Glycogen metabolism Pathways and glycogen storage diseases (GSD)

• Glycogen metabolism is a vital process in the human body, responsible for the storage and release of glucose, which is a primary source of energy.

• This process includes two main pathways: glycogenesis (the synthesis of glycogen) and glycogenolysis (the breakdown of glycogen).

• Abnormalities in these processes can lead to glycogen storage diseases (GSD), a group of inherited metabolic disorders.

• Below is a detailed explanation of glycogen metabolism pathways followed by an overview of notable GSD types.

Glycogen Metabolism Pathways

1) Glycogenesis (Synthesis of Glycogen)

• Purpose: Converts glucose into glycogen for storage, mainly in the liver and muscles.

Key Steps:

• Glucose to G6P: Phosphorylation of glucose to glucose-6-phosphate (G6P) by hexokinase (or glucokinase in the liver).

• Isomerization: G6P isomerized to glucose-1-phosphate (G1P) by phosphoglucomutase.

• UDP-Glucose Formation: G1P is activated to UDP-glucose by UDP-glucose pyrophosphorylase.

• Glycogen Synthesis: Glycogen synthase adds glucose units to glycogen via α-1,4-glycosidic bonds.

• Branching: Branching enzyme forms α-1,6-linked branches for structure and solubility.

2) Glycogenolysis (Breakdown of Glycogen)

• Purpose: Breaks down glycogen into glucose for energy.

Key Steps:

• Glycogen to G1P: Glycogen phosphorylase cleaves α-1,4 bonds, releasing glucose-1-phosphate.

• Debranching: Debranching enzyme removes α-1,6 branches, releasing glucose.

• G1P to G6P: G1P is converted to G6P by phosphoglucomutase.

• Glucose Release: In the liver, glucose-6-phosphatase converts G6P to free glucose, released into the blood.

Glycogen Storage Diseases (GSD)

• GSDs result from enzyme deficiencies affecting glycogen metabolism, causing abnormal glycogen accumulation or structure.

1) GSD Type I (Von Gierke Disease)

• Enzyme Deficiency: Glucose-6-phosphatase

• Symptoms: Hypoglycemia, hepatomegaly, growth retardation, lactic acidosis

• Affected Tissues: Liver and kidneys

2) GSD Type II (Pompe Disease)

• Enzyme Deficiency: Lysosomal acid α-glucosidase

• Symptoms: Muscle weakness, cardiomegaly, respiratory issues

• Affected Tissues: Muscles and heart

3) GSD Type III (Cori Disease)

• Enzyme Deficiency: Debranching enzyme

• Symptoms: Hepatomegaly, muscle weakness, hypoglycemia

• Affected Tissues: Liver, muscles