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Biochemistry I Lecture 31 April 8, 2013 Lecture 31: Hormonal Regulation of Glucose/Glycogen [Liver] Glycogen Metabolism: The Rules: 1. Regulation makes physiological sense. 2. Opposing pathways are coordinately regulated (if one is on, other is off) 3. Low blood glucose (or request for additional glucose) causes: Enzymes become phosphorylated via hormone signal. Directly affecting glycogen metab. F2-6P levels become low due to enz. Phosphorylation (F2-6P follows glucose levels), affecting glycolysis/gluconeogenesis. CH2OH O O CH2OH CH2OH CH2OH CH2OH O O O O O CH2OH CH2OH O O O O O O CH2OH O O O CH2OH CH2 OH O [glycogen synthase] O CH2OH O O O O O O O O O CH2OH CH2OH CH2OH OH CH2OH CH2OH P O O O O O [glycogen phosphorylase] O O CH2 OH O OH Hormonal Control of Pathways: Secretion of epinephrine (also known as adrenaline) occurs during dangerous situations, indicative of high energy needs. Secretion of epinephrine is under control of the central nervous system. This leads to the phosphorylation of many enzymes. Secretion of glucagon from the - cells in the pancreas occurs when blood glucose levels are low. This also leads to the phosphorylation of many enzymes. Secretion of insulin from the -cells pancreas occurs when blood glucose levels are high. This leads to the dephosphorylation of the enzymes that were phosphorylated due to epinephrine or glucagon. Pancreas Adrenal Gland cells epinephrine (adrenaline) glucagon 1 epinephrine receptor Glycogen breakdown Gluconeogenesis Glucose Blood Muscle Dephosphorylation Cyclase GDP G-protein (GTP) 4 ATP G-protein (GDP) O ATP 5 Activated kinase 1 N NH2 O O P O O P Protein kinase A OH N O N OH OH cAMP OH N Activates Glycogen synthase N O N OH N protein phosphatase N Glycogen synthase Glycogen phosphorylase Glycogen phosphorylase Insulin NH2 O P O cAMP Protein kinase A Glycogen phosphorylase Insulin receptor O O P O O O O P Adenyl O GTP 2 3 Glycogen synthase Glycogen Glucose synthesis oxidation Outside glucagon receptor 6 insulin glucagon Molecular events that lead to protein: Phosphorylation Cell Membrane cells P P P Glycogen synthase Glycogen phosphorylase OH OH O Biochemistry I Lecture 31 April 8, 2013 A. Low Blood Sugar or Epinephrine: Proteins phosphorylated. 1. Glucagon and/or epinephrine bind to G-protein coupled receptors on the surface of the cell. 2. The Binding of ligand to receptor generates a binding site for G-protein/GDP complex inside the cell via allosteric changes, thus transmitting the signal across the membrane. 3. Receptor-G-protein interaction exchanges GDP for GTP, G-protein-GTP complex binds to Adenylate cyclase, activating it, also by an allosteric change. 4. Adenylate cyclase converts ATP to cAMP. cAMP is called a '2nd messenger' . N N O O O N N N P O O N O P Each receptor binding event produces 1000-2000 N O P O O N O molecules of cAMP. G-protein/GTP complex decays O N O O to GDP complex, ending cAMP synthesis unless O P O OH O hormones are still present. OH OH cAMP ATP (3'-5' cyclic AMP) 5. cAMP activates protein kinase A. 6. Protein kinase A activation results in the phosphorylation of the following targets related to glycogen metabolism, resulting in the breakdown of glycogen to glucose-1-phosphate. N a. glycogen synthase (inactivating it) b. glycogen phosphorylase, activating it, leading to glycogen breakdown. B. High Blood Sugar: Proteins dephosphorylated -Glycogen synthesized, Glucose used for energy production (if needed). O H3C To reverse the above effects we need to de-phosphorylate the proteins that were CH3 N N phosphorylated in the above reactions. Thus occurs in two steps: N 1. cAMP levels drop since they are no longer elevated due to absence of glycogen N O and/or epinephrine. Caffeine inhibits the decay of cAMP. CH3 2. A protein phosphatase is activated leading to loss of phosphate groups. glycogen synthase becomes active, leading to the synthesis of glycogen. Caffeine Control of Glycogen Metabolism: Glycogen synthesis and degradation is directly controlled by protein phosphorylation. Low Glucose High Glucose Levels CH2OH CH2OH O O O CH2OH CH2 OH CH2 OH O CH2 OH O CH2OH CH2OH CH2 OH OH O O CH2OH O O O O O O O CH2OH CH2 OH CH2OH O O CH2OH O O O CH2OH CH2OH CH2 OH O OH O O CH2OH O O O O CH2 OH CH2OH O O CH2OH CH2 OH O CH2OH O OH O CH2OH O O O O O O O O O O O O CH2OH [glycogen synthase] O OH 2 O CH2 OH O O O O P O O O O O CH2OH CH2OH CH2 OH CH2 OH O O O [glycogen synthase] CH2 OH CH2OH O O [glycogen phosphorylase] O O CH2OH O O O P O O O O O [glycogen phosphorylase] CH2OH O O O Biochemistry I Lecture 31 A. Regulation of PFK-1/bisPhosphatase by energy sensing and F26P April 8, 2013 B. Regulation of glycogen synthesis & degradation by enzyme phosphorylation. O H2 C P O O O OH H2C CH2OH O HO O O OH [glycogen phosphorylase] OH Glycolysis OFF AMP ON [PFK-1] ADP OFF [Fructose-bis phosphatase-1] ATP ON F 2,6 P H2 C P O O O O O O CH2OH CH2OH CH2OH CH2OH O O O H2C O HO O CH2OH CH2 OH CH2OH O O O O O O O CH2 OH [glycogen synthase] P O O O O O O O CH2OH O O O O CH2OH CH2OH OH O O O CH2OH O O Gluconeogenesis OFF P O O O O O CH2OH CH2OH CH2OH CH2OH O O OH O O OH OH C. Regulation of Glycolysis/Gluconeogenesis in the liver by F-2,6P Levels. Glucose OPO3 CH2 H2 C OH O High blood Glucose Protein Phosphorylation HIGH LOW F2,6P levels LOW HIGH ADP OH Fructose-6phosphate PFK-2 OH OH ATP bisPhos-2 ADP PFK-1 OPO3 Low blood Glucose ATP CH2 bisPhos-1 OPO3 H2C O OPO3 CH2 CH2OH O OH 1-6 fructose phosphate OPO3 OH 2-6 fructose phosphate (Regulatory) OH OH PYR Gluconeogenesis Low Blood Glucose low F2,6P High Blood Glucose Levels high F2,6P (Enzymes phosphorylated) (Enzymes dephosphorylated) Fructose-6-P ATP [PFK-2] Enz Glycolysis OH Pi ATP [FBPase-2] [PFK-2] P Enz ADP Enz P Fructose-6-P Pi [FBPase-2] OH Enz ADP OH Fructose 2,6bisP Fructose 2,6bisP F2,6 Allosteric regulation of Glycolysis and Gluconeogenesis ATP Fructose-6-P [PFK] Activated by F2-6P Pi [Fructose-1-6 bisphosphatase] Inhibited F2-6P ADP ATP Fructose-6-P [PFK] Activated by F2-6P Pi [Fructose-1-6 bisphosphatase] Inhibited F2-6P ADP Fructose 1,6bisP Glycolysis Gluconeogenesis Fructose 1,6bisP Glycolysis Gluconeogenesis F2-6P is required for glycolysis to be active in the liver. If f26P levels are low (glucose demand) the liver will not undergo glycolysis. 3