Carbohydrate Metabolism › Glycogen Metabolism

Glycogen Metabolism Control

Notes

Glycogen Metabolism Control

Sections

REGULATED ENZYMES

Glycogen synthase: glucose 1P polymerization to glycogen

• Catalyzes rate-limiting step in glycogen synthesis
• Active form: dephosphorylated
• Inactive form: phosphorylated

Glycogen phosphorylase: releases glucose 1P residues from glycogen

• Catalyzes rate-limiting step in glycogenolysis
• Active form: phosphorylated
• Inactive form: dephosphorylated
• Activated by phosphorylase kinase

Phosphorylase kinase: phosphorylates glycogen phosphorylase

• Activate form: phosphorylated
• Inactive form: dephosphorylated

KEY ORGANS

Liver

• Regulates blood glucose, responds to needs of all organs
• Insulin, glucagon & epinephrine receptors

Skeletal muscle

• Synthesizes/breaks down glycogen based on own metabolic needs
• Only insulin and epinephrine receptors (NOT glucagon)

REGULATORY MECHANISMS

  1. Hormonal: insulin (high glucose), glucagon (low glucose) & epinephrine (stress)

Glucagon (low glucose) & epinephrine (stress):

• Activate protein kinase A (PKA) in cAMP-dependent manner
• PKA phosphorylates glycogen synthase (inactivates it)
• PKA phosphorylates phosphorylase kinase (activates it)
• Phosphorylase kinase phosphorylates glycogen phosphorylase (activates it)
• Upregulates glycogenolysis, down regulates glycogen synthesis

Insulin (elevated glucose):

• Activates phosphoprotein phosphatase (PPP)
• PPP dephosphorylates glycogen synthase (activates it)
• PPP dephosphorylates phosphorylase kinase (inactivates it)
• Upregulates glycogen synthesis, down regulates glycogenolysis

Glucagon receptor NOT in muscle: muscle only responds to stress (epinephrine)

  1. Allosteric regulation

Both hepatic and muscle cells

• Glycogen synthase activation: glucose 6P (glucose 1P --> glucose 6P)
• Glycogen phosphorylase inhibition: glucose 6P, ATP (energy abundance)

Liver only

• Glycogen phosphorylase inhibition: glucose

Muscle only

• Glycogen phosphorylase activation: Ca2+, AMP (low energy)
• Muscle contraction: Ca2+ released from sarcolemma & allosterically activates phosphorylase kinase --> activates glycogen phosphorylase

CLINICAL CORRELATION

McArdle's Disease (Type V glycogen storage disease)

• Muscle glycogen phosphorylase deficiency
• Glycogen accumulates in muscle
• Muscle cramps & decreased exercise tolerance

Full-Length Text

  • Here we will learn how glycogen metabolism is regulated.
  • To begin, start a table to learn the key enzymes regulated in glycogen metabolism.
  • Denote that glycogen synthase catalyzes the rate-limiting step in glycogen synthesis.
  • Denote that glycogen phosphorylase catalyzes the rate-limiting step in glycogenolysis.
  • Next, denote that there are two regulatory mechanisms:
    • Hormonal regulation, which involves insulin, glucagon and epinephrine.
    • Allosteric regulation.
  • Finally, denote that there are two key organs that synthesize and degrade glycogen:
    • The liver, which regulates blood glucose and responds to the needs of all organs.
    • Skeletal muscle, which synthesizes and breaks down glycogen based on its own metabolic needs.
    • Cardiac muscle also synthesizes a small amount of glycogen, but it is not a major energy source.

We will learn their similarities and differences with regard to metabolic control.

Let's start by illustrating hormonal control in the liver.

  • Draw portions of a hepatic cell membrane with three receptors embedded within it: a glucagon receptor, adrenoreceptor, and an insulin receptor.

We will return to them shortly.

Now, let's add glycogen metabolism and the two regulated enzymes.

