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Glycogen Glycogen • Liver – ~ 4 % 72 g • Muscle – ~ 1 % 245 g • Extracellular glucose – 0,1 % 10 g Adult - man 70 kg His liver 1,8 kg His muscle mass 35 kg Blood volume 10 l 2 Glycogen • Muscle: – Glucose substrate for muscle glycolysis • Liver: – Glucose store, – Export of hexose – Blood sugar • Glycogenosis – Deff. Of enzymes – Muscle weakness N 3 Glycogen level of liver 4 • As a meal containing carbohydrates is eaten and digested, • blood glucose levels rise • pancreas secretes insulin. • Glucose from the portal vein enters the liver cells (hepatocytes). • Insulin acts on the hepatocytes to stimulate the action of several enzymes, including glycogen synthase. • Glucose molecules are added to the chains of glycogen as long as both insulin and glucose remain plentiful. In this postprandial or "fed" state, the liver takes in more glucose from the blood than it releases. • . 5 • After a meal has been digested and glucose levels begin to fall, insulin secretion is reduced, and glycogen synthesis stops. • About four hours after glycogen begins to be broken down and converted again to glucose. 6 Glycogen metabolism 7 Glycogen synthesis • Muscle – Hexokinase • Liver – Glucokinase • Phosphoglucomutase – Glucose-1,6-P cofactor • Glycogen – Primer: glycogenin • 37 kDa glycosilated Tyr 8 Synthesis of glycogen 9 Synthesis of glycogen glikogenin 10 11 Synthesis of glycogen 12 Glycogenolysis 13 Glycogen Glygenolysis Glycogenesis Glucose-1-P 14 Effect of epinephrin X Stimulus ATP cAMP 40X Inakt. Protein Kinase A Aktive Protein Kinase A 10X Adrenal cortex Phosphorylase Kinaseb Phosphorylase Kinase a 100X Epinephrin Glykogen phosphorylaseb Glykogen phosphorylasea 1000X Glykogen Glukose 1 P 10000X Cent. Nervous syst. X R 15 GDP b g a ATP GTP NH2 O N H2C H O P cAMP N N N O H O OH O 16 4 cAMP R R R R C C C C 18 Protein Kinase Reactions •Serine-Threonine Kinase / cAMP depentent Protein Kinase O O P O OH ATP ADP O CH2 CH2 CH CH Ser Serine-Threonine Kinase Phospho-Ser O O P O OH ATP ADP O CH3 CH CH3 CH CH CH Thr Serine-Threonine Kinase Phospho-Thr 19 Tein, koffein cAMP AMP PKA PKA Phosphorylase-kinase b Ca2+ Phosphorylase b Phosphorylase-kinase a AMP Phosphorylase a 20 21 Glycogen Glycogenolysis Glycogenesis Glucose-1-P 22 GLYCOGEN SYNTHASE ALSO IS PHOSPHORYLATED 23 Glycogen synthase • Glycogen synthasea –dephosphorylated • Glycogen synthaseb –phosphorylated – 4 identical subunit – 7 Ser-OH residues/subunit 24 Glycogen synthase • 6 different protein kinases – – – – – Phophorylase kinase (Ca2+/Calmodulin dep) Ca2+/Calmodulin dep. GSK-3: GSK-4 GSK-5 • Glucose-6-P: allosteric activator of Glycogenesynthase kinaseb • Insulin/muscle: – dephosphorylation / activation of Glycogen-synthaseb 25 Protein Kinase Glycogen Synthase Phosphorylation Site Phos b Kinase II A-Kinase IA, IB, II, and IV Ca/Calmodulin - Dependent Protein Kinase IB, II Glycogen Synthase Kinase 3 IIIA, IIIB, IIIC Glycogen Synthase Kinase 4 II Casein Kinase I Nearly all sites Casein Kinase II V Protein Kinase C IA 26 Name Type Enzyme Deficiency Tissues Chiefly Affected Clinical Consequences Von Gierke's Disease I Glucose 6-phosphatase Liver, kidney Severly enlarged liver, severe hypoglycemia, lactic acidosis, ketosis, hyperuricemia, hyperlipemia Pompe's Disease II 1,4-D-Glucosidase (lysosomal) Liver, heart, muscle Cardiac failure in infancy Cori's Disease III Amylo-1,6-glucosidase ("Debranching" enzyme) Liver, muscle Similar to Type I, but milder Andersen's Disease IV "Branching" enzyme Liver Liver cirrhosis, death usually before 24 months McArdle's Disease V Phosphorylase Muscle Muscle cramps, easily fatigued Hers' Disease VI Phosphorylase Liver Similar to Type I, but milder Tarui's Disease VII Phosphofructokinase Muscle Similar to Type V VIII Phosphorylase kinase Liver Enlarged liver, hypoglycemia IX Glycogen synthase Liver 27 Von Gierke’s Disease Glucose 6-phosphatase: liver and kidney Here is another liver with a pale, bulging surface. This time the liver is filled with glycogen in von Gierke's disease, the glycogen storage disease of children. Severly enlarged liver, severe hypoglycemia, lactic acidosis, ketosis, hyperuricemia, hyperlipemia 28 POMPE'S DISEASE Without mannose 6-phosphate tags, acid maltase (1,4-D-Glucosidase) enzyme molecules can't enter muscle cells from the bloodstream. When mannose 6-phosphate tags are added to acid maltase enzyme molecules, the molecules stick to receptors (docking sites) on the muscle cells and are carried deeper inside the cells, where they're needed. ENZYME TREATMENT BENEFITS BABIES WITH POMPE'S DISEASE Babies with a metabolic muscle disorder known as Pompe's disease, or acid maltase deficiency, usually don't survive infancy because they lack a vital enzyme that normally breaks down glycogen in the heart and skeletal muscle cells. Cardiac failure in infancy; liver, heart, muscle 29 Forbe’s disease, Type III glycogenosis • also called Cori's disease , or glycogenosis type III rare hereditary disease in which the the metabolic breakdown of glycogen to the simple sugar glucose is incomplete, allowing intermediate compounds to accumulate in the cells of the liver. Affected persons lack the enzyme amylo-1,6-glucosidase, one of several enzymes involved in glycogen breakdown. Children with the disease have enlarged livers (which usually… 30 Andersen’s disease • also called Glycogenosis Type Iv, extremely rare hereditary metabolic disorder produced by absence of the enzyme amylo-1:4,1:6transglucosidase (branching enzyme), which is an essential mediator of the synthesis of glycogen. An abnormal form of glycogen, amylopectin, is produced and accumulates in body tissues, particularly in the liver and heart. Affected children appear normal at birth but fail to thrive and later lose… Liver cirrhosis, death usually before 24 months 31 McArdle's Disease Phosphorylase stain: Normal more darkly than type I Phosphorylase stain: Absent Muscle fibers stain yellow Myophosphorylase deficiency: McArdle's disease 32