Glycogen Metabolism

Glycogen Metabolism

Glycogen is the storage form of glucose in animals, equivalent to starch in plants. It is a highly branched polymer of glucose with α-1,4 glycosidic bonds in chains and α-1,6 bonds at branch points. Stored in liver (glucose reservoir for blood sugar) and muscle (fuel for muscle contraction).

Glycogenesis (Synthesis)

Requires UDP-glucose as the activated glucose donor.

  1. Glucose → G6P (Glucokinase/Hexokinase)
  2. G6P → G1P (Phosphoglucomutase)
  3. G1P + UTP → UDP-glucose + PPi (UDP-glucose pyrophosphorylase) — driven by pyrophosphatase
  4. UDP-glucose → added to glycogen chain by Glycogen Synthase (rate-limiting; adds α-1,4 links)
  5. Branching enzyme: transfers 6–7 residues to C6, creating α-1,6 branch point (every 8–12 residues)

A protein primer (glycogenin) serves as initiator — glycogen synthase cannot start a new chain from scratch.

Glycogenolysis (Breakdown)

  1. Glycogen Phosphorylase (rate-limiting): Cleaves α-1,4 bonds releasing Glucose-1-phosphate (using inorganic phosphate, not water — phosphorolysis). Cannot pass within 4 residues of branch point.
  2. Debranching enzyme (bifunctional): Transfers 3 residues to chain end (transferase), then cleaves α-1,6 bond (glucosidase) releasing free glucose (not phosphorylated). Free glucose from branches exits cells; G1P is retained.
  3. G1P → G6P (Phosphoglucomutase)
  4. In liver: G6P → Glucose (G6Pase) → exported to blood
  5. In muscle: G6P → enters glycolysis directly (no G6Pase)

Hormonal Regulation

  • Glucagon/Epinephrine (cAMP cascade): Receptor → Gs protein → Adenylyl cyclase → ↑cAMP → PKA → phosphorylates: ① Phosphorylase kinase (active) → phosphorylates Glycogen Phosphorylase → active (phospho-a form) → glycogenolysis ↑ ② Glycogen Synthase (inactive phospho-b form) → glycogenesis ↓
  • Insulin: Activates Protein Phosphatase 1 → dephosphorylates Phosphorylase (inactive) and Glycogen Synthase (active) → promotes glycogenesis and stops glycogenolysis.
  • AMP (muscle): Directly activates Glycogen Phosphorylase b without phosphorylation (local energy sensor).

Glycogen Storage Diseases (GSDs)

  • Type I (Von Gierke): G6Pase deficiency; cannot release glucose from liver
  • Type II (Pompe): Lysosomal α-1,4-glucosidase (acid maltase) deficiency; glycogen in all organs; cardiomegaly
  • Type III (Cori/Forbes): Debranching enzyme deficiency; abnormal short outer branches
  • Type V (McArdle): Muscle Phosphorylase deficiency; exercise intolerance, myoglobinuria
  • Type VI (Hers): Liver Phosphorylase deficiency; mild hypoglycemia