G 22 kJ mol 1 Pyruvate Kinase G 17 kJ mol 1 G 84 kJ mol 1 2 ATP Pyruvate Carboxylase PEP Carboxykinase G 38 kJ mol 1 6 ATP The conversion of fructose 1 6 bisphosphate into fructose 6 phosphate Gluconeogenesis is not merely exactly the reverse of Glycolysis Hexokinase Glucose 6 Phosphatase G 13 kJ mol G 33 kJ mol 1 Phosphofructokinase PFK 2 Fructose 1 6 bisphosphatase F 1 6 Bpase G 16 kJ mol G 22 kJ mol 1 Pyruvate Kinase G 17 kJ mol 1 G 84 kJ mol 1 2 ATP Pyruvate Carboxylase G 25 kJ mol PEP Carboxykinase G 38 kJ mol 1 6 ATP Need two molecules of pyruvate to generate one glucose Gluconeogenic speci c enzymes The genera6on of glucose from glucose 6 phosphate Overall cost of gluconeogenesis Coordinated Reciprocal Regula6on of Glycolysis and Gluconeogenesis Energy Status of the cell And Blood SugarLevel Glucose metabolism High blood glucose glycolysis Glycogen synthesis FA synthesis Insulin release Low blood glucose gluconeogenesis Glycogen breakdown TG breakdown Decrease blood sugar level Glucose metabolism High blood glucose Glycolysis Glycogen synthesis FA synthesis Glucagon release Low blood glucose Gluconeogenesis Glycogen breakdown TG breakdown Increase blood sugar level Reciprocal regula6on Glycolysis Acetyl CoA PKA Gluconeogenesis Reciprocal regula6on ADP PFK PFK1 citrate Fructose 2 6 bisphosphate F2 6 BP Phosphofructokinase 2 PFK2 PFK1 Inac6vates F1 6 BPase The domain structure of the bifunc6onal regulatory enzyme phosphofructokinase 2 PFK2 fructose 2 6 bisphosphatase X The domain structure of the bifunc6onal regulatory enzyme phosphofructokinase 2 PFK2 fructose 2 6 bisphosphatase F6P S6mulates PFK1 glycolysis F2 6BP Inhibits F1 6 Bisphosphatase gluconeogenesis X The domain structure of the bifunc6onal regulatory enzyme phosphofructokinase 2 PFK2 fructose 2 6 bisphosphatase P F2 6BP F6P Glycolysis Gluconeogenesis LOW BLOOD SUGAR causes phosphoryla6on of the bifunc6onal regulatory enzyme phosphofructokinase 2 PFK2 fructose 2 6 bisphosphatase Glucagon PKA ATP ADP P X PKA inhibits PFK2 F2 6BP F6P X HIGH BLOOD SUGAR dephosphorylate the bifunc6onal regulatory enzyme phosphofructokinase 2 PFK2 fructose 2 6 bisphosphatase Insulin high F6P Pi Phosphoprotein Phosphatase P H2O inhibits F2 6BPase F6P F2 6BP Hormonal Regula6on Glucagon Glucagon receptor cAMP PKA Enzyme phosphoryla6on The ac6va6on of protein kinase A by a G protein pathway glucagon Chapt 13 p218 Glucagon receptor The regula6on of protein kinase A R regulatory domain C cataly6c domain glucagon insulin Glucagon receptor S6mulates phosphoprotein phosphatase X Dephosphorylates PKA substrates Gluconeogenesis precursors Lactate Some amino acids Pyruvate Some amino acids PEP Glycerol GAP The Cori Cycle Fate of Pyruvate under ANAEROBIC condi6ons in animals and other microorganisms Lac6c acid Fermenta6on LDH Reversible reac6on Blood sugar too high insulin Low energy charge Low ATP s6mulates glycolysis insulin Inhibit gluconeogenesis Generates ATP Generates anabolic precursors Lowers blood sugar level Increases blood sugar level Uses ATP Blood sugar too Low glucagon High energy charge High ATP s6mulates Inhibit glycolysis glucagon gluconeogenesis Generates ATP Generates anabolic precursors Lowers blood sugar level Increases blood sugar level Uses ATP Learn from top down Insulin take glucose out of the blood Glucagon adds glucose to the blood Learn the purpose of each pathway Determine if by insulin glucagon and energy charge ATP AMP Glycolysis takes glucose out of the blood makes ATP Gluconeogenesis adds glucose to the blood uses ATP The Pentose Phosphate Pathway Glucose 6 P is common to several metabolic pathways Glycogen Glucoronate Glucosamine 6 phosphate Pathways Requiring NADPH Source of biosynthe6c reducing power in all organisms Synthesis FaOy acid Cholesterol NeurotransmiOer Nucleo6de Detoxi caPon Reduc6on of oxidized glutathione Cytochrome p450 monooxygenase Two phases of PPP Oxida6ve phase NADPH Ribulose 5 phosphate Irreversible Non oxida6ve phase interconversion of sugars Reversible Phase 1 Oxida6ve phase In three irreversible steps H2O 2H Phase 2 Non Oxida6ve Isomeriza6on Ketopentose aldopentose Epimeriza6on The nonoxida6ve
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