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Glycogen metabolism

Last updated: February 4, 2021

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Glycogen is an essential complex polymer consisting of multiple chains of glucose molecules. It is present in all types of cells, with the exception of erythrocytes. Most of the body's glycogen is stored in the liver and skeletal muscle. Fully replenished glycogen stores can provide blood glucose for approximately 12–48 hours during fasting periods. Glycogen metabolism is primarily regulated by insulin, glucagon, and epinephrine. Insulin increases glycogenesis and decreases glycogenolysis in the liver and muscle; glucagon and epinephrine decrease glycogenesis in the liver and increase glycogenolysis in the liver and muscle.

  • Function: Glycogen is the most important carbohydrate storage medium in the body and is found in cytosolic granules.
  • Total glycogen storage: ∼ 400–450 g (provides glucose for 12–48 hours)
  • Chemical structure
    • Branched polymer consisting of multiple linked glucose chains
    • Branches: α-1,6-glycosidic bonds
    • Linkages: α-1,4-glycosidic bonds

The periodic acid–Schiff stain is an immunohistochemical technique used to visualize polysaccharides such as glycogen.

1.) Synthesis of UDP-glucose

2.) Initial chain formation

  • Glycogenin
    • An enzyme comprised of a homodimer protein that is at the core of each glycogen unit and is the starting point of glycogen synthesis
    • Catalyzes the formation of short glycogen chains by polymerizing a few UDP-glucose molecules

3.) Chain elongation

The rate-determining enzyme of glycogenesis is glycogen synthase.

4.) Branching of glycogen chains

  • Branching enzyme: an enzyme with glucosyltransferase activity that introduces branches to the glycogen chain to allow for further chain elongation at multiple sites within the glycogen complex
    • Catalyzes the formation of α-1,6-glycosidic bonds: hydrolyzes a chain of 6 glucose units off the original chain → attachment of molecules to C6 atom of another glucose unit within the original chain
    • Branches are introduced at least 4 glucose units apart from one another.

The sequence of glycogen synthesis starting from glucose: Glc → Glc-6-P → Glc-1-P → UDP-Glc → glycogen

1.) Release of glucose

  • Cleavage of α-1,4-glycosidic bonds: glycogen phosphorylase (cofactor vitamin B6) cleaves off glucose-1-P; through a phosphoric reaction until 4 terminal glucose residues remain on a branch (referred to as limit dextrin).
  • Cleavage of α-1,6-glycosidic bonds
    • Debranching enzymes: an enzyme that has glucosyltransferase as well as glucosidase activity
      • First step: glycosyltransferase; (or 4-α-D-glucanotransferase): transfers 3 out of the 4 remaining glucose residues of the branch to a nearby branch
      • Second step: glucosidase (or amylo-α-1,6-glucosidase): cleaves off remaining glucose unit (alpha-1,6 linkage) from branch; through a hydrolytic reaction → release of nonphosphorylated, free glucose molecules and a linear chain of glycogen

A part of glycogen is not degraded by glycogen phosphorylase and debranching enzymes but in lysosomes by lysosomal alpha-glucosidase. Deficiency of this enzyme results in Pompe disease (glycogen storage disease II).

Cori disease is a type of glycogen storage disorder (type III) caused by a deficiency in the glycogen debrancher enzyme (α-1,6-glucosidase).

McArdle disease is a glycogen storage disease characterized by a deficiency in glycogen phosphorylase in skeletal muscles.

2) Glucose utilization

After glycogenolysis, the phosphoglucomutase (isomerase) transduces glucose-1-P into glucose-6-P

  • In muscle
    • Instant metabolization of glucose-6-P during exercise (glycolysis)
    • Hexokinase: converts free glucose to glucose-6-P
  • In liver: Glucose-6-phosphatase: glucose-6-P → free glucose → release into systemic circulation → increase in serum glucose levels

The rate-determining enzyme in glycogenolysis is glycogen phosphorylase.

Glycogen storage diseases are caused by inherited enzyme deficiencies of glycogenolysis, which result in the accumulation of normal or pathologically structured glycogen in cells of the skeletal muscles and the liver, the main glycogen stores in the body.

The increased presence of phosphate in cells is a starvation signal: All enzymes that raise blood sugar levels are active in their phosphorylated form!

Hormonal regulation of glycogen metabolism
Insulin Glucagon Epinephrine Cortisol

Glycogenesis (glycogen via glycogen synthase)

Glycogenolysis (glycogen via glycogen phosphorylase)

Serum glucose

Mechanism of action in liver

Mechanism of action in muscle
  • -

Insulin stimulates storage of lipids, proteins, and glycogen.

Glycogen synthase is stimulated by glucose-6-phosphate, insulin, and cortisol. It is inhibited by epinephrine and glucagon.

Nonhormonal regulation of glycogen metabolism

Glycogen synthesis

Glycogenolysis Serum glucose Metabolic effect
Glucose-6-P Anabolic effect
ATP
Muscle contraction : Catabolic effect
AMP

These regulatory processes only take place in skeletal muscle, not in the liver.