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GLUCONEOGENESIS Synthesis of glucose from noncarbohydrate precursors Learning objectives: List gluconeogenic precursors List the enzymes and intermediates involved in gluconeogenesis List the irreversible and regulated steps of gluconeogenesis Discuss regulation of gluconeogenesis Gluconeogenic precursors • 18 amino acids (diet and degradation of protein) • Lactate (anaerobic glycolysis) • Glycerol (hydrolysis of triacylglycerols) Notable exception: Fatty acids Gluconeogenic precursors Lactate and some amino acids can be converted to pyruvate Some amino acids can be converted to oxaloacetate Glycerol can be converted to dihydroxyacetone phosphate Gluconeogenic pathway describes conversion of pyruvate to glucose Main organs producing glucose via the gluconeogenic pathway are liver and kidney Gluconeogenic pathway is NOT a simple reversal of glycolysis The 3 irreversible steps of glycolysis Hexokinase/Glucokinase Phosphofructokinase Pyruvate kinase must be circumvented The 7 reversible steps of glycolysis are part of gluconeogenesis All the intermediates of glycolysis are part of gluconeogenesis In addition, gluconeogenesis involves oxaloacetate and (indirectly) malate O- O C C C O O- O O H C OH CH2 CH2 C C O- Oxaloacate O O- Malate Stoichiometry 2 Pyruvate + 4 ATP + 2 GTP + 2 NADH + 2 H+ + 6 H2O → 1 Glucose + 4 ADP + 2 GDP + 6 Pi + 2 NAD+ Pyruvate carboxylase Pyruvate + CO2 + ATP + H2O Oxaloacetate + ADP + Pi + 2 H+ This reaction occurs in the mitochondria It is a regulated step Biotin is a coenzyme for the reaction Pyruvate is transported from the cytoplasm to the mitochondria. In the mitochondria, pyruvate is converted to oxaloacetate by pyruvate carboxylase Oxaloacetate can not be transported to the cytoplasm. Oxaloacetate is reduced in the mitochondria to malate: Oxaloacetate + NADH + H+ Malate dehydrogenase Malate + NAD+ Malate is transported to the cytoplasm and reoxidized back to oxaloacetate: Malate dehydrogenase Malate + NAD+ Oxaloacetate + NADH + H+ Phosphoenolpyruvate carboxykinase (PEPCK) Oxaloacetate + GTP It is a regulated step Phosphoenolpyruvate + GDP + CO2 Fructose-1,6bisphosphatase Fructose 1,6-bisphosphate + H2O Irreversible Regulated step Fructose 6-phosphate + Pi Glucose-6-phosphatase Glucose 6-phosphate + H2 O Glucose + Pi Irreversible Regulated step Only present in large amount in liver and kidney Reaction occurs in the endoplasmic reticulum P Glucose-6-phosphatase catalytic subunit Glucose-6-phosphate transporter P P Endoplasmic reticulum Glycerol kinase Glycerol phosphate + ADP + H+ Glycerol + ATP Glycerol phosphate dehydrogenase Glycerol phosphate + NAD+ Dihydroxyacetone phosphate + NADH + H+ Pyruvate carboxylase Oxaloacetate + ADP + Pi + 2 H+ Pyruvate + CO2 + ATP + H2O + Acetyl CoA (High energy signal) LIVER IN THE FASTED STATE Energy is derived mostly from fatty acids Pyruvate dehydrogenase Acetyl-CoA Pyruvate Pyruvate carboxylase Fatty acids + Oxaloacetate Phosphoenolpyruvate carboxykinase (PEPCK) Oxaloacetate + GTP Phosphoenolpyruvate + GDP + CO2 Phosphoenolpyruvate carboxykinase is regulated at the level of gene transcription + - Glucagon, glucocorticoids (fasted state) Insulin (fed state) Fructose-1,6bisphosphatase Fructose 1,6-bisphosphate + H2O + Fructose 6-phosphate + Pi AMP (low-energy state) Fructose 2,6-bisphosphate (fed state, high insulin/glucagon ratio) ATP (high-energy state) Glucose-6-phosphatase Glucose 6-phosphate + H2 O Glucose + Pi The catalytic subunit of glucose-6-phosphatase is regulated at the level of gene transcription + + Glucagon, glucocorticoids (fasted state) Insulin (fed state) Glucose (fed state) - “Paradoxical regulation” Glycolysis Gluconeogenesis Glucose Glucokinase + + Glucose-6-phosphatase Insulin Glucose Glucose-6-phosphate + + Insulin Glucagon Glucose Glycolysis Gluconeogenesis Fructose-1,6bisphosphatase Fructose 6-phosphate Phosphofructokinase + + ATP + ATP - Fructose 2,6-bisphosphate Citrate H+ Fructose 2,6-bisphosphate AMP Fructose 1,6-bisphosphate AMP Glycolysis Gluconeogenesis Phosphoenolpyruate Pyruvate kinase PEPCK - Glucagon - ATP - Alanine + Fructose 1,6-bisphosphate + Glucose + - Glucagon Insulin Pyruvate carboxylase + Pyruvate Acetyl-CoA Allosteric regulator of glycolysis and gluconeogenesis Fructose 2,6-bisphosphate Phosphofructokinase 2 Fructose 6-phosphate + ATP Fructose 2,6-bisphosphate + ADP Fructose bisphosphatase 2 Fructose 2,6-bisphosphate + H2O Fructose 6-phosphate + Pi G-6-P F-6-P PFK 2 FBPase 2 F-2,6-P2 + FBPase 1 PFK 1 F-1,6-P 2 + PK The PFK2 and FBPase 2 activities are located in a single protein: The bifunctional enzyme Fasted state: High Glucagon -> High cAMP -> activation of PKA -> phosphorylation of bifunctional enzyme -> inhibition of PFK2, activation of FBPase2 -> decrease in fructose 2,6-bisphosphate -> no stimulation of glycolysis, no inhibition of gluconeogenesis -> Gluconeogenesis prevails! Fed state: Low Glucagon -> No/Low cAMP -> no activation of PKA -> dephosphorylation of bifunctional enzyme prevails -> activation of PFK2, inhibition of FBPase2 -> increase in fructose 2,6-bisphosphate -> stimulation of glycolysis, inhibition of gluconeogenesis -> Glycolysis prevails! The Cori cycle LIVER Glucose Gluconeogenesis Lactate Bloodstream MUSCLE Glucose Glycolysis Lactate