Glycogenolysis | Anatomy2Medicine
glycogenolysis steps

Glycogenolysis

 

  • Glycogen degradation

 

      • Action of glycogen phosphorylase
        • the key regulatory enzyme for glycogen degradation
        • removes glucose residues, one at a time, from the nonreducing ends of glycogen molecules.
        • Glycogen phosphorylase

 

  • Phosphorylase uses Pi to cleave a-1,4 bonds, producing glucose 1-phosphate.

 

          • Phosphorylase can continue to hydrolyze a-1,4 linkages until it reaches a point four glucose units from an a-1,6 branch.
      • Removal of branches
        • The four units remaining at a branch are removed by the debranching enzyme, which has both glucosyl 4:4 transferase and a-1,6-glucosidase activity.
        • The last glucose unit at the branchpoint,which is linked alpha-1,6, is hydrolyzed by alpha-1,6-glucosidase, forming free glucose.
      • Degradation of glycogen chains
        • The phosphorylase/debranching process is repeated, generating glucose 1-phosphate and free glucose in about a 10:1 ratio that reflects the length of the chains in the outer region of the glycogen molecule.
      • Fate of glucosyl units released from glycogen
        • In the liver

 

  • glycogen is degraded to maintain blood glucose.
  • Glucose1-phosphate is converted to glucose 6-phosphate
  • Enzyme:  phosphogluco mutase.

 

          • Inorganic phosphate is released from glucose 6-phosphate and free glucose enters the blood.
            • Enzyme :  glucose 6-phosphatase,

 

  • This enzyme also acts in gluconeogenesis.

 

        • In muscle
          • glycogen is degraded to provide energy for contraction.
          • Phosphoglucomutase converts glucose 1-phosphate to glucose 6-phosphate, which enters the pathway of glycolysis and is converted either to lactate or to CO2 and H2O through the Krebs tricarboxylic acid cycle
          • leads to the generation of ATP via oxidative phosphorylation.
          • Muscle does not contain glucose 6-phosphatase and, therefore, does not contribute to the maintenance of blood glucose (MCQ)

 

  • Lysosomal degradation of glycogen

 

        • Glycogen is degraded by an alpha-glucosidase located in lysosomes.
        • Lysosomal degradation is not necessary for maintaining normal blood glucose levels.

 

  • Regulation of glycogen degradation

 

    • 2 Hormones stimulate glycogen degradation.

 

  • Glucagon, a peptide hormone, acts on liver cells

 

      • epinephrine (adrenaline) acts on both liver and muscle cells

 

  • cAMP cascade initiated by hormones lead to Glycogenolysis

 

    • Step 1: Adenylate cyclase
      • converts ATP to 3’,5’-cyclic adenosine monophosphate (cAMP)
      • Glucagon and epinephrine, via G proteins, activate it in the cell membrane
      • Adenylate cyclase is also called adenyl or adenylyl cyclase.
    • Step 2: Protein kinase A
      • consists of two regulatory and two catalytic subunits
      • cAMP activates it
      • cAMP binds to the regulatory (inhibitory) subunits, releasing the catalytic subunits in an active form.
      • Protein kinase A
        • phosphorylates glycogen synthase
          • causing it to be less active, thus decreasing glycogen synthesis.
        • Phosphorylates phosphorylase kinase
    • Step 3: Phosphorylase kinase phosphorylates phosphorylase b, converting it to its active form, phosphorylase a.
    • Step 4 : Phosphorylase a cleaves glucose residues from the nonreducing ends of glycogen chains, producing glucose 1-phosphate, which is oxidized or, in the liver, converted to blood glucose.
  • The cAMP cascade
    • The cAMP-activated process is a cascade in which the initial hormonal signal is amplified many times.
    • One hormone molecule, by activating the enzyme adenylate cyclase, produces many molecules of cAMP, which activate protein kinase A.
    • One active protein kinase A molecule phosphorylates many phosphorylase kinase molecules, which convert many molecules of phosphorylase b to phosphorylase a.
    • One molecule of phosphorylase a produces many molecules of glucose 1-phosphate from glycogen.
    • The net result is that one hormone molecule can generate tens of thousands of molecules of glucose 1-phosphate, which form glucose 6-phosphate.
    • Oxidation of many thousands of molecules of glucose 6-phosphate can generate hundreds of thousands of molecules of ATP.
  • AMP and Ca2+ stimulate glycogen breakdown in muscle.

 

    • Applied aspects :

 

  • Hers disease

 

        • A genetic deficiency of liver phosphorylase

 

  • type VI GSD

 

        • extreme enlargement of the liver

 

  • McArdle disease

 

        • Muscle phosphorylase deficiency

 

  • type V GSD.

 

        • disorder presents with exercise-induced cramps and pain secondary to rhabdomyolysis.
        • Most patients live normally, avoiding strenuous exercise
        • severe rhabdomyolysis leading to myoglobinuria can lead to life-threatening renal failure.

 

  • Cori disease

 

        • a type III GSD
          • results from a deficiency of debranching enzyme
        • Type IIIa
          • a deficiency of both liver and muscle enzymes
          • manifests with hepatomegaly, hypoglycemia during fasting, and myopathy
          • it is managed by small meals or continuous nasogastric feeding
        • Type IIIb disease

 

  • a deficiency of the liver enzyme only
  • with no muscular involvement.
  • Pompe disease

 

        • a type II GSD
          • a lysosomal storage disease
          • deficiency of the lysosomal acid alpha-glucosidase enzyme.

 

  • It is the only glycogen storage disease with a defect in lysosomal metabolism,

 

          • Accumulation of glycogen within the lysosome
          • results in the formation of large lysosomes, which ultimately compromises muscle cellular function.

 

  • Type IIa

 

          • infantile form
          • presents with muscle weakness (floppiness), with death by 2 years secondary to heart muscle dysfunction.
        • The milder IIb (juvenile) and IIc (adult) forms
          • have delayed and progressive onset
          • dominated by skeletal muscle weakness.

 

  • type IX GSD

 

      • Deficiency of phosphorylase kinase
      • It most commonly results in hepatomegaly, growth retardation, delayed motor development, and increased blood lipids
      • Phosphorylase kinase is a complex enzyme, consisting of multiple subunits that are encoded by different genes, located on separate chromosomes. Several different subtypes of this disease have been identified
      • most common form is the X-linked form.