Glycogen metabolism

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)
  • Liver: ∼ 150 g (stabilization of blood glucose when needed)
  • Muscle: ∼ 250 g(energy storage for muscle)
  • Extracellular matrix: ∼ 15 g (0.1% of ECM)
  • Erythrocytes do not store glycogen
• 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

• UDP-glucose: an activated form of glucose and the building block for glycogen synthesis and glycogenolysis
• Process
  • Glucokinase converts glucose + ATP → glucose-6-P + ADP
  • Phosphoglucomutase (isomerase) converts glucose-6-P → glucose-1-P
  • UDP-glucose pyrophosphorylase converts glucose-1-P + UTP → UDP-glucose + PPi (pyrophosphate)

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

• Glycogen synthase
  • A key regulatory enzyme that binds UDP-glucose molecules to the growing glycogen chain
  • Catalyzes the formation of α-1,4-glycosidic bonds between UDP-glucose and the hydroxyl group of the C4 atom at the free end of the glycogen chain

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.

• Glycogen metabolism is primarily regulated by hormones (e.g., insulin, glucagon, epinephrine).
• In skeletal muscle, glycogen metabolism is also regulated allosterically (e.g., ATP, AMP, Ca²⁺).
• Regulation is based on the phosphorylation and dephosphorylation of the key regulatory enzymes, which include:
  • Glycogen synthase (glycogenesis): active when dephosphorylated
  • Glycogen phosphorylase (glycogenolysis): active when phosphorylated
  • Glycogen phosphorylase kinase: The conversion of inactive glycogen phosphorylase to active glycogen phosphorylase requires phosphorylation by the enzyme phosphorylase kinase.

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

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.

• Muscle contraction increases intracellular calcium levels → ↑ calmodulin
  • Activates glycogen phosphorylase kinase, which activates glycogen phosphorylase through phosphorylation
  • Net effect: increased glycogenolysis (new glucose immediately available for metabolization)

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

• Glycogen storage disorders
  • Von Gierke disease
  • Pompe disease
  • Cori disease
  • McArdle disease