# Lecture 18: Glycogen Metabolism

## Biochemistry

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## Learning Objectives

By the end of this lecture, students will be able to:

1. Describe the structure of glycogen and its role as an energy reserve
2. Explain the reactions of glycogenolysis (glycogen degradation)
3. Explain the reactions of glycogenesis (glycogen synthesis)
4. Describe the hormonal regulation of glycogen metabolism by insulin, glucagon, and epinephrine
5. Explain the signal transduction cascade involving cAMP and protein kinase A
6. Identify glycogen storage diseases and their biochemical basis

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## Lecture Content

### I. Glycogen Structure and Function

Glycogen is the main storage form of glucose in animals, structured as a branched polymer of glucose with alpha-1,4 glycosidic bonds in the linear chains and alpha-1,6 glycosidic bonds at branch points occurring every 8 to 12 residues. It is stored primarily in the **liver** (approximately 100 g, for maintaining blood glucose during fasting) and **skeletal muscle** (approximately 400 g, for local fuel during contraction). Glycogen is stored in granules that contain the enzymes for its synthesis and degradation. Each glycogen molecule has one reducing end and many non-reducing ends, with synthesis and degradation occurring at the non-reducing ends. The high degree of branching provides numerous non-reducing ends for rapid glucose mobilization.

### II. Glycogenolysis (Glycogen Breakdown)

**Glycogen phosphorylase** cleaves alpha-1,4 bonds from the non-reducing ends by phosphorolysis (not hydrolysis), producing glucose-1-phosphate. It stops 4 residues from a branch point, leaving a limit dextrin, and requires pyridoxal phosphate (PLP, vitamin B6) as a cofactor. The **debranching enzyme** is bifunctional: its transferase activity moves a block of 3 glucose residues from the branch to a nearby non-reducing end, and its alpha-1,6-glucosidase activity hydrolyzes the single remaining alpha-1,6-linked glucose, releasing free glucose. Approximately 8% of glucose from glycogen is released as free glucose (from branch points) and 92% as glucose-1-phosphate. **Phosphoglucomutase** then converts glucose-1-phosphate to glucose-6-phosphate. In the liver only, **glucose-6-phosphatase** (located in the ER membrane) hydrolyzes glucose-6-phosphate to free glucose for release into the blood. Muscle and brain lack this enzyme and therefore cannot export glucose.

### III. Glycogenesis (Glycogen Synthesis)

Glycogen synthesis begins with hexokinase or glucokinase phosphorylating glucose to glucose-6-phosphate, followed by phosphoglucomutase converting it to glucose-1-phosphate. **UDP-glucose pyrophosphorylase** then activates glucose by forming UDP-glucose from glucose-1-phosphate and UTP, with PPi hydrolysis driving the reaction forward. **Glycogen synthase**, the **rate-limiting enzyme**, adds glucose from UDP-glucose to the non-reducing end of a growing chain via an alpha-1,4 bond. This enzyme requires a pre-existing glycogen primer or **glycogenin**, a self-glucosylating protein that initiates glycogen synthesis by adding the first approximately 8 glucose residues using UDP-glucose at a tyrosine attachment point. The **branching enzyme** transfers a block of approximately 7 glucose residues from a chain of at least 11 to create a new alpha-1,6 branch point.

### IV. Regulation of Glycogen Metabolism

#### Glycogen Phosphorylase Regulation

Glycogen phosphorylase exists as **phosphorylase a** (phosphorylated, active) and **phosphorylase b** (dephosphorylated, less active, requiring AMP for activity in muscle). Phosphorylase kinase activates it by adding phosphate, while **protein phosphatase 1 (PP1)** inactivates it by removing phosphate. In muscle, phosphorylase b is allosterically activated by AMP (an energy depletion signal) and inhibited by ATP and G6P. In the liver, phosphorylase a is inhibited by glucose, which binds and promotes dephosphorylation.

#### Glycogen Synthase Regulation

Glycogen synthase exists as **synthase a** (dephosphorylated, active) and **synthase b** (phosphorylated, less active) -- note that this is the **opposite** pattern from phosphorylase. Multiple kinases (GSK-3, PKA, phosphorylase kinase) phosphorylate and inactivate it, while PP1 dephosphorylates and activates it. Glucose-6-phosphate is an allosteric activator that can partially activate even the phosphorylated form.

<image>A diagram showing the reciprocal regulation of glycogen phosphorylase and glycogen synthase. Panel A: Glycogen phosphorylase shown in its two forms — phosphorylase b (less active, dephosphorylated, T state) and phosphorylase a (active, phosphorylated, R state). Phosphorylase kinase adds the phosphate; PP1 removes it. Allosteric effectors are shown (AMP activates b form in muscle; glucose promotes dephosphorylation of a form in liver). Panel B: Glycogen synthase in its two forms — synthase a (active, dephosphorylated) and synthase b (less active, phosphorylated). Multiple kinases (PKA, GSK-3, phosphorylase kinase) phosphorylate it; PP1 dephosphorylates it. G6P allosterically activates the b form. Panel C: A summary showing that phosphorylation simultaneously activates glycogenolysis (phosphorylase) and inhibits glycogenesis (synthase), ensuring coordinated regulation.</image>

### V. Hormonal Regulation -- Signal Transduction Cascades

#### Glucagon (Liver) and Epinephrine (Muscle and Liver)

The cAMP cascade begins when glucagon (in the liver) or epinephrine (via beta-adrenergic receptors) binds to a G-protein-coupled receptor, activating the stimulatory G-protein (Gs) and then **adenylyl cyclase**, which converts ATP to **cAMP**. cAMP activates **protein kinase A (PKA)**, which phosphorylates phosphorylase kinase (activating it and thereby activating glycogenolysis), glycogen synthase (inactivating it and inhibiting glycogenesis), and PFK-2/FBPase-2 in the liver (activating FBPase-2, decreasing F-2,6-BP, and promoting gluconeogenesis over glycolysis). cAMP is degraded by **phosphodiesterase** (PDE), terminating the signal; caffeine inhibits PDE, prolonging cAMP signaling.

Epinephrine also acts on liver alpha-1 receptors, activating phospholipase C to produce IP3 and DAG. IP3 triggers Ca2+ release from the ER, and Ca2+ directly activates phosphorylase kinase via its calmodulin subunit.

#### Insulin (Fed State)

Insulin activates **PP1**, which dephosphorylates phosphorylase a to the less active b form (inhibiting glycogenolysis) and glycogen synthase b to the active a form (promoting glycogenesis). Insulin also activates phosphodiesterase to degrade cAMP, opposing glucagon and epinephrine. Through activation of **protein kinase B (Akt)**, insulin phosphorylates and inhibits **GSK-3**, preventing glycogen synthase phosphorylation and promoting glycogen storage.

### VI. Glycogen Storage Diseases (GSD)

Glycogen storage diseases are inherited enzyme deficiencies affecting glycogen metabolism, characterized by abnormal glycogen accumulation in excess amount or with abnormal structure.

| Type | Name | Enzyme Deficiency | Key Features |
|------|------|-------------------|-------------|
| 0 | - | Glycogen synthase | Hypoglycemia, no glycogen stored |
| Ia | Von Gierke | Glucose-6-phosphatase | Severe fasting hypoglycemia, hepatomegaly, lactic acidosis, hyperlipidemia |
| II | Pompe | Acid maltase (lysosomal alpha-1,4-glucosidase) | Glycogen accumulates in lysosomes; cardiomegaly, muscle weakness; fatal in infantile form |
| III | Cori/Forbes | Debranching enzyme | Hepatomegaly; abnormal glycogen with short branches (limit dextrin); milder than type I |
| IV | Andersen | Branching enzyme | Abnormal glycogen (long, unbranched); hepatosplenomegaly, cirrhosis |
| V | McArdle | Muscle glycogen phosphorylase | Exercise intolerance, muscle cramps, myoglobinuria; no rise in blood lactate after exercise |
| VI | Hers | Liver glycogen phosphorylase | Hepatomegaly, mild hypoglycemia |

<image>A clinical summary diagram of glycogen storage diseases. A glycogen metabolism pathway is shown in the center with each enzyme labeled. At each enzyme step, the corresponding GSD type is indicated with a brief clinical description. Von Gierke disease (type Ia) is at glucose-6-phosphatase, Pompe disease (type II) at lysosomal glucosidase, Cori disease (type III) at the debranching enzyme, Andersen disease (type IV) at the branching enzyme, and McArdle disease (type V) at muscle phosphorylase. For each disease, a small icon or image represents the key clinical feature: enlarged liver for hepatomegaly, enlarged heart for Pompe, a person exercising with distress for McArdle.</image>

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