Glycogenolysis

Summary

Glycogenolysis is the biochemical pathway that breaks down the body’s glycogen stores to release glucose.

The pathway of glycogen breakdown varies depending on whether a straight chain of glycogen or branch point is being broken down, as well as on where in the cell this breakdown occurs.

Most glycogen is found in the cytoplasm, and breakdown of straight chains in the cytoplasm occurs at the end residues, or ends of the straight chain.

Here, glycogen phosphorylase works to cleave the terminal residue from the chain, releasing glucose-1-phosphate in the process. This formally breaks an alpha-1,4-linkage. This reaction is highly regulated, being stimulated by glucagon and epinephrine, but inhibited by insulin. Glycogen phosphorylase is also defective or mutated to cause McArdle disease.

The glucose-1-phosphate that is released is then acted upon by a mutase enzyme to form glucose-6-phosphate. This glucose-6-phosphate is the final product of this breakdown, since it can then enter glycolysis or gluconeogenesis as needed by the cell.

The breakdown of straight chains of glycogen proceeds until it hits a branching point or fork, also known as a limit dextrin. This describes a point that is exactly 4-residues or less from where the branch starts. At these points, debranching enzymes are needed to clear the branch. These debranching enzymes can break the alpha-1,6-linkage that makes up the branch point. Notably, debranching enzymes are deficient or mutated to cause Cori disease.

Finally, glycogen breakdown in lysosomes occurs very differently than it does in the cytoplasm. In the lysosome, acid maltase works to directly release glucose from glycogen. This acid maltase enzyme is deficient or mutated to cause Pompe disease.

Key Points

• Glycogenolysis
  • Etymology
    • Glycogenolysis = glycogen + lysis (to cut)
      • Refers to cutting apart glycogen
  • Summary
    • Breaks down glycogen to release sugar
      • Allows the organism to use sugar stores to maintain sufficient blood glucose levels
      • Glycogen is a storage form of polymerized sugar that appears as clear cytoplasmic granules
      • Glycogen stains pink/purple with the PAS reaction
    • Glycogen is a branched polymer
      • Branching increases solubility of glycogen in aqueous environment of cell, and adds more terminal residues (where reactions can occur)
        • Increases rate of glycogen formation and breakdown
      • Straight chains formed by alpha-1,4 bonds
      • Branch points formed by alpha-1,6 bonds
    • Glycogen is primarily found in the liver and in skeletal muscle
      • Liver: to maintain blood glucose levels
      • Skeletal muscle: to meet exercise demands
  • Reaction Pathway
    • From straight (alpha-1,4) glycogen chain
      • Single residue at end of chain cleaved → glucose-1-phosphate
        • Via glycogen phosphorylase
          • Deficient in McArdle Disease
        • Continues until a branch point at a limit dextrin (4 residues from a branch point)
          • This is the “limit” for glycogen phosphorylase, where glycogen phosphorylase can no longer free glucose from the end of the chain
        • Irreversible (main regulatory step)
      • Glucose-1-phosphate → glucose-6-phosphate (G6P)
        • Via phosphoglucomutase (isomerization reaction)
        • Glucose-6-phosphate can enter glycolysis for energy production or gluconeogenesis for glucose release
    • At branch points
      • Debranching occurs via debranching enzymes
        • Refers to 4-alpha-D-glucanotransferase and alpha-1,6-glucosidase
        • Deficient in Cori Disease
      • 4-alpha-D-glucanotransferase (glucosyltransferase) transfers fragment of 3 glucose residues (out of 4) of limit dextrin branch to end of main chain
        • Moves branched fragment of 3 residues, connecting to end of main chain via an alpha-1,4 bond
        • These can be removed in turn by glycogen phosphorylase
      • Alpha-1,6-glucosidase removes final branched glucose residue
        • Breaks the final glucose residue attached by alpha-1,6 bond via hydrolysis
        • Produces glucose directly (not glucose-6-phosphate)
    • In lysosome only (small amounts)
      • Glycogen → Glucose
        • Via alpha-1,4-glucosidase (acid maltase)
          • Deficient in Pompe Disease
          • This enzyme can degrade glycogen in both a straight chain or branched form to form glucose
          • This occurs in small amounts relative to glycogenolysis in the cytoplasm above
          • This reaction occurs more often in lysosomes of cells with high glycogen stores (e.g. cardiomyocytes and hepatocytes)
  • Regulation
    • Glycogen phosphorylase reaction is the primary regulatory step
    • Stimulated by glucagon and epinephrine
      • High glucagon and epinephrine representative of fasting state (low glucose)
      • Both glucagon and epinephrine activate phosphorylase kinase which adds a phosphate group to glycogen phosphorylase to activate the enzyme
      • Goal is to mobilize glucose to sustain rest of body
    • Inhibited by insulin
      • High insulin representative of fed state (high glucose)
      • No need to mobilize glucose when sugar levels are high