Biochemistry - Glycogenolysis

Introduction

• Glycogen, or animal starch, is a branched polysaccharide and a carbohydrate reserve stored in the liver and muscle.
• Glycogenesis: Formation of glycogen from glucose.
• Glycogenolysis: Breakdown of glycogen to glucose.
• Regulated by hormones: insulin, glucagon, cortisol.
• Enzyme: phosphorylase initiates glycogenolysis.
• Abnormal glycogen metabolism can lead to glycogen storage diseases.

Fundamentals of Glycogenolysis

• Initiated by the enzyme phosphorylase which cleaves 1 4 linkages to produce glucose-1-P.
• Phosphorylase activity is activated by phosphorylation.
• Glycogenolysis is crucial during fasting and intense exercise.
• Adrenaline increases cAMP, activating phosphorylase.
• Muscles and liver use glycogen differently.

Cellular Level

• Glycogenolysis occurs in cytosol and lysosomes.
• Enzymes involved differ between these cellular locations.
• In muscle, glucose uptake involves GLUT1 and GLUT4.
• In liver, glucagon facilitates glycogenolysis via cAMP.

Molecular Level

• Steps of Glycogenolysis:
  1. Glycogen phosphorylase cleaves glucosyl 1 4 linkages.
  2. -1,4 -1,4 glucan transferase transfers trisaccharide units.
  3. Debranching enzyme (amylo-1,6-glucosidase) releases free glucose.
  4. Phosphoglucomutase converts glucose-1-P to glucose-6-P.
• In liver, glucose-6-phosphatase converts glucose-6-P into free glucose.
• Muscle lacks glucose-6-phosphatase, leading to energy production through glycolysis.

Function

• Glycogen is rapidly mobilized for energy.
• Liver glycogenolysis maintains blood glucose levels during fasting.
• Muscle glycogenolysis supports quick ATP generation during exercise.
• Glycogen serves as a precursor for other metabolic pathways.

Mechanism

• Glycogen metabolism is regulated by glycogen synthase and phosphorylase.
• Glycogen phosphorylase activity is modulated by allosteric regulation and phosphorylation.
• Glucose-6-phosphate is used for various metabolic pathways.
• Glycogen degradation in lysosomes involves acid maltase.

Testing

• Glycogen visualization requires electron microscopy.
• Histological methods can indicate glycogen presence but lack specificity.
• DNA mutational analysis helps diagnose glycogen storage diseases.
• Glycogenolysis and gluconeogenesis are explored using isotopes and spectroscopy.

Pathophysiology

• Disruptions in glycogenolysis can lead to diseases affecting liver, muscle, brain, kidney.
• Common Glycogen Storage Diseases:
  • von Gierke disease: deficiency in glucose-6-phosphatase.
  • Pompe disease: mutations in lysosomal alpha-glucosidase.
  • Cori disease: deficiency in glycogen debranching enzyme.
  • McArdle disease: deficiency in muscle glycogen phosphorylase.
  • Hers disease: deficiency in liver glycogen phosphorylase.
  • Lafora progressive myoclonus epilepsy: glycogen phosphorylation abnormalities.

Clinical Significance

• Glycogenolysis is vital in regulating blood glucose and providing energy for muscle contractions.
• Impairments can lead to glycogen storage diseases.