Glycogen metabolism

Abstract

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.

Overview

  • 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
  • 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.

Glycogen synthesis

1.) Synthesis of UDP-glucose

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

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!

Glycogenolysis

Release of glucose

  • Cleavage of α-1,4-glycosidic bonds
  • Cleavage of α-1,6-glycosidic bonds
    • Debranching enzymes: An enzyme that as 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.

Regulation

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

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

Overview

Glycogenesis (↑ glycogen)

Key enzyme: glycogen synthase

Glycogenolysis (↓ glycogen)

Key enzyme: glycogen phosphorylase

Serum glucose
Anabolic Insulin
Glucagon
Catabolic Epinephrine
Anabolic (liver) and catabolic (muscle) Cortisol

Insulin

  • In liver and muscle: Activation of tyrosine kinasecAMP → activation of protein phosphatase 1 (PP 1) → PP 1-mediated dephosphorylation deactivates glycogen phosphorylase and activates of glycogen synthaseglycogenolysis 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: (same mechanism as epinephrine) activation of G protein-coupled receptor → stimulation of adenylate cyclasecAMPactivation of protein kinase A (PKA) PKA-mediated phosphorylation activates glycogen phosphorylase and deactivates of glycogen synthaseglycogenolysis and ↓ glycogen synthesis
  • Net effect: decreased synthesis of glycogen, increased glycogenolysis, increased serum glucose levels

Epinephrine

Allosteric / non-hormonal regulation

Glycogen synthesis

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

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

Clinical significance

last updated 08/29/2018
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