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.