Lecture 16 Chapters 17 26 Gluconeogenesis and the Pentose Phosphate Pathway 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 Glycerol Amino acids Lactate Lactate 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 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 G 33 kJ mol 1 G 22 kJ mol 1 G 17 kJ mol 1 G 84 kJ mol 1 2 ATP G 38 kJ mol 1 6 ATP equivalent Glycolysis Reaction 10 G 31 7 kJ mol after ATP production Pyruvate kinase Gluconeogenesis Reactions 1 2 PEP Carboxykinase ATP CO2 ADP GTP ADP CO2 5 Pyruvate is Converted to Oxaloacetate in Mitochondria BIOTIN BIOTIN Vit B7 In Mitochondria Oxaloacetate must move out to the cytoplasm to be converted to PEP Carboxylation of Pyruvate Pyruvate Carboxylate carboxyphosphate HCO3 ATP HOCO2 PO32 ADP carboxylated biotin Biotin E HOCO2 PO32 CO2 Biotin E Pi CO2 Biotin E pyruvate Biotin E oxaloacetate G for the last step is 20 kJ mol 1 Oxalacetate can then be converted to Phosphophenolpyruvate carboxykinase Oxaloacetate can then be converted to Phosphoenolpyruvate Need two molecules of pyruvate to generate one glucose Gluconeogenesis is not exactly the reverse of Glycolysis G 33 kJ mol 1 G 22 kJ mol 1 G 17 kJ mol 1 G 84 kJ mol 1 2 ATP G 38 kJ mol 1 6 ATP equivalent The conversion of fructose 1 6 bisphosphate into fructose 6 phosphate Need two molecules of pyruvate to generate one glucose Overall cost of gluconeogenesis 2 Pyruvate 4 ATP 2 GTP 2 NADH 2 H 6 H2O Glucose 4 ADP 2 GDP 6 Pi 2 NAD Go 38 kJ mol 1 Coordinated Reciprocal Regulation of Glycolysis and Gluconeogenesis Energy Status of the cell And Blood Sugar Level 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 regulation 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 Inhibits F1 6 Bisphosphatase gluconeogenesis F6P F2 6BP The domain structure of the bifunctional regulatory enzyme phosphofructokinase 2 PFK2 fructose 2 6 bisphosphatase Glycolysis Gluconeogenesis X F2 6BP F6P LOW BLOOD SUGAR causes phosphorylation of the bifunctional regulatory enzyme phosphofructokinase 2 PFK2 fructose 2 6bisphosphatase Glucagon ATP PKA X ADP F2 6BP PKA inhibits PFK2 F6P HIGH BLOOD SUGAR dephosphorylate the bifunctional regulatory enzyme phosphofructokinase 2 PFK2 fructose 2 6 bisphosphatase X Insulin high F6P Pi Phosphoprotein Phosphatase H20 inhibits F2 6BPase F6P F2 6BP Hormonal Regulation Glucagon Glucagon receptor cAMP PKA Enzyme phosphorylation The activation of protein kinase A by a G protein pathway Glucagon Glucagon receptor The regulation of protein kinase A R regulatory domain C catalytic domain glucagon Glucagon receptor insulin Stimulates phosphoprotein phosphatase X Dephosphorylates PKA substrates Gluconeogenesis precursors The Cori Cycle Fate of Pyruvate under ANAEROBIC conditions in animals and other microorganisms Lactic acid Fermentation Lactate Dehydrogenase Reversible reaction Blood sugar too HIGH insulin Low energy charge Low ATP stimulates glycolysis Generates ATP Generates anabolic precursors Lowers blood sugar level insulin Inhibit gluconeogenesis Increases blood sugar level Uses ATP Blood sugar too LOW Glucagon HIGH energy charge High ATP Inhibits glycolysis Generates ATP Generates anabolic precursors Lowers blood sugar level Glucagon Stimulates gluconeogenesis Increases blood sugar level Uses ATP Summary 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 PPP Glycogen Glucoronate Glucosamine 6phosphate Glucose 6 P is common to several metabolic pathways 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 H2O 2H decarboxylase G 6P Dehydrogenase 6 Phosphogluconate Decarboxylase Phase 2 Non Oxidative Ribose 5 phosphate Ribulose 5 phosphate Xylulose 5 phosphate Phase 2 Non Oxidative Step 1 Isomerization Ketopentose aldopentose Similar Isomerization conserved mechanism Epimerization D37 D37 trans 2 3 enediol intermediate D37 Nonoxidative phase includes three other reactions C5 C5 C3 C7 C4 C5 overall 3 C5 Transketolase Transaldolase Transketolase C3 C7 C6 C4 C6 C3 2 C6 C3 C5 C5 Transketolase Thiamine pyrophosphate TPP Donor ketose Recipient aldose C3 C7 Ylid form Ketose donor Tpp Aldose acceptor Pyrimidine ring Thiazole ring Thiamine pyrophosphate C3 C7 Transaldolase C6 C4 C4 C5 Transketolase C6 C3 Balancing the needs for ATP NADPH and ribose 5 phosphate Glucose 6 P dehydrogenase Ribose 5 phosphate needs exceed the needs for NADPH GAP The NADPH and ribose 5 phosphate needs are balanced More NADPH is needed than ribose 5 phosphate GAP NADPH and ATP are both required Learning Goals Know the main entry points of noncarbohydrates precursors into gluconeogenesis Differentiate and contrast the coordinated regulation of glycolysis and gluconeogenesis Be able to identify the two stages of the pentose phosphate pathway and explain how the
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