Lecture 16 Chapters 17 26 Gluconeogenesis and the Pentose Phosphate Pathway Gluconeogenesis is an important metabolic pathway during times of fasting Outline Glucose can be synthesized from noncarbohydrate precursors Gluconeogenesis and glycolysis are reciprocally regulated The Cori cycle Purpose of the Pentose Phosphate Pathway PPP Oxidative phase Nonoxidative phase Balancing the cellular needs for ATP NADPH and ribose 5 P The Liver Regulates Blood Sugar Levels Lactate glycerol Amino acids Gluconeogenesis Glycogenolysis Converted to glucose Lactate To the liver http dtc ucsf edu types of diabetes type1 understandingtype 1 diabetes how the body processes sugar the liverblood 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 reactions in the Gluconeogenesis pathway CANNOT be the exact reverse of the reactions 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 Reaction 10 G 31 7 kJ mol after removing the energy used to phosphorylate ADP Pyruvate kinase Gluconeogenesis Reactions 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 biotin vit B7 as a coenzyme proesthetic group Acetyl CoA CO2 Carboxybiotin In Mitochondria Citric acid cycle Carboxylation of Pyruvate Pyruvate Carboxylate carboxyphosphate Carboxylated biotin 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 specific 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 G 33 kJ mol 1 Phosphofructokinase PFK G 22 kJ mol 1 Pyruvate Kinase G 17 kJ mol 1 G 84 kJ mol 1 2 ATP Glucose 6 Phosphatase G 13 kJ mol 2 Fructose 1 6 bisphosphatase F 1 6 Bpase G 16 kJ mol 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 specific enzymes The generation of glucose from glucose 6 phosphate Overall cost of gluconeogenesis Coordinated Reciprocal Regulation 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 Glucagon release Glycolysis Glycogen synthesis FA synthesis Increase blood sugar level Low blood glucose Gluconeogenesis Glycogen breakdown TG breakdown Reciprocal regulation Glycolysis Acetyl CoA PKA Gluconeogenesis Reciprocal regulation ADP PFK PFK1 citrate Fructose 2 6 bisphosphate F2 6 BP Phosphofructokinase 2 PFK2 PFK1 Inactivates F1 6 BPase The domain structure of the bifunctional regulatory enzyme phosphofructokinase 2 PFK2 fructose 2 6 bisphosphatase The domain structure of the bifunctional regulatory enzyme phosphofructokinase 2 PFK2 fructose 2 6 bisphosphatase X Stimulates PFK1 glycolysis F6P F2 6BP Inhibits F1 6 Bisphosphatase gluconeogenesis The domain structure of the bifunctional regulatory enzyme phosphofructokinase 2 PFK2 fructose 2 6 bisphosphatase P X F2 6BP Glycolysis Gluconeogenesis F6P LOW BLOOD SUGAR causes phosphorylation of the bifunctional regulatory enzyme phosphofructokinase 2 PFK2 fructose 2 6bisphosphatase Glucagon ATP PKA P ADP PKA inhibits PFK2 X F2 6BP F6P HIGH BLOOD SUGAR dephosphorylate the bifunctional regulatory enzyme phosphofructokinase 2 PFK2 fructose 2 6 bisphosphatase Insulin high F6P Pi Phosphoprotein Phosphatase P H2O F6P inhibits F2 6BPase X F2 6BP Hormonal Regulation Glucagon Glucagon receptor cAMP PKA Enzyme phosphorylation The activation of protein kinase A by a G protein pathway glucagon Chapt 13 p218 Glucagon receptor The regulation of protein kinase A R regulatory domain C catalytic domain glucagon insulin Glucagon receptor Stimulates 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 conditions in animals and other microorganisms Lactic acid Fermentation LDH Reversible reaction Blood sugar too high insulin Low energy charge Low ATP stimulates 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 stimulates 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 biosynthetic reducing power in all organisms Synthesis Fatty acid Cholesterol Neurotransmitter Nucleotide Detoxification Reduction of oxidized glutathione Cytochrome p450 monooxygenase Two phases of PPP Oxidative phase NADPH Ribulose 5 phosphate Irreversible Non oxidative phase interconversion of sugars Reversible Phase 1 Oxidative phase In three irreversible steps H2 O 2H Phase 2 Non Oxidative Isomerization
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