Lecture 34: Glycogen

Glycogen Metabolism and Glucose Homeostasis

  • Lecturer: Dr. Katrine Wallis

    • Email: Katrine.wallis@warwick.ac.uk

    • Office: D134

Glycogen Structure and Function

  • Definition: Glycogen is a highly branched polymer of glucose residues.

  • Functions:

    • Serves as a store of glucose to maintain blood glucose levels.

    • Provides energy generation in muscles.

  • Storage Details:

    • Stored as insoluble granules:

      • Liver: up to 10% w/w (~100g)

      • Skeletal Muscle: up to 2% w/w (~400g)

  • Note: Remember the structure of glycogen from earlier lectures.

Glycogen and its Metabolic Pathways

  • Glycogen Interconversion:

    • Key Molecules:

      • Glycogen → Glucose-1-P → Glucose-6-P → Glucose (export to blood)

      • Supports various metabolic pathways:

        • Glycolysis

        • Pentose phosphate pathway

    • Enzymes involved:

      • Glycogen phosphorylase

      • Phosphoglucomutase

      • Glucose-6-phosphatase

Importance of Glycogen

  • Need for Glycogen:

    • Fatty acids cannot be metabolized anaerobically.

    • Blood glucose must be maintained for brain function.

    • Animals cannot convert fatty acids to glucose.

Glyoxylate Pathway

  • Applicability: Only occurs in plants and bacteria.

  • Process: Converts citrate to acetyl-CoA, producing glucose and fatty acids.

Glycogen Structure

  • Glycogen Molecular Structure:

    • Consists of:

      • a-1,6 linkages (branching)

      • a-1,4 linkages (linear).

  • Note: Two types of glycosidic bonds exist within glycogen.

Glycogen Breakdown Process

  • Phosphorolytic Cleavage:

    • Catalyzed by glycogen phosphorylase, producing glucose-1-phosphate and glycogen with reduced residues.

    • Saves one ATP molecule in energy expenditure.

Glycogen Degradation Steps

  • Cleavage Process:

    • Cleaves a-1,4 glycosidic bonds until four residues are left.

    • Transferase moves three residues to the other branch.

    • α-1,6 glycosidase removes the branch point residue.

Glycogen Synthesis

  • Energy Requirement:

    • Glycogen synthesis requires energy input through coupling to UTP cleavage.

  • Key Enzymes:

    • UDP-glucose pyrophosphorylase for synthesis.

Glycogen Primer and Branching

  • Glycogen Primer:

    • Composed of four or more α-1,4 linked glucose residues attached to tyrosine in glycogenin.

  • Branching Enzyme:

    • Attaches a-1,6 linkages to the glycogen molecule.

    • Andersen's Disease: Caused by lack of branching enzyme, leading to liver failure.

Glycogen-Storage Diseases

  • Types of Diseases:

    • I. Von Gierke Disease - Glucose 6-phosphatase deficiency.

    • II. Pompe Disease - Lysosomal a-1,4-glucosidase deficiency.

    • III. Cori Disease - Debranching enzyme deficiency.

    • IV. Andersen Disease - Branching enzyme deficiency.

    • V. McArdle Disease - Phosphorylase deficiency.

    • VI. Hers Disease - Liver phosphorylase deficiency.

    • VII. Phosphofructokinase deficiency.

    • VIII. Phosphorylase kinase deficiency.

    • Note: Most are inherited as autosomal recessives; Type VIII is sex-linked.

Glycogen Metabolism Regulation

  • Metabolism Control: Glycogen phosphorylase and glycogen synthase are reciprocally regulated by hormones.

    • Hormonal Regulation:

      • Breakdown: Glucagon and adrenaline.

      • Synthesis: Insulin.

  • Enzyme Regulation:

    • Phosphorylation and allosteric effectors regulate enzyme activity based on energy states.

Reciprocal Regulation Mechanism

  • Regulatory States:

    • Activity switch: Same signal can have opposite effects on glycogen synthesis and breakdown.

    • Protein kinase A is fundamental in this signaling pathway.

Phosphorylase States

  • Phosphorylase Forms:

    • Exists as relaxed (active) and tense (inactive) state.

    • Regulation by phosphorylation shifts conformational states regulating activity.

Energy Status Regulation

  • Muscle Phosphorylase:

    • Allosterically activated by AMP, inhibited by ATP and G-6-P based on available energy status.

Allosteric Regulation in Liver

  • Phosphorylase Regulation:

    • Glucose shifts the equilibrium to inactive T state, preventing further glycogen breakdown when glucose is sufficient.

Isozymes of Phosphorylase

  • Isozymes Defined:

    • Multiple forms of the same enzyme with different structures and regulation mechanisms.

Glucose Homeostasis

  • Organ Coordination:

    • Maintains glucose levels through organ collaboration to regulate blood glucose concentrations based on energy needs.

Pancreatic Regulation of Blood Glucose

  • Hormone Actions:

    • High blood glucose triggers insulin secretion (promotes glucose uptake).

    • Low blood glucose triggers glucagon secretion (promotes glycogen breakdown).

Mobilization of Glucose During Fasting

  • Hormonal Responses:

    • Glucagon and epinephrine released during stress, exercise mobilizing glucose for energy via glycogenolysis and gluconeogenesis.

The Cori Cycle

  • Process:

    • Involves conversion of lactate back to glucose in the liver from pyruvate generated in muscles.

Importance of the Cori Cycle

  • Application: Critical in high-energy demanding situations like marathon running where muscles rely on aerobic respiration more than on the Cori cycle for ATP.

Summary of Glycogen Metabolism

  • Key Points:

    • Hormonal regulation is crucial for maintaining glucose levels.

    • Glycogen synthesis and breakdown are reciprocally regulated to prevent futile cycling.

    • Understanding these pathways is essential for grasping energy metabolism in the body.