Glycogen Metabolism Lecture PDF

BIOCHEMISTRY Sidrah Shams Ph. D. Molecular Medicine 1 Glycogen metabolism Because of the importance of maintaining blood glucose levels, the synthesis (glycogenesis) and degradation (glycogenolysis) of its glycogen storage form are tightly regulated. In the liver---glycogenesis accelerate...

BIOCHEMISTRY Sidrah Shams Ph. D. Molecular Medicine 1 Glycogen metabolism Because of the importance of maintaining blood glucose levels, the synthesis (glycogenesis) and degradation (glycogenolysis) of its glycogen storage form are tightly regulated. In the liver---glycogenesis accelerates---well fed, whereas glycogenolysis accelerates---fasting. In skeletal muscle- glycogenolysis- during active exercise, and glycogenesis begins as soon as the muscle is again at rest. Glycogen is stored in large cytosolic granules. The glycogen in muscle provides a quick source of energy for either aerobic or anaerobic metabolism. 2 Muscle glycogen can be exhausted in less than an hour during vigorous activity. Liver glycogen can be depleted in 12 to 24 hours. In humans, the total amount of energy stored as glycogen is far less than the amount stored as fat (triacylglycerol), but fats cannot be converted to glucose in vertebrates and cannot be catabolized anaerobically. 3 Glycogenolysis Breakdown of glycogen to glucose 1-phosphate. Glucagon, Nephrin, Epinephrin. Glycogen phosphorylase catalyzes the reaction in which an (α1→4) glycosidic linkage between two glucose residues at a non-reducing end of glycogen undergoes attack by inorganic phosphate (Pi), removing the terminal glucose residue as α-D-glucose 1-phosphate. Glycogen phosphorylase acts repetitively on the non- reducing ends of glycogen branches until it reaches a point four glucose residues away from an (α1→6) branch point where its action stops. 4 5 Further degradation by glycogen phosphorylase can occur only after the debranching enzyme, formally known as oligo (α1→6) to (α1→4) glucantransferase, catalyzes two successive reactions that transfer branches. Once these branches are transferred and the glucosyl residue at C-6 is hydrolyzed, glycogen phosphorylase activity can continue. 6 Glucose 1-Phosphate Can Enter Glycolysis or, in Liver, Replenish Blood Glucose Glucose 1-phosphate, the end product of the glycogen phosphorylase reaction, is converted to glucose 6-phosphate by phosphoglucomutase, which catalyzes the reversible reaction. The glucose 6-phosphate formed from glycogen in skeletal muscle can enter glycolysis and serve as an energy source to support muscle contraction. 7  In liver, glycogen breakdown serves a different purpose: to release glucose into the blood when the blood glucose level drops, as it does between meals. This requires the enzyme glucose 6- phosphatase, present in liver and kidney but not in other tissues. Because muscle and adipose tissue lack glucose 6-phosphatase, they cannot convert the glucose 6-phosphate formed by glycogen breakdown to glucose, and these tissues therefore do not contribute glucose to the blood. 8 Synthesis of glycogen (glycogenesis) Insulin Glycogen synthesis takes place in virtually all animal tissues but is especially prominent in the liver and skeletal muscles. UDP-glucose pyrophosphorylase, in a key step of glycogen biosynthesis. Transfer of the glucose residue from UDP-glucose to a non-reducing end of a branched glycogen molecule. Glycogen synthase cannot make the (α1→6) bonds found at the branch points of glycogen; these are formed by the glycogen- branching enzyme, also called amylo (1→ 4) to (1→ 6) transglycosylase, or glycosyl (4 → 6) transferase.9 10 Formation of a sugar nucleotide. 11 Branch synthesis in glycogen 12 Glycogen synthase cannot initiate a new glycogen chain de novo. It requires a primer, usually a preformed (α1→ 4) polyglucose chain or branch having at least eight glucose residues. So, how is a new glycogen molecule initiated? The intriguing protein glycogenin is both the primer on which new chains are assembled and the enzyme that catalyzes their assembly. The nascent chain is extended by the sequential addition of seven more glucose residues, each derived from UDP-glucose; the reactions are catalyzed by the chain-extending activity of glycogenin. At this point, glycogen synthase takes over, further extending the glycogen chain. 13 READ THE BOOK: Lipincott 14 15