Carbohydrate Metabolism › Glycogen Metabolism

Glycogenolysis

Notes

Glycogenolysis

Sections

GLYCOGEN
• Body's glucose reserve
• Can be mobilized more quickly/efficiently than fats
• Stored in liver & muscle
• Mobilized during fast (low insulin: glucagon)

ENZYMES OF GLYCOGENOLYSIS

Glycogen phosphorylase

• Breaks alpha (1,4) bonds

Debranching enzyme

• Breaks alpha (1,6) bonds
• Aka alpha 1,6 glucosidase

Glucose 6-phosphatase

• Tissue specific: liver only

GLYCOGENOLYSIS

  1. Glycogen phosphorylase removes terminal residues of glycogen branches
    • Cleaves alpha (1,4) glycosidic bonds until 4 glucose residues remain per branch
    • Cleaves 1 glucose residue at a time
    • Glycogen + Pi --> Glucose 1-phosphate
  2. Debranching enzymes transfers 3 residues of shortest branches to longer ones
    • One glucose residue remains per branch
    • Creates more alpha (1,4) linkages for glycogen phosphorylase to hydrolyze
  3. Debranching enzyme cleaves last glucose residue from short branches
    • Cleaves alpha (1,6) bond
    • Glycogen + H2O --> Glucose
    • Releases residue as glucose NOT glucose 1P
  4. Repeat: glycogen phosphorylase & debranching enzyme degrade glycogen to glucose & glucose 1P

LIVER VERSUS MUSCLE: FATES OF GLUCOSE & GLUCOSE 1P
• Both organs: glucose 1P reversibly converts to glucose 6P

Muscle

• Glucose 6P enters glycolysis --> Pyruvate + ATP
• If O2 is present: pyruvate decarboxylation --> acetyl CoA --> aerobic respiration
• If O2 is absent (exercising muscle): anaerobic glycolysis --> lactate
• Both pyruvate fates produce ATP: fuel for muscle cells
• Stores glycogen for its own use

Liver

• Glucose 6-phosphatase: Glucose 6P --> Glucose + Pi (enzyme NOT in muscle)
• Hepatic glucose released into circulation: fuels peripheral tissues (brain & rbc's)

CLINICAL CORRELATION

Von Gierke's Disease (Type I glycogen storage disease)

• Glucose 6-phosphatase deficiency in liver/kidney
• Frequent hypoglycemia: cannot mobilize glycogen during fast
• Treatment: frequent feedings with slowly digested carbohydrates (i.e. uncooked starch) to maintain blood glucose

Full-Length Text

  • Here we'll learn how glycogen is mobilized and broken down in the body, and we'll learn the function of glycogen metabolism in two key organs.
  • To begin, start a table to learn some key points about glycogen mobilization.
  • Denote that glycogen is the body's glucose reserve, and that it can be mobilized more quickly and efficiently than fats.
  • Denote that the liver and muscle both store glycogen.

We will distinguish their roles in glycogen degradation shortly.

  • Denote that it is mobilized during fasting state when the insulin to glucagon ratio is low.
  • Finally, denote that there are three key enzymes involved in glycogen degradation.
    • Glycogen phosphorylase, which breaks alpha (1,4) bonds.
    • Debranching enzyme, which breaks alpha (1,6) bonds thus it is also known as alpha 1,6-glucosidase.
    • Glucose 6-phosphatase, which is a tissue-specific enzyme; later we'll learn how glycogen breakdown is different in liver and muscle.

To begin, let's illustrate glycogen breakdown.

  • Draw a branching glycogen polymer bound to glycogenin.
    • It comprises glucose residues.

Let's specifically draw the glucose residues of the top branch.

  • Label the first four glucose residues.
  • Now, draw two terminal glucose residues.
    • These terminal residues will be the first to break off.
  • Now, label the first four residues of the remaining branches.
  • Next, add the terminal glucose-residues to each branch as follows:
    • 1 on the second branch,
    • 2 on the third branch
    • 1 on the last branch.
  • This is our starting glycogen substrate.

Now, let's draw the product.

