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)
- Branched polymer consisting of multiple linked glucose chains
- Branches: α-1,6-glycosidic bonds
- Linkages: α-1,4-glycosidic bonds
1.) Synthesis of UDP-glucose
- UDP-glucose: an activated form of glucose and the building block for glycogen synthesis and glycogenolysis
2.) Initial chain formation
3.) Chain elongation
- 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.
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
- Debranching enzymes: an enzyme that has glucosyltransferase as well as glucosidase activity
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).
2) Glucose utilization
- In muscle
- In liver: Glucose-6-phosphatase: glucose-6-P → free glucose → release into systemic circulation → increase in serum glucose levels
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:
|Hormonal regulation of glycogen metabolism|
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|Serum glucose|| || || || |
Mechanism of action in liver
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|Mechanism of action in muscle|| || |
|Nonhormonal regulation of glycogen metabolism|
|Glycogenolysis||Serum glucose||Metabolic effect|
|Muscle contraction :||↓||↑||↑||Catabolic effect|
- Muscle contraction increases intracellular calcium levels → ↑ calmodulin