Biochemistry - Glycogenolysis

Introduction

• Glycogen: Known as animal starch, a branched polysaccharide stored in liver and muscle.
• Glycogenolysis: Breakdown of glycogen into glucose.
  • Catalyzed by increased cAMP.
  • Regulated by insulin, glucagon, and cortisol.
  • Initiated by enzyme phosphorylase, yielding glucose-1-phosphate (Glucose-1-P).
• Metabolic Pathways: Glycolysis, glycogenesis, gluconeogenesis.
• Impairment: Leads to glycogen storage diseases.

Fundamentals

• Phosphorylase: Enzyme catalyzing phosphorolytic cleavage producing glucose-1-P.
  • Activated by phosphorylation.
• Liver: Breaks down glycogen to raise blood glucose, particularly for brain and RBC.
• Muscles: Use glycogen for energy, especially during anaerobic glycolysis.
  • Adrenaline stimulates glycogen breakdown.
• Glycogen Stores: Liver stores deplete after 12-18 hours of fasting.

Cellular Level

• Locations: Cytosol and lysosomes, with different degradation enzymes.
• Transporters: GLUT1 and GLUT4 for glucose uptake in skeletal muscle.
• Activation: Glucagon and AMP activate phosphorylase in liver and muscle respectively.

Molecular Level

• Phosphorylase Kinase (PhK): Activates phosphorylase.
• Steps of Glycogenolysis:
  1. Phosphorylase cleaves glucosyl -1-4 linkages.
  2. Glucan transferase modifies chain for debranching.
  3. Debranching enzyme releases free glucose.
  4. Phosphoglucomutase converts glucose-1-P to glucose-6-P.
• Liver: Dephosphorylates glucose-6-P to release free glucose.
• Muscles: Lack glucose-6-phosphatase, convert glucose-6-P to pyruvate and lactic acid.

Function

• Energy Reserves: Glycogen and lipids.
  • Glycogen provides rapid energy, important in low lipid conditions.
• Muscle: Critical for ATP generation and fatigue resistance.
• Pentose Phosphate Pathway: Glycogenolysis provides precursors.

Mechanism

• Regulation: By glycogen synthase and glycogen phosphorylase.
  • Phosphorylation and hormonal signals.
• Degradation: Cleaves glucose residues and debranches glycogen.
• Lysosomal Degradation: Enzyme acid maltase involved.
• Blood Glucose Maintenance: Balance between glucose entry and removal.

Testing

• Visualization: Requires electron microscopy.
• Histological Staining: Periodic Acid Schiff staining, though not specific.
• Novel Methods: Recombinant protein assays for glycogen detection.
• Glycogen Storage Diseases: DNA mutational analyses replacing liver biopsies.

Pathophysiology

• Diseases: Include glycogen storage diseases, lysosomal storage diseases.
• von Gierke Disease: Deficiency in glucose-6-phosphatase.
• Pompe Disease: Mutation in lysosomal alpha-glucosidase.
• Cori Disease: Deficiency in debranching enzyme.
• McArdle Disease: Deficiency in muscle glycogen phosphorylase.
• Hers Disease: Deficiency in liver glycogen phosphorylase.
• Lafora Epilepsy: Increased glycogen phosphorylation, leading to toxicity.

Clinical Significance

• Role in Energy Production: Immediate glucose source during muscle contraction.
• Implications: Inherited metabolic disorders due to impaired glycogenolysis.

References

• Multiple references providing detailed biochemical studies and findings.