  • Redraw our glycogen polymer, but remove the terminal glucose residues in each branch.
    • There should be four glucose residues remaining in each branch.
  • Now, indicate that the first key enzyme, glycogen phosphorylase, catalyzes this reaction.
  • Write that it removes each glucose residue 1 at a time.
  • So, in our case, show that this reaction occurs once per glucose residue, for a total of 6 times.
  • Show that a phosphate is consumed per glucose residue, each of which is released as glucose 1-phosphate.
  • Now, to clarify this point, write that glycogen phosphorylase cleaves alpha (1,4) glycosidic bonds until 4 glucose residues remain in each branch.

How do we cleave these remaining residues?

  • Create a small box to show the actions of debranching enzyme.
  • Re-draw the ends of the long branches.
  • Then, show that debranching enzyme transfers the last 3 residues of the shortest branches to the longer branches.

Let's draw this product.

  • Draw our glycogen polymer with two, elongated branches.
  • Show that the top branch has the original 4 residues plus the transferred 3 glucose residues.
  • Show that the bottom does as well.
  • Show that the shortest branches are now only one glucose-residue long.
  • Write that debranching enzyme creates more alpha 1,4 linkages, and therefore a more linear chain, for glycogen phosphorylase to hydrolyze.

Now, we'll see how debranching enzyme further debranches the product.

  • Establish another insert.
  • Draw the branch points of our product.
  • Draw the single glucose residues.
  • Then, splice them from their branches.

Let's see the final product.

  • Redraw glycogen one last time, and remove the last glucose residues of the shorter branches.
  • Write that debranching enzyme cleaves these alpha 1,6 bonds.
  • Show that it does this one glucose residue at a time, so this reaction occurs 2 times.
  • Indicate that one water molecule is consumed per residue, and that each is released as glucose, not glucose 1-phosphate.
  • Next, use a series of arrows to show that glycogen phosphorylase and debranching enzyme continue to breakdown glycogen to glucose and glucose 1-phosphate.

Finally, let's learn the fates of glucose and glucose 1-phosphate in the two organs that can synthesize and store glycogen: the liver and muscle.

  • First, draw a chart with two columns: liver and muscle.
  • Draw glucose 1-phosphate, the product of glycogen phosphorylase, at the top of each column.
    • Show that glucose 1-phosphate reversibly converts to glucose 6-phosphate in both organs.

Now, this is where the fates of glycogen products diverge.

Let's start with the muscle.

  • Indicate that glucose 6-phosphate enters glycolysis to produce pyruvate and ATP.
  • Now, indicate that pyruvate has two fates in the muscle depending on oxygen conditions:
    • If oxygen is present, pyruvate decarboxylation produces acetyl CoA, which can then continue through aerobic respiration.
    • If oxygen is absent, as in exercising muscle, pyruvate may enter anaerobic glycolysis to produce lactate.
  • However, indicate that both of these fates produce energy as ATP.
  • To emphasize this point, write that the muscle glycogenolysis produces fuel for muscle cells.

Now, for the liver.

  • Indicate that glucose 6-phosphate is dephosphorylated to produce glucose.
  • Show that glucose 6-phosphatase catalyzes this reaction, the last key enzyme in glycogen breakdown.
  • Now, highlight this enzyme and write that it is NOT in the muscle.
  • Next, show that hepatic glucose is released into circulation.
  • Why?
    • The brain and red blood cells are glucose-requiring tissues.
    • They must use glucose for energy and depend on hepatic glycogen when blood glucose is low.
  • Finally, write that hepatic glucose fuels peripheral tissues, particularly the brain and red blood cells.
    • The muscle, however, stores glycogen for its own use.
  • As a clinical correlation, write that Von Gierke's Disease (Type I glycogen storage disease), is a glucose 6-phosphatase deficiency in the liver and kidney.
    • Patients experience frequent hypoglycemia because they cannot mobilize glycogen in times of fast.
    • The most common treatment involves frequent feedings with carbohydrates that are very slowly digested, such as uncooked cornstarch, so that blood glucose levels remain within a normal range.