Glycogen Synthesis and Regulation

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Overview of Lecture Content

• Topic: Glycogen Synthesis
• Outline:
  • Glycogen synthesis pathway
  • Reciprocal regulation of glycogen degradation and synthesis
• Recommended Exercises: See problems 1-3, 5-8, 15-16, and 18 at the end of Chapter 25.

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The Role of Phosphorylation

• Key Functions of Phosphorylation:
  • Energy storage and activation
  • Molecular labeling for function or localization
  • Regulation of enzymatic activity
• Mechanisms:
  • Often involves non-protein molecules (e.g., glucose)
  • Not always reliant on phosphatase/kinase activity
  • Involves both protein and non-protein molecules (e.g., NADPH, GM).

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Pathways for Glycogen Synthesis and Degradation

• Primary Precursors: Glycogen synthesis uses uridine diphosphate glucose (UDP-glucose).
• Activation Process: Linkage to nucleotide diphosphate activates the C-1 position of glucose.

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Synthesis of UDP-glucose

• Catalyzing Enzyme: UDP-glucose pyrophosphorylase forms UDP-glucose from glucose 1-phosphate and UTP.
• Reaction Characteristics:
  • Reaction is reversible.
  • Inorganic pyrophosphatases quickly convert PPi into 2 Pi, driving many reactions via hydrolysis.

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Role of Glycogen Synthase

• Glycogen Synthase Function: Transfers glucose from glucose-UDP to the glycogen chain.
• Key Characteristics:
  • Adds to the non-reducing end of glycogen.
  • Committed step in glycogen synthesis.
  • Requires a polysaccharide primer with at least four units.

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Glycogenin: The Initiator of Glycogen Synthesis

• Structure of Glycogenin: Composed of two identical subunits.
• Function:
  • Each subunit adds at least eight glucose molecules to the other subunit.
  • The first glucose attaches to a tyrosine.
  • Subsequent monomers linked by α-1,4 bonds.

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Interaction Between Glycogenin and Glycogen Synthase

• Visual representation of glycogenin-synthase interactions.

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Branching Enzyme Role in Glycogen Structure

• Function: Creates branches in glycogen polymers.
• Characteristics:
  • Acts on chains with at least 11 residues.
  • Transfers seven or more glucose units with a new α-1,6 linkage.
• Biological Importance:
  • Increases solubility and number of terminal ends for enzyme action (phosphorylase/synthase).

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Efficiency of Glycogen Storage

• Cost of Addition: Adding a glucose monomer costs two ATP.
• Yield from Glucose Release: Release of glucose as glucose 1-phosphate yields ~30 ATP.
• Net Efficiency: Approximately 94% efficiency in storage, slightly less (~91%) at branch points.

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Relationship with Glycolysis and Gluconeogenesis

• Co-regulation: Glycogen synthesis and degradation linked with glycolysis and gluconeogenesis (Chapters 16 and 17).

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Glycogen Synthase Regulation Overview

• Regulatory Factors:
  • Phosphorylation and levels of glucose 6-phosphate.
  • Synthase A (dephosphorylated) is more active; Synthase B (phosphorylated) is less active.
• Allosteric Regulation: In liver, glucose 6-phosphate stabilizes the R state of Synthase B.

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Phosphorylation Analysis of Glycogen Synthase

• Specific Residue of Interest: Ser 641 phosphorylation's impact on activity.

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Reciprocal Regulation by Hormones

• Influence of Glucagon and Epinephrine:
  • Act through protein kinase A (PKA).
  • Phosphorylation Effects:
  • Activates phosphorylase kinase and phosphorylase.
  • Inhibits glycogen synthase.

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Role of Protein Phosphatase 1 (PP1)

• Functions:
  • Downregulates glycogen degradation.
  • Upregulates glycogen synthesis during exercise/fasting.

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Regulating Protein Phosphatase 1 Activity

• Interaction with Regulatory Subunits:
  • GM (in muscle) and GL (in liver).
• Effects of PKA Phosphorylation:
  • Causes dissociation, lowering PP1 activity and influencing glycogen metabolism.

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Recap of PP1 Regulation

• Identical Role in Glycogen: Regulates synthesis and degradation mechanisms.
• Insulin Levels:
  • Influences phosphorylase activity and overall glycogen metabolism.

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Insulin Signaling and Glycogen Synthesis

• Regulatory Mechanisms:
  • Increases glucose transporters in cell membranes.
  • Inactivates glycogen synthase kinase to enhance glycogen synthesis.

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Impact of Blood-Glucose Levels on Glycogen Metabolism

• Responsive Changes: Glycogen phosphorylase and synthase activities respond to blood-glucose levels.

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Phosphorylase Activity in the Liver

• Active Forms: In liver, phosphorylase a (usually phosphorylated) is active in R state.
• Regulation by Glucose: Binds at active sites and promotes T state stabilization, inactivating the enzyme.

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Additional Regulation Dynamics in the Liver

• Default Form of Phosphorylase: Binds and inactivates PP1.
• Effect of Blood-Glucose Increase: Leads to transitions favoring dephosphorylation activities and synthesizing processes.

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Summary of Glycogen Regulation by PP1

• High Insulin Context: Drives regulatory dynamics favoring glycogen synthesis through PKA and PP1 activation.

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Clinical Insights on Diabetes Mellitus

• Type 1 Diabetes: Insulin-dependent; includes autoimmune destruction issues.
• Type 2 Diabetes: Non-insulin dependent (insulin resistance); normal insulin but unresponsive cells.

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Glycogen Storage Diseases Overview

• Disease Mechanisms: Genetic defects in glycogen metabolism contribute to various diseases.
• Examples:
  • von Gierke disease (inactive glucose 6-phosphatase)
  • McArdle disease (phosphorylase activity)

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Summary of Glycogen Storage Diseases