4/4/2017

Objectives
• Discuss the basic structure of glycogen
• Discuss how glycogen is catabolized and
synthesized
• Discuss the reciprocal hormonal regulation of
glycogenolysis and glycogen synthesis
• Discuss the importance of glycogen in
maintaining blood glucose levels
CHEM 160
GLYCOGEN METABOLISM

Glycogen Structure Glycogen Structure

 Principal storage form  Principal storage form
of glucose found mainly of glucose found mainly
in the liver and muscle in the liver and muscle
 A homopolymer of α-D-  A homopolymer of α-D-
glucose glucose
 Linkage: α-1,4  Linkage: α-1,4
 Branching: α -1,6 (at
about every 8-10
Glycogen is stored as residues)
granules in hepatocytes

Glycogen Structure Glycogen as a Fuel Reserve

O
C H 2O H
O  Controlled breakdown of glycogen increase the
HO
amount of glucose that is available between
OH
O
C H 2O H
O meals.
C H 2O H
O
O HO
OH C H 2O H
O
 Glycogen is mobilized to maintain blood glucose
HO
OH C H 2O H
O
O
HO
α−1,6 levels in between meals
O OH
HO
C H 2O H
 Glucose from glycogen can provide energy
OH
O
O O
whenever the requirement is sudden (as in
α−1,4 HO
OH CH2 during strenuous activity)
O
O
HO O
OH

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Muscle and Liver Glycogen Glycogen

Breakdown:
 Liver glycogen is degraded
for
GLYCOGENOLYSIS Glycogen
phosphorylase

• distribution to other
organs through the blood
• maintaining proper blood Transferase activity of
debranching enzyme
glucose levels
 Muscle glycogen is degraded
for its use in energy
production. (α1-6) glucosidase activity of
debranching enzyme
Glucose

Glycogen Breakdown: GLYCOGENOLYSIS 1. Release of Glc as Glc-1-P

Gen steps HO
CH2OH O

GLYCOGEN
Phosphorylation of a Glucose Residue.
HO
OH CH2OH O (glucose)n
O

HO
CH2OH
Remodelling OH
O
Pi
Non-reducing endphosphorylase
glycogen HO
OH
 De-branching O

CH2OH O
HO
Glucose 1-phosphate Isomerization.
CH2OH O
HO
HO
OH CH2OH
HO
OH O
O PO32- GLYCOGEN HO
glucose-1-P OH
(glucose)n-1
O

1. Release of Glc as Glc-1-P 1. Release of Glc as Glc-1-P

• Action of glycogen phosphorylase continues until
there are about 4 residues left from the branch
point
• Glucose released is already phosphorylated
without consuming ATP.
• Glc-1-P cannot leave the cell and go to the
bloodstream.
• It readily enters the glycolytic pathway