  • Draw glycogen as a branched structure at the center of the cell.
  • Draw glucose 1-phosphate below it.
  • Show that glycogen synthase polymerizes glucose 1-phosphate to form glycogen.
  • Show that glycogen phosphorylase does the opposite, cleaving glucose residues from glycogen.
  • Now, divide our cell in half: with glycogen synthesis on one side and glycogenolysis on the other.

Let's start with synthesis.

  • Indicate that glycogen synthase has an active and an inactive form.
  • Show that inactive glycogen synthase has a phosphate group attached.

Now, for glycogen phosphorylase.

  • Indicate that it also has an active and inactive form.
  • Now, show that this time the active form is phosphorylated.

Let's review this point for emphasis: glycogen synthase is ACTIVE when it is DEphosphorylated, glycogen phosphorylase is ACTIVE when it is phosphorylated.

  • Next, indicate that glycogen phosphorylase is phosphorylated (activated) by another enzyme called phosphorylase kinase.
  • Show that phosphorylase kinase also has an active and inactive form.
  • Indicate that like glycogen phosphorylase, its active form is phosphorylated.

Now, let's learn how glucagon, epinephrine and insulin regulate these enzymes. Start with glucagon and epinephrine.

  • First, write that glucagon is secreted when blood glucose is low.
  • Then, write that epinephrine is secreted in response to stress.
    • Stress can be physiologic, as in during exercise or pathologic, such as blood-loss induced shock, or psychological.
  • Now, draw protein kinase A (PKA) in our hepatocyte.
  • Show that glucagon and epinephrine activate PKA in cAMP-dependent manner.
  • Indicate that PKA phosphorylates glycogen synthase and phosphorylase kinase.
    • Thus, glucagon and epinephrine block glycogen synthase and promote glycogen breakdown.

Now, for insulin.

  • Write that insulin is secreted when blood glucose is elevated.
  • Show that insulin activates phosphoprotein phosphatase (PPP) in the hepatocyte.
  • Indicate that PPP dephosphorylates glycogen synthase and glycogen phosphorylase kinase.
    • Thus, insulin activates the synthetic pathway and blocks glycogen breakdown.
  • Hepatic cells have all three receptors:
    • glucagon,
    • epinephrine and
    • insulin.

What about muscle cells?

  • Write that muscle cells lack glucagon receptors: they only promote glycogenolysis in response to stress.
    • Unlike hepatic cells, they do not have to respond to the rest of the body's needs when blood glucose is low.

Finally, let's illustrate allosteric regulation. We will start with the allosteric regulators common to both liver and muscle cells, and introduce key differences at the end.

  • Redraw our glycogen to glucose 1-phosphate reaction.
  • Now, show that glucose 6-phosphate activates glycogen synthase in both the liver and skeletal muscle.
    • Recall, glucose 6-phosphate reversibly converts to the substrate, glucose 1-phosphate.
    • This is feed forward activation.
  • Now for glycogen phosphorylase, which is a little more complicated.
  • Show that the following allosterically inhibit glycogen phosphorylase in both the liver and skeletal muscle:
    • Glucose 6-phosphate, which reciprocally activates glycogen synthesis.
    • ATP, a marker of energy abundance.

From here, muscle and liver cell regulation differs.

  • Indicate that in the liver, glucose is also an allosteric inhibitor of glycogen phosphorylase.
    • This makes sense as the liver mobilizes glycogen in response to low blood glucose levels, not just its own energy needs.
  • Indicate that in the muscle, calcium and AMP are allosteric activators of glycogen phosphorylase.
    • Calcium releases from the sarcolemma during muscle contraction and AMP is a marker of low energy.
    • Thus, the muscle mobilizes glycogen only in response to its own energy needs.
  • As a clinical correlation, denote that McArdle's Disease (Type V Glycogen storage disease) results from a muscle glycogen phosphorylase deficiency.
    • As a result, glycogen accumulates in the muscle and patients experience muscle cramps and a decreased exercise tolerance.