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Glycogen Synthesis and Metabolism

Glycogen Synthesis

  • Importance of Glycogen:
    • Carbohydrate-rich meals (like pasta and pizza) are vital for endurance events (e.g., marathons), ensuring sufficient muscle glycogen.

25.1 Glycogen Is Synthesized and Degraded by Different Pathways

  • Separate Pathways:

    • Glycogen synthesis and breakdown do not occur via the same reactions; distinct pathways enhance flexibility in metabolizing energy and controlling enzyme action.

  • Key Questions:

    1. What are the steps involved in glycogen synthesis?
    2. How is glycogen synthesis regulated?

  • Activated Precursor:

    • UDP-glucose (not glucose 1-phosphate) acts as the donor for glycogen biosynthesis. This molecule is activated due to the hydroxyl group on its C-1 carbon atom being esterified to diphosphate.

  • Formation of UDP-glucose:

    • Synthesized from glucose 1-phosphate and UTP by UDP-glucose pyrophosphorylase, releasing pyrophosphate (PPi).
    • PPi is quickly hydrolyzed, reinforcing the irreversibility of the UDP-glucose formation.

  • Glycogen Synthase Function:

    • Catalyzes the transfer of glucose from UDP-glucose to the nonreducing end of glycogen chains.
    • Forms ext{C-4} linkages to extend the glycogen polymer.
    • Isozymes: There are two forms (liver-specific and muscle-specific).

  • Priming with Glycogenin:

    • Glycogenin catalyzes the initial polymerization of glucose (10-20 units) on its own tyrosine residue, enabling glycogen synthase to extend the polymer further.

  • Branching Enzyme:

    • Responsible for forming ext{α-1,6} linkages that create branches within glycogen. It transfers a block of 7 glucose residues from a longer chain to form a new branch.

25.2 Metabolism in Context

  • Reciprocal Regulation of Glycogen Metabolism:

    • Glycogen synthesis and breakdown are tightly coordinated to prevent simultaneous operation.
    • Regulators: Glucagon and epinephrine initiate breakdown via cAMP pathways, inhibiting synthesis.

  • Protein Kinase A:

    • This kinase activates glycogen breakdown and inhibits synthesis through phosphorylation of key enzymes (e.g., glycogen phosphorylase and glycogen synthase).

  • Dephosphorylation by Protein Phosphatase 1 (PP1):

    • Reacts post-exercise to facilitate glycogen replenishment by reversing phosphorylative actions on both phosphorylase and synthase, thereby enhancing glycogen synthesis.

  • Insulin Role:

    • Facilitates glycogen synthesis by enhancing glucose transport into cells through GLUT4 and deactivating glycogen synthase kinase, leading to glycogen synthase activation via PP1.

  • Glucose Regulation in Liver:

    • Blood glucose levels (4.4 to 6.7 mM) directly influence glycogen synthesis by shifting the activity of phosphorylase a (a glucose sensor), aiding in glucose homeostasis.

  • Clinical Insight into Diabetes:

    • Diabetes mellitus results from an imbalance between insulin (deficiency in Type 1 and insulin resistance in Type 2) and glucagon, leading to excessive glucose production and reduced utilization.

  • Glycogen storage diseases further illustrate defects in metabolism that affect glucose homeostasis and energy regulation.

Key Terms

  • UDP-glucose: An activated glucose donor for glycogen synthesis.
  • Glycogen synthase: Enzyme that catalyzes the addition of glucose units to glycogen.
  • Glycogenin: Autoglycosylating protein that initiates glycogen synthesis.
  • Glycogen synthase kinase (GSK): Enzyme that regulates glycogen synthase activity.
  • Protein phosphatase 1 (PP1): Key regulator that activates glycogen synthase and deactivates glycogen phosphorylase.