Glycogen Synthesis | Anatomy2Medicine
Glycogenesis Synthesis Steps

Glycogen Synthesis

    • Glycogen
      • consists of chains of alpha-1,4–linked D-glucose residues with branches that are attached by alpha-1,6 linkages
      • Glycogen is synthesized from glucose.
      • Glycogen degradation produces glucose 1-phosphate as the major product, but free glucose is also formed.

 

  • Liver glycogen is used to maintain blood glucose during fasting or exercise.

 

      • Muscle glycogen is used to generate ATP  for muscle contraction.

 

  • Glycogen structure

 

      • Frequency at which alpha-1,6 branch occurs is at every 8 to 10 residues.
      • One glucose unit, located at the reducing end of each glycogen molecule, is attached to the protein glycogenin.
      • The glycogen molecule branches like a tree and has many nonreducing ends at which addition and release of glucose residues occur during synthesis and degradation, respectively.

 

  • Glycogen synthesis
  • Synthesis of uridine diphosphate (UDP)-glucose

 

        • UDP-glucose is the precursor to glycogen synthesis.
        • Glucose enters cells and is phosphorylated to glucose 6-phosphate
          • Enzyme : Hexokinase or by Glucokinase in the liver).
          • ATP provides the phosphate group.

 

  • glucose 6-phosphate is converted to glucose 1-phosphate.

 

          • Enzyme : Phosphoglucomutase

 

  • Glucose 1-phosphate reacts with uridine triphosphate (UTP), forming UDP-glucose

 

          • Enzyme : UDP-glucose pyrophosphorylase
          • Inorganic pyrophosphate (PPi) is released in this reaction.
        • PPi is cleaved to two inorganic phosphates (Pi).
          • Enzyme :  pyrophosphatase
        • This removal of product helps to drive the process in the direction of glycogen synthesis.
      • Action of glycogen synthase
        • Glycogen synthase
          • key regulatory enzyme for glycogen synthesis
          • It transfers glucose residues from UDP-glucose to the nonreducing ends of a glycogen primer.
        • UDP is released and reconverted to UTP by reaction with ATP.
        • The primers, which are attached to glycogenin, are glycogen molecules that were partially degraded in the liver during fasting or in muscle and liver during exercise.
      • Formation of branches
        • When a chain contains 11 or more glucose residues, an oligomer, 6 to 8 residues in length, is removed from the nonreducing end of the chain.

 

  • It is reattached via an alpha-1,6 linkage to a glucose residue within an alpha-1,4–linked chain.

 

      • These branches are formed by the branching enzyme
        • a glucosyl 4:6 transferase that breaks an a-1,4 bond and forms an a-1,6 bond.
      • The new branch points are at least 4 residues and an average of 7 to 11 residues from previously existing branch points.
  • Applied aspects :
    • type 0 glycogen storage disease (GSD).
      • Genetic deficiency of glycogen synthase
      • fasting hypoglycemia with occasional muscle cramping.
      • It can usually be managed with frequent meals and feeding of uncooked cornstarch to prevent overnight hypoglycemia.
    • Andersen disease
      • a type IV GSD
      • results from a genetic deficiency of this branching enzyme
      • Children fail to thrive.
      • There is not an increased accumulation of glycogen, but rather, the glycogen has very long outer branches.
      • This structural abnormality leads to a reduced solubility of the glycogen, causing progressive scarring of the liver (cirrhosis), which leads to death at about 5 years of age.

 

 

  • Regulation of glycogen synthesis

 

      • Factors that promote glycogen synthesis in the liver
        • Insulin
          • elevated after a meal
          • stimulates the synthesis of glycogen in liver and muscle.
        • In the fed state, glycogen degradation decreases
          • glucagon is low
          • cAMP cascade is not activated.
          • cAMP is converted to AMP by a cell membrane phosphodiesterase.
          • As cAMP decreases, the regulatory subunits rejoin the catalytic subunits of protein kinase A, and the enzyme is inactivated.
        • Dephosphorylation of phosphorylase kinase and phosphorylase a causes these enzymes to be inactivated.

 

  • Insulin causes activation of the phosphatases that dephosphorylate these enzymes.

 

      • Glycogen synthesis is promoted by activation of glycogen synthase and by the increased concentration of glucose, which enters liver cells from the hepatic portal vein.
        • The inactive, phosphorylated form of glycogen synthase is dephosphorylated, causing the enzyme to become active.
        • Insulin causes activation of the phosphatase that catalyzes this reaction.
    • Factors that promote glycogen synthesis in muscle
      • After a meal , all agents that stimulate glycogen degradation are low
        • muscle will have low levels of cAMP, AMP, and Ca2+ (if the muscle is not contracting),
      • In addition, epinephrine, another agent that activates glycogenolysis, is low.
        • Consequently, muscle glycogen degradation will not occur.
      • Insulin stimulates glycogen synthesis by mechanisms similar to those in the liver.
      • In addition, insulin stimulates the transport of glucose into muscle cells, providing increased substrate for glycogen synthesis.