Glycogen, a readily mobilized fuel store, is a branched polymer of glucose residues. Most of the glucose units in glycogen are linked by α-1,4-glycosidic bonds. At about every twelfth residue, a branch is created by an α-1,6-glycosidic bond. Glycogen is present in large amounts in muscle cells and in liver cells, where it is stored in the cytoplasm in the form of hydrated granules.

21.1 Glycogen Breakdown Requires the Interplay of Several Enzymes

Most of the glycogen molecule is degraded to glucose 1-phosphate by the action of glycogen phosphorylase, the key enzyme in glycogen breakdown. The glycosidic linkage between C-1 of a terminal residue and C-4 of the adjacent one is split by orthophosphate to give glucose 1-phosphate, which can be reversibly converted into glucose 6-phosphate. Branch points are degraded by the concerted action of an oligosaccharide transferase and an α-1,6-glucosidase.

21.2 Phosphorylase Is Regulated by Allosteric Interactions and Reversible Phosphorylation

Phosphorylase b, which is usually inactive, is converted into active phosphorylase a by the phosphorylation of a single serine residue in each subunit. This reaction is catalyzed by phosphorylase kinase. The a form in the liver is inhibited by glucose. In liver, phosphorylase is activated to liberate glucose for export to other organs, such as skeletal muscle and the brain. The b form in muscle can be activated by the binding of AMP, an effect counteracted by ATP and glucose 6-phosphate. In contrast to liver, muscle phosphorylase is activated to generate glucose for use inside the cell as a fuel for contractile activity.

21.3 Epinephrine and Glucagon Signal the Need for Glycogen Breakdown

Epinephrine and glucagon stimulate glycogen breakdown through specific 7TM receptors. Muscle is the primary target of epinephrine, whereas the liver is responsive to glucagon. Both signal molecules initiate a kinase cascade that leads to the activation of phosphorylase kinase, which in turn converts glycogen phosphorylase b to the phosphorylated a form.

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21.4 Glycogen Is Synthesized and Degraded by Different Pathways

The pathway for glycogen synthesis differs from that for glycogen breakdown. UDP-glucose, the activated intermediate in glycogen synthesis, is formed from glucose 1-phosphate and UTP. Glycogen synthase catalyzes the transfer of glucose from UDP-glucose to the C-4 hydroxyl group of a terminal residue in the growing glycogen molecule. Synthesis is primed by glycogenin, an autoglycosylating protein that contains a covalently attached oligosaccharide unit on a specific tyrosine residue. A branching enzyme converts some of the α-1,4 linkages into α-1,6 linkages to increase the number of ends so that glycogen can be made and degraded more rapidly.

21.5 Glycogen Breakdown and Synthesis Are Reciprocally Regulated

Glycogen synthesis and degradation are coordinated by several amplifying reaction cascades. Epinephrine and glucagon stimulate glycogen breakdown and inhibit its synthesis by increasing the cytoplasmic level of cyclic AMP, which activates protein kinase A. Protein kinase A activates glycogen breakdown by attaching a phosphate to phosphorylase kinase and inhibits glycogen synthesis by phosphorylating glycogen synthase. Glycogen synthase kinase also inhibits synthesis by phosphorylating the synthase.

The glycogen-mobilizing actions of protein kinase A are reversed by protein phosphatase 1, which is regulated by several hormones. Epinephrine inhibits this phosphatase by blocking its attachment to glycogen molecules and by turning on an inhibitor. Insulin, in contrast, triggers a cascade that phosphorylates and inactivates glycogen synthase kinase. Hence, glycogen synthesis is decreased by epinephrine and increased by insulin. Glycogen synthase and phosphorylase are also regulated by noncovalent allosteric interactions. In fact, phosphorylase is a key part of the glucose-sensing system of liver cells. Glycogen metabolism exemplifies the power and precision of reversible phosphorylation in regulating biological processes.