Biochemistry department Glycogen Metabolism Dr. Sooad Al-Daihan Biochemistry department

Glycogen Glycogen is a homopolysaccharide of D-glucose residues linked by: α(14) glycosidic bonds, mainly α(16) glycosidic bonds, at branch points. Each branch is made of 6‐12 glucose units Glucose is stored as glycogen predominantly in liver and muscle cells.

Function of Glycogen: Liver glycogen: Muscle glycogen: It maintains normal blood glucose concentration especially during the early stage of fast (between meals). After 12‐18 hours fasting, liver glycogen is depleted. Muscle glycogen: It acts as a source of energy within the muscle itself especially during muscle contractions. Muscle glycogen is depleted after prolonged exercise.

Substrates for glycogen synthesis: Glycogenesis: Glycogenesis is the formation of glycogen in liver and muscles It occurs in the cytosol Substrates for glycogen synthesis: In liver Blood glucose Other hexoses: fructose & galactose glucose, then to glycogen Non carbohydrate sources: glycerol & lactate In muscles Blood glucose ONLY gluconeogenesis

Continue.. Uridine diphosphate glucose (UDP‐glucose) is the immediate precursor for glycogen synthesis UDP‐glucose is formed from glucose‐1‐phosphate: Cleavage of PPi is the only energy cost for glycogen synthesis (one ~P bond per glucose residue)

Continue.. Glycogenin is an enzyme that initiates glycogen synthesis by catalyzing the attachment of a glucose molecule to one of its own tyrosine residues. UDP is released as a product Glycogenin then catalyzes glucosylation at C4 of the attached glucose (UDP‐glucose again the donor), to yield an O‐linked disaccharide with α(14) glycosidic linkage This is repeated until a short linear glucose polymer (glycogen primer) with α(14) glycosidic linkages is built up on Glycogenin.

Continue.. Glycogen Synthase then catalyzes elongation of glycogen chains initiated by Glycogenin by transfering the glucose moiety of UDP-glucose to the hydroxyl at C4 of the terminal residue of a glycogen chain to form an a(1®4) glycosidic linkage branches up to 11 glucose units. A branching enzyme transfers a segment (minimum 6 Glc residues) from the end of a glycogen chain to the C6 hydroxyl of a glucose residue of glycogen to yield a branch with an α(16) linkage. The new branches are elongated by the glycogen synthase and the process is repeated.

Glycogenolysis: Glycogenolysis is the breakdown of glycogen into glucose (in liver) and lactic acid (in muscles). It occurs in the cytosol. Two major enzymes participate in all glycogen degradation: Glycogen phosphorylase Glycogen de-branching enzyme  has 2 independent active sites, consisting of residues in different segments of a single polypeptide chain: Transferase α (16) glucosidase

Continue.. Glycogen Phosphorylase (the key enzyme of glycogenolysis) catalyzes phosphorolytic cleavage (addition of Pi) of the α(14) glycosidic linkages of glycogen, releasing glucose‐1‐phosphate as reaction product Always acts at nonreducing end, stops at fourth glucose from α (16) branch point The transferase 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 . The α(16) glucosidase then catalyzes hydrolysis of the α(16) linkage by adding H2O, yielding free glucose The major product of glycogen breakdown is glucose‐1‐phosphate, from Phosphorylase activity.

Continue.. Glucose‐1‐P formed by phosphorolytic cleavage of glycogen is converted into glucose‐6‐P by Phosphoglucomutase Glucose 6‐phosphate derived from glycogen can be: Used as a fuel for anaerobic or aerobic metabolism as in, for instance, muscle; Converted into free glucose in the liver and subsequently released into the blood to maintain a relatively level of blood glucose; Processed by the pentose phosphate pathway to generate NADPH or ribose in a variety of tissues

Regulation of Glycogen Metabolism Glycogen synthase and glycogen phosphorylase are the targets of: Allosteric modulators Covalent reversible modification (phosphorylation) The actions of the hormones epinephrine, glucagon, and insulin on both enzymes are indirect

Regulation by Covalent Modification -Low levels of glucose induce release of glucagon -Acts primarily on liver cells. Glucagon: - Low levels of glucose induce release of Epinephrine - Acts primarily on skeletal muscle. Epinephrine: They BOTH Stimulates glycogen breakdown & inhibits glycogenesis. Insulin: -High levels of glucose induce release of insulin from β‐ cells of islets of Langerhan in the pancreas. -Detected by receptors at surface of muscle and liver cells. Stimulates glycogenesis & inhibits glycogenolysis

Continue.. Green=Active Red=Inactive

Continue.. Green=Active Red=Inactive