Last edited: 9/3/2021

1. REGULATION OF GLYCOGEN METABOLISM

Glycogen Metabolism: Allosteric and Hormonal Regulations Medical Editor: Jona Frondoso

OUTLINE (A) ACTIVATORS OF GLYCOGEN SYNTHASE

(1) Glucose-6-phosphate
I) REGULATION OF ENZYMES
II) GLYCOGEN SYNTHASE Allosteric activator of glycogen synthase
III) GLYCOGEN PHOSPHORYLASE ↑ Glucose-6-phosphate = ↑ blood glucose → (+)
IV) GLYCOGEN STORAGE DISEASES (II) glycogenesis → ↓ glucose (Figure 1)
V) APPENDIX
V) REVIEW QUESTIONS (2) Insulin
Insulin – released when ↑ blood glucose levels
Insulin binds to tyrosine kinase receptor in the plasma
membrane
I) REGULATION OF ENZYMES

(1) Allosteric Regulation

Regulates the enzyme by binding to another site other than
the active site resulting to a change in the overall three-
dimensional structure of the enzyme
Can be either allosteric activators or allosteric inactivators

(2) Hormonal Regulation

Insulin
o Hormone secreted by the beta cells of the pancreas in
response to high blood glucose levels [Nelson& Cox, 2005]
o
Glucagon
o Hormone secreted by the alpha cells of the pancreas
in response to low blood glucose levels [Nelson& Cox, 2005]
Figure 1. Activation of glycogen synthase by binding of insulin
to the tyrosine kinase receptor.
(3) Two Main Enzymes of Glycogen Metabolism
(B) INHIBITORS OF GLYCOGEN SYNTHASE
Glycogen Synthase
o Enzyme of glycogenesis (1) Glucagon, Epinephrine, Norepinephrine
Glycogen Phosphorylase Inhibits glycogen synthase through the formation of protein
o Enzyme of glycogenolysis kinase A (Figure 2)

(i) Gs protein
(4) G-protein coupled receptor (GPCR)
Binding of glucagon, Epi, or NE to GPCR
Transmembrane receptor in the plasma membrane [Nelson &
Cox, 2005]
Stimuli:
o Glucagon
o Epinephrine (Epi)
o Norepinephrine (NE)

(5) Tyrosine kinase receptor

Enzyme-linked receptor located at the plasma membrane
[Nelson & Cox, 2005]
Stimulus: Insulin

II) GLYCOGEN SYNTHASE

Enzyme of glycogenesis
o Glycogenesis: Glucose → Glycogen
Forms the α-1,4-glycosidic bonds elongating the glycogen
polymer

Remember
Glycogen synthase
Inactive form = phosphorylated = Type B Figure 2. Inhibition of glycogen synthase by glucagon,
Active form = dephosphorylated = Type A epinephrine, and norepinephrine via activation of the Gs
pathway.

REGULATION OF GLYCOGEN METABOLISM METABOLISM: Note #1. 1 of 5

 III) GLYCOGEN PHOSPHORYLASE (2) Glucagon, Epinephrine, Norepinephrine
Activates glycogen phosphorylase by the formation of
Enzyme of glycogenolysis
phosphorylase kinase
o Glycogenolysis: Glycogen → Glucose
Has 2 mechanisms:
Catalyzes the sequential phosphorolysis of glycogen to
release glucose-1-phosphate (i) Gs protein
Binding of glucagon, Epi, or NE to GPCR
Remember
Glycogen phosphorylase
Inactive form = dephosphorylated = Type B
Active form = phosphorylated = Type A

Protein kinase A (PKA)

(A) ACTIVATORS OF GLYCOGEN PHOSPHORYLASE

(1) Adenosine monophosphate (AMP)
Allosteric activator of glycogen phosphorylase (Figure 3)
Breakdown product of cross-bridge formation in the
muscles
o Only coming from the muscles
ATP in the muscles can be further broken down into AMP
and pyrophosphate (PPi)
o ATP → AMP + PPi
↑ AMP = ↑ ATP breakdown for muscle contraction
↑ AMP → (+) glycogenolysis

Figure 4. Activation of glycogen phosphorylase by glucagon,

epinephrine, and norepinephrine via activation of Gs protein.

(ii) Gq protein
Figure 3. Allosteric activation of glycogen phosphorylase by
AMP. Binding of Epi or NE to GPCR

Phosphorylase kinase phosphorylates glycogen phosphorylase

Figure 5. Activation of glycogen phosphorylase by epinephrine

and norepinephrine via activation of Gq pathway.

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 (4) Insulin
Remember
Has two mechanisms
Phosphorylase kinase
(i) Inactivation of phosphoprotein kinase (Type A)
Inactive form = dephosphorylated = Type B
Active form = phosphorylated = Type A Insulin binds to tyrosine kinase receptor in the plasma
membrane

(B) INHIBITORS OF GLYCOGEN PHOSPHORYLASE

(1) Glucose-6-phosphate
Allosteric inhibitor of glycogen phosphorylase
↑ Glucose-6-phosphate = ↑ blood glucose
(ii) Inactivation of glycogen phosphorylase
Insulin binds to tyrosine kinase receptor in the plasma
membrane

(2) ↑ Adenosine triphosphate

Allosteric inhibitor of glycogen phosphorylase
↑ ATP = ↑ glucose breakdown = ↑ ATP (cells can only store
so much ATP) (Figure 6)
↑ ATP

(3) ↑ Free glucose

Allosteric inhibitor of glycogen phosphorylase in the liver
only
↑ glucose = ↓ glucose coming into the cell = ↑ blood
glucose (Figure 6)
↑ glucose

IV) GLYCOGEN STORAGE DISEASES (II)

Causes significant damage on the heart, liver, spleen, and
other tissues
(1) Pompe’s Diseases
GSD Type II
Caused by deficiency in lysosomal α-1,4-glycosidase
Lysosomal α-1,4-glucosidase
o Aka acid maltase
o Responsible for 1-2% of glycogenolysis
Figure 6. Allosteric activation of glycogen phosphorylase by
high amounts of G6P, ATP, and free glucose. (2) Von Gierke’s Disease
GSD Type I
Caused by deficiency in glucose-6-phosphate
Most dangerous GSD
o Usually children never live past the age of 1-year-old
Table 1, Glycogen Storage Diseases (GSD)
Type GSD Deficient Enzyme
I Von Gierke Glucose-6-phosphatase
II Lysosomal α-1,4-
Pompe
glycosidase
III Cori Debranching enzyme
IV Andersen Branching enzyme
V Muscle glycogen
McArdle
phosphorylase
VI Hepatic glycogen
Hers
phosphorylase

REGULATION OF GLYCOGEN METABOLISM METABOLISM: Note #1. 3 of 5

Remember:
Villainous President Called And Molested Her
V - illainous
P - resident
C - alled
A - nd
M - olested
H - er

Figure 7. Inhibition of glycogen phosphorylase by insulin via

formation of phosphoprotein phosphatase (PPP).

V) APPENDIX

Table 2. Summary of the Allosteric and Hormonal Regulators of Glycogen Synthase and Glycogen Phosphorylase and their Mechanisms
Type Activators Mechanism Inhibitors Mechanism
Glucagon
G6P Allosteric activation

Glycogen Hormonal regulation

synthase Epinephrine Gs protein → ↑cAMP
Hormonal regulation
Insulin
(+) phosphoprotein phosphatase
Norepinephrine

AMP (muscle) Allosteric activation G6P Allosteric activation

Glycogen Glucagon ↑ ATP Allosteric activation

phosphorylase Hormonal regulation
Gs protein → ↑cAMP
↑ Free glucose
Epinephrine Gq protein → ↑ IP3 and DAG Allosteric activation
(liver)
Hormonal regulation
Norepinephrine Insulin (+) phosphoprotein phosphatase

Figure 8. Regulation of Glycogen Metabolism.

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 V) REVIEW QUESTIONS
Insulin promotes glycogenesis by
a. Binding to another site other than the active site
b. Phosphorylation of phosphorylase kinase B by
protein kinase A
c. Formation of Ca2+-calmodulin complex via the IP3-
DAG pathway
d. Dephosphorylation of glycogen synthase by protein
phosphatase.

Glucagon promotes glycogenolysis by

a. Activation of either Gs or Gq proteins
b. Formation of cAMP by activating adenylate cyclase
c. Formation of Ca2+-calmodulin complex via the IP3-
DAG pathway
d. All of the choices are correct.

Which of the following is statements is correct?

a. Glycogen synthase, when dephosphorylated, is
active
b. Glycogen phosphorylase, when phosphorylated, is
inactive
c. Phosphorylase kinase, when phosphorylated, is
inactive
d. Two of the choices are correct.

Which of the following GSDs is correctly matched to

its deficient enzyme?
a. Cori – branching enzyme
b. Pompe – acid maltase
c. Von Gierke - Lysosomal α-1,4-glycosidase
d. Andersen – debranching enzyme

Activation of glycogen degradation by release of

Ca2+ in the liver is due to:
a. Glucagon binding to beta-adrenergic receptors on
the cell membrane
b. Activation of protein kinase A by phospholipase C
c. Increased synthesis of cAMP from ATP
d. Formation of Ca2+-calmodulin complex that activates
hepatic phosphorylase kinase

CHECK YOUR ANSWERS

VI) REFERENCES

Nelson, D., & Cox, M. (2005). Lehninger Principles of

Biochemistry (4th ed.). New York: W.H. Freeman and Company.

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