Week 2

Glycogen Overview

  • Glycogen is the major carbohydrate storage form in animals and is comparable to starch in plants.

  • Primary storage locations in the body:

    • Liver: 6-8% of wet weight.

    • Muscle: Rarely exceeds 1% of wet weight but overall glycogen pool in muscle is 3 to 4 times greater than in the liver.

  • Glycogen is found in the cytosol of cells and can contain up to 60,000 glucose residues.

  • Glycogen molecule characteristics:

    • Hydrophilic nature: Exists in a hydrated state as glycogen granules (65% water).

    • Size comparison: If a dog stored glycogen like fat, it would weigh nearly twice as much, hindering mobility.

    • Energy storage in birds: Migrating birds primarily store energy as fat for similar mobility reasons.

Glycogenolysis

  • Definition: The process of glycogen breakdown.

  • Location & Triggers:

    • Occurs in the liver during exercise and starvation.

    • Muscle glycogen breakdown (glycogenolysis) more reliant on exercise.

  • Output:

    • Free glucose generated from glycogenolysis in the liver; this glucose enters the bloodstream.

    • Muscle glycogenolysis does not release glucose, as muscle lacks glucose-6-phosphatase (Glc-6-Pase).

  • Muscle glycogen must be oxidized in situ for energy.

Glycogenesis

  • Definition: The biosynthesis of glycogen from glucose and its metabolites.

  • Key Points:

    • Involves different pathways, allowing independent operation from glycogenolysis.

    • Regulated by hormones and neurotransmitters.

Glycogen Storage Diseases

  • A group of inherited metabolic disorders leading to abnormal glycogen mobilization or deposition.

  • Symptoms may include: muscular weakness, exercise intolerance, and potentially death.

Metabolic Pathways

  • Glycogenesis and glycogenolysis occur via separate metabolic pathways, considered continuous and dynamic physiological processes.

    • Glycogenesis pathway breakdown:

    1. Glucose is phosphorylated by hexokinase (HK) or glucokinase.

    2. Glucose-6-phosphate (Glc-6-P) is converted to glucose-1-phosphate (Glc-1-P) by phosphoglucomutase (PGM).

    3. Glc-1-P is converted to uridine diphosphate-glucose (UDP-Glc) by UDP-Glc pyrophosphorylase.

    4. UDP-Glc facilitates entry into other pathways like lactate synthesis and glycogen synthesis.

  • Glycogen Synthase:

    • Catalyzes the rate-limiting step in glycogenesis.

    • Activation involves dephosphorylation by protein phosphatase 1, stimulated by insulin.

Mechanisms of Glycogen Metabolism

  • Glycogen Structure:

    • Composed of glucose linked by α-1,4 glycosidic bonds, with branching (at every 10 glucose residues) via α-1,6 bonds established by branching enzyme.

    • Glycogen metabolism occurs at non-reducing ends during synthesis and degradation.

  • Glycogenolysis Process:

    • Involves two-step reactions: shortening of chains by phosphorylase and removal of branches by a debranching enzyme.

    • Glc-1-P is released, which can be converted to Glc-6-P.

    • About 90% of glycogen breakdown results in Glc-1-P and 10% yields free glucose, usable in the Embden-Meyerhoff pathway or released into the bloodstream.

Role of Enzymes and Hormones

  • Key Enzymes:

    • Glycogen Phosphorylase: Essential for glycogenolysis, exists in active phosphorylated or inactive dephosphorylated forms.

    • Phosphorylase Kinase: Activated by cAMP machinery, hormones (e.g., epinephrine, glucagon) stimulate breakdown pathways.

    • Insulin’s Role: Activates glycogen synthase via protein phosphatase 1, promoting glycogen storage.

  • Calcium's Role:

    • Ca++ acts as an allosteric activator of phosphorylase kinase, synchronizing glycogenolysis with muscle contraction.

Glycogen Storage Diseases in Animals

  • Notable diseases include:

    • Type I von Gierke's disease: Glc-6-Pase deficiency.

    • Type II Pompe's disease: Glycogen branching enzyme deficiency.

    • Type III Cori's disease: Debranching enzyme deficiency.

  • Symptoms and issues associated with these diseases:

    • Exercise intolerance, low blood glucose levels, increased rates of gluconeogenesis, hepatomegaly, hyperlipidemia, ketonemia.

Clinical Considerations and Objectives

  • Objectives:

    • Discuss energy storage preference in animals (triglyceride vs. glycogen).

    • Explain the ineffectiveness of muscle glycogenolysis in contributing glucose to circulation.

    • Describe metabolic regulation mechanisms for glycogenesis and glycogenolysis pathways.

    • Review hormone actions and influences on glycogen metabolism.

  • Diagnostic Approaches:

    • Enzyme assays of tissues to diagnose glycogen storage diseases (vary based on disease type).

Questions for Understanding

  1. The intracellular protein linked to glycogen is: c. Glycogenin.

  2. Which enzyme is activated through dephosphorylation by protein phosphatase 1? a. Glycogen Synthase.

  3. Which ribonucleotide participates in glycogen formation? e. UDP.

  4. Which is associated with inactivation of phosphorylase kinase in liver cells? e. Phosphodiesterase.

  5. Deficiency in which enzyme would not cause glycogen storage disease? c. Hexokinase (Liver).

  6. Pompe’s-like disease is best associated with: b. Branching enzyme deficiency.