Glycogen Metabolism II

Question 1

3 key events of glycogenesis

Answer 1

Trapping and Activation of Glucose

Elongation of a glycogen primer

Branching of glycogen chains

Question 2

Explain Trapping and Activation of Glucose

Answer 2

• Glucokinase/hexokinase in cytosol of hepatocytes and
muscle cells catalyze phosphorylation of glucose to
glucose-6-phosphate
• This traps the glucose in these cells
• Phosphoglucomutase then reversibly isomerizes glucose-6- phosphate to glucose-1-phosphate
• Uridine diphosphate(UDP)-glucose pyrophosphorylase
then transfers the glucose-1-phosphate to uridine
triphosphate (UTP) which generates UDP-glucose (active
form of glucose)
• Breakdown of pyrophosphate to Pi generates energy and drives the reaction forward

Question 3

Explain elongation of a glycogen primer

Answer 3

• Preexisting short glycogen polymer serves as a primer to which glucose units are added
• Primer formation done by Glycogenin, a Mn requiring protein
• Glycogen synthase (rate limiting enzyme).
Catalyzes the transfer of glucose from UDP glucose onto the non-reducing end of glycogen chain. Forms α-1,4 glycosidic bonds between glucose molecules

Question 4

Explain branching of glycogen chains

Answer 4

• When glycogen chain reaches 11 residues, a fragment of the chain (about 7 residues long) is broken off at an α -1, 4 link and reattached elsewhere through an α -1, 6 link by glucosyl (4:6) transferase.
• The new branch point must be at least 4 residues away from a preexisting branch
• Branching increases solubility of glycogen and increases number of terminal non-reducing ends. Increases rate at which glycogen can be synthesized and degraded

Question 5

Regulation of Glycogen Synthesis

Answer 5

Glycogen synthase: Key enzyme
 Exists in 2 forms, one form present in liver and second in muscle and other tissues
 Active non-phosphorylated “a” form
 Inactive phosphorylated “b” form
 Interconversion mediated by covalent modification (fine tuning role)
 Phosphorylated by several kinases most importantly
glycogen synthase kinase (GSK)
 GSK under the control of insulin and PKA
 Allosteric regulation – gluc-6-phosphate powerful activator, stabilizing R state

Question 6

Regulation of Glycogen Metabolism

Answer 6

• Regulation very important to maintain blood sugar and provide energy to muscles
• Pathways of synthesis and degradation are independent
• Allows for independent regulation
• Two key enzymes: glycogen phosphorylase and
glycogen synthase, the rate limiting steps of degradation and synthesis, respectively.
• Both enzymes are regulated by reversible phosphorylation, but effects are in opposite directions
• Glucagon and epinephrine control both glycogen breakdown and synthesis via PKA!!!
• Glycogenesis favored in fed state (when glucose and
insulin high and cellular ATP high - signal of high energy)
• When glycogen synthesis favored, the depospho form
glycogen synthase (active) and glycogen phosphorylase
(inactive) are predominant
• Glycogenolysis favored in fasting state (when blood
glucose levels are low and glucagon levels are high and
cellular calcium and AMP are elevated (in exercising
muscles)
• When glycogen degradation is favored phosphorylated
forms of glycogen synthase (inactive) and glycogen
phosphorylase (active) are predominant

Question 7

Mechanism of Regulation by Insulin

Answer 7

• High blood glucose
• Release of insulin by β cells of pancreas
• Binding of insulin to its receptor tyrosine kinase
• Activation of signaling cascade
• Four key proteins:
– GLUT 4 (glucose transporter)
– Protein kinase B (PKB)
– Protein phosphatase 1 (PP1)
– Glycogen synthase kinase 3 (GSK3)

Question 8

Regulation by Insulin

Answer 8

• Formation of the insulin receptor complex
• Activation of PKB
• Translocation of GLUT to membrane
• PKB phosphorylates PP1 (activate) and GSK3
(inactivate)
• Active PP1 dephosphorylates glycogen synthase
(activate) and dephosphorylates glycogen
phosphorylase (inactivate)
• Net result - activation of glycogen synthase and
inactivation of glycogen phosphorylase

Question 9

Type 2 diabetes

Answer 9

• Reduced sensitivity to insulin
• Called insulin resistance
• Mutations in insulin receptor and/or
downstream signaling proteins
• Down-regulation in receptor levels triggered
by elevated insulin (leading to endocytosis
and degradation of the insulin receptor). Not
replaced by translation

Question 10

Von Gierke

Answer 10

Defective enzyme:
- glucose 6-phosphatase or transport system
Organ affected:
- liver and kidney
Glycogen in the affected organ:
- increased amount; normal structure
Clinical features:
- massive enlargement of the liver
- failure to thrive
- severe hypoglycemia, ketosis, hyperuricemia, hyperlipemia

Question 11

Pompe

Answer 11

Defective enzyme: 
     - alpha-1,4-glucosidase (lysosomal)
Organ affected:
     - all organs
Glycogen in the affected organ:
     - massive increase in amount; normal structure
Clinical features:
     - cardiorespiratory failure causes death, usually before age 2

Question 12

McArdle

Answer 12

Defective enzyme:
- phosphorylase
Organ affected:
- muscle
Glycogen in the affected organ:
- moderately increased amount; normal structure
Clinical features:
- limited ability to perform strenuous exercises because of painful muscle cramps;
otherwise patient is normal and well-developed

Question 13

Hers

Answer 13

Defective enzyme: 
     - phosphorylase
Organ affected:
     - liver
Glycogen in the affected organ:
     - increased amount
Clinical features:
    - like type I, but milder course