03: Carbohydrate Metabolism: Glycogenesis and Glycogenolysis Notes

Carbohydrate Metabolism: Glycogenesis and Glycogenolysis

Section Objectives

• Describe the structure of glycogen.
• Explain the role of glycogen in liver and muscle.
• Define and explain glycogenesis.
• Define and explain glycogenolysis.
• Identify enzymes, intermediates, co-factors involved.
• Explain regulation of glycogen metabolism and influence of hormones.

Structure of Glycogen

• Storage form of glucose:
• Glycogen is a branched polymer of glucose.
• Comprised of multiple -(D-glucose) units linked by α–(1,4) glycosidic bonds.
• Branches formed every 12 or 14 glucose residues via α-(1,6) bonds.
• Advantages of branching:
• Increased packing of glucose units.
• Prevention of crystallization.
• Non-reducing ends exist on each branch; only one reducing end capped by glycogenin.

Glycogenesis (Synthesis of Glycogen)

• Process Overview:
• Anabolic pathway.
• Converts α-D-glucose to glycogen, primarily stored in liver and skeletal muscle.
• Roles:
• Liver Glycogen: Maintains blood glucose during well-fed state; decreases in starvation.
• Muscle Glycogen: Provides fuel for ATP synthesis during exertion.

Steps in Glycogenesis

1. Conversion of glucose 6-phosphate to glucose 1-phosphate by Phosphoglucomutase.
2. Synthesis of UDP-glucose using UDP-glucose pyrophosphorylase.
3. Initiating a primer using glycogenin.
4. Chain elongation through glycogen synthase.
5. Formation of branches via 4:6 transferase (branching enzyme).

Detailed Process of Glycogenesis

• Step 1: Glucose 6-phosphate to Glucose 1-phosphate:
• Interconverted by Phosphoglucomutase.
• Step 2: UDP-glucose Synthesis:
• UDP-glucose created from glucose 1-phosphate and UTP.
• Step 3: Primer Synthesis:
• Glycogenin acts as a primer, accepting glucose residues.
• Step 4: Chain Elongation:
• Glycogen synthase extends chains by linking glucose units via α-(1,4) bonds.
• Step 5: Branching:
• Enzyme transfers 5-8 residues from a non-reducing end to create branches via α-(1,6) linkages.

Glycogenolysis (Breakdown of Glycogen)

• Definition: Breakdown of glycogen to release glucose 1-phosphate and α-D-glucose.
• Economics of Glycogenolysis:
• A catabolic pathway; different enzymes than in glycogenesis.
• Not a direct reversal process.

Steps in Glycogenolysis

1. Shortening of chains by Glycogen phosphorylase.
2. Debranching (move 3 residues) via 4:4 transferase.
3. Debranching (remove 1 glucose) using 1:6 glucosidase.
4. Conversion of glucose 1-phosphate to glucose 6-phosphate via Phosphoglucomutase.

Detailed Process of Glycogenolysis

• Step 1: Glycogen phosphorylase cleaves α-(1,4)-linkages to release glucose 1-phosphate, ceasing 4 residues from any branch point (limit dextrin).
• Step 2: 4:4 transferase removes three glucosyl units for re-attachment.
• Step 3: Amylo-α-(1,6) glucosidase removes one glucose residue attached by α-(1,6) bond.
• Step 4: Conversion of glucose 1-phosphate to glucose 6-phosphate occurs in liver for blood glucose release; muscle cells utilize for energy via glycolysis.

Regulation of Glycogen Metabolism

• Regulated tightly to maintain glucose levels:
• In liver: Glycogenesis increases in fed state, glycogenolysis in fasting.
• In muscle: Glycogenolysis accelerates during exercise, glycogenesis at rest.

Hormonal Regulation

• Insulin promotes glycogenesis, opposing glucagon and epinephrine, which stimulate glycogenolysis.
• Active forms:
• Glycogen synthase a (active) / Glycogen synthase b (inactive).
• Glycogen phosphorylase a (active) / Glycogen phosphorylase b (inactive).

Mechanisms of Hormonal Regulation

• Insulin activates signaling pathways to increase glycogen synthesis.
• Glucagon/Epinephrine trigger cAMP pathways increasing glycogen breakdown.
• Processes are coordinated; while one pathway is active, the other is suppressed (reciprocal regulation).