Glycogen Metabolism

Glycogen Metabolism Dr. Gamal Gabr, College of Pharmacy

Glycogen is a polymer of glucose residues linked by • a(14) glycosidic bonds, mainly • a(16) glycosidic bonds, at branch points. Glucose is stored as glycogen predominantly in liver and muscle cells.

Glycogenesis and glycogenolysis • Glycogen is the storage form of glucose. • Both glycogenesis and glycogenolysis are controlled primarily by three hormones: insulin, glucagon, and epinephrine.

Glycogenesis • Glycogen synthesis occurs after a meal, when blood glucose levels are high. • It has long been recognized that the consumption of a carbohydrate meal is followed by liver glycogenesis • The synthesis of glycogen from glucose-6-phosphate involves the following set of reactions:- • Synthesis of glucose-1-phosphate • Synthesis of UDP-glucose • Synthesis of glycogen from UDP-glucose

Glycogen Synthesis

Glycogenesis

Glycogenolysis • Glycogen degradation requires the following two reactions:- • Removal of glucose from the non-reducing ends of glycogen • Hydrolysis of the a (1,6) glycosidic bonds at branch points of glycogen

Glycogen Catabolism(Degradation) Glycogen Phosphorylase: catalyzes phosphorolytic cleavage of the a(14) glycosidic linkages of glycogen, releasing glucose-1-phosphate as reaction product. glycogen(n residues) + Pi Glycogen Phosphorylase glycogen (n–1 residues) + glucose-1-phosphate

Glycogen Degradation • Glycogen Phosphorylase • Hydrolyzes glucose units from glycogen • Produces glucose-1-P • Removal of branch points • Debranching enzyme complex • Glucantransferase: Transfers 3 glucose residues from a 4-residue limit branch to the end of another branch, diminishing the limit branch to a single glucose residue. • Alpha-1,6-glucosidase: Catalyzes hydrolysis of the a(16) linkage, yielding free glucose

Glycogenolysis • Glycogen phosphorylase uses inorganic phosphate (Pi) to cleave the _(1,4) linkages on the outer branches of glycogen to yield glucose-1-phosphate. • Glycogen phosphorylase stops when it comes within four glucose residues of a branch point. • Amylo-_(1,6)-glucosidase, also called debranching enzyme, begins the removal of _(1,6) branch points by transferring the outer three of the four glucose.

Glycogenolysis

Major Factors Affecting Glycogen Metabolism • The binding of glucagon (released from the pancreas in response to low blood sugar) and/or epinephrine (released from the adrenal glands in response to stress) to their cognate receptors on the surface of target cells initiates a reaction cascade that converts glycogen to glucose-1-phosphate and inhibits glycogenesis. • Insulin inhibits glycogenolysis and stimulates glycogenesis in part by decreasing the synthesis of cAMP and activating phosphoprotein phosphatase. • adenylate cyclase is a cytoplasmic protein.

Major Factors Affecting Glycogen Metabolism

Regulation of Glycogen Synthase Fasting • cAMP activates Protein Kinase A • Protein kinase A phosphorylates and inactivates glycogen synthase • Little glycogen synthesis during fasting

Regulation of Glycogen Synthase Feeding • Insulin • Reduces [cAMP] • Stimulates phosphodiesterase • Induces and activates protein phosphatase-1 • Activates glycogen synthase • Feeding results in glycogen synthesis

Regulation of Glycogen PhosphorylaseFasting • Glucagon or epinephrine • Increase [cAMP] • Activates Protein Kinase A • Phosphorylates and activates glycogen phosphorylase • Fasting results in increased glycogenolysis

Regulation of Glycogen Phosphorylase Feeding • Insulin • Reduces [cAMP] • Induces and activates Protein Phosphatase-1 • Inactivates Glycogen Phosphorylase • Feeding results in decreased glycogenolysis

Coordinated Regulation of Glycogen Metabolism

Glycogen Storage Diseases Glycogen Storage Diseases are genetic enzyme deficiencies associated with excessive glycogen accumulation within cells. Some enzymes whose deficiency leads to glycogen accumulation are part of the inter-connected pathways

Glycogen Metabolism