Glycogen metabolism

Glycogen is an essential storage molecule for carbohydrates in the human body. It is a complex polymer consisting of multiple chains of glucose molecules and is present in all types of cells, with the exception of erythrocytes. Liver and skeletal muscle are the main storage organs. Fully replenished glycogen stores can provide blood glucose for approx. 12–48 hours when fasting. Regulation of glycogen metabolism is mediated through hormonal activities, mainly those of insulin, glucagon, and epinephrine.

• Function: Glycogen is the most important carbohydrate storage medium in the human body, found in cytosolic granules.
• Total glycogen storage (provides glucose for 12–48 hours): ∼ 400–450 g
  • Liver: ∼ 150 g → stabilization of blood glucose when needed
  • Muscle: ∼ 250 g → energy storage for muscle
  • Extracellular matrix (0.1% of ECM) ∼ 15 g
  • No storage in erythrocytes!
• Chemical structure:
  • Branched polymer; consisting of multiple linked glucose chains
  • Branches: α-1,6-glycosidic bonds
  • Linkages: α-1,4-glycosidic bonds

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

1.) Synthesis of UDP-glucose

• UDP-glucose: activated form of glucose; building block for glycogen synthesis and glycogenolysis
• Phosphoglucomutase (= isomerase): glucose-6-P → glucose-1-P
• UDP-glucose pyrophosphorylase: glucose-1-P + UTP → UDP-glucose + PP_i (pyrophosphate)

2.) Starting point of glycogen synthesis

• Glycogenin
  • Homodimer protein at the core of each glycogen unit
  • Creates the starting point of glycogen synthesis by polymerizing a few glucose molecules

3.) Chain elongation

• Glycogen synthase creates α-1,4-glycosidic bonds: attaches UDP-glucose to C4-atom of previous glucose unit → glucose-glucose + UDP

4.) Branching of glycogen chains

• Branching enzyme
  • Creates 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 each other

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

The rate-determining enzyme of glycogenesis is glycogen synthase!

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)
    • Stimulated by epinephrine, glucagon, AMP
    • Inhibited by glucose-6-phosphate, insulin, ATP
• 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 → this releases non-phosphorylated, 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).

Glucose utilization

• Phosphoglucomutase (isomerase): glucose-1-P → glucose-6-P
• In muscle:
  • Instant metabolization of glucose-6-P during exercise in muscle (glycolysis)
  • Hexokinase: converts free glucose to glucose-6-P
• In liver:
  • Glucose-6-phosphatase: glucose-6-P → free glucose → release into systemic circulation → increases serum glucose levels

The rate-determining enzyme in glycogenolysis is glycogen phosphorylase.

Disruptions in glycogen degradation lead to an accumulation of normal or pathologically structured glycogen in cells. Glycogen storage diseases are caused by inherited enzyme deficiencies of glycogenolysis and primarily affect skeletal muscles and the liver, the main glycogen stores in the body.

Glycogen metabolism is regulated mainly by hormones. It is based on the phosphorylation and dephosphorylation of glycogen phosphorylase and glycogen synthase by the cAMP-dependent protein kinase A. Since the glycogen in the liver has different functions from that in skeletal muscle, each is regulated differently. For example, skeletal muscle also has allosteric (non-hormonal) regulation via ATP, AMP, and calcium ions.

Key regulatory enzymes

• Glycogen synthase (↑ glycogen): active when dephosphorylated
• Glycogen phosphorylase (↓ glycogen): 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!

Overview

Insulin

• In liver and muscle: activation of tyrosine kinase → ↓ cAMP → activation of protein phosphatase 1 (PP 1) → PP 1-mediated dephosphorylation deactivates glycogen phosphorylase and activates glycogen synthase → ↓ glycogenolysis and ↑ glycogen synthesis
• Net effect: increased synthesis of glycogen, decreased glycogenolysis, decreased serum glucose levels

Insulin stimulates storage of lipids, proteins, and glycogen.

Glucagon

• In liver: activation of G protein-coupled receptor → stimulation of adenylate cyclase → ↑ cAMP → activation of protein kinase A (PKA) → PKA-mediated phosphorylation activates glycogen phosphorylase and deactivates of glycogen synthase → ↑ glycogenolysis and ↓ glycogen synthesis (same mechanism as epinephrine)
• Net effect: decreased synthesis of glycogen, increased glycogenolysis, increased serum glucose levels

Epinephrine

• In liver and muscle: activation of (beta-adrenergic) G protein-coupled receptor → stimulation of adenylate cyclase → ↑ cAMP → activation of protein kinase A (PKA) → PKA-mediated phosphorylation activates glycogen phosphorylase and deactivates of glycogen synthase → ↑ glycogenolysis and ↓ glycogen synthesis (same mechanism as glucagon)
• In liver only: activation of alpha-adrenergic receptors →; activation of protein kinase C/phospholipase C → increased intracellular calcium → ↑ calmodulin: activates glycogen phosphorylase kinase → phosphorylation and activation of glycogen phosphorylase → ↑ glycogenolysis and ↓ glycogen synthesis
• Net effect: decreased synthesis of glycogen, increased glycogenolysis, increased serum glucose levels

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 by phosphorylation
  • Net effect: increased glycogenolysis; new glucose immediately available for metabolization

These regulatory processes are only present in skeletal muscle, not in the liver.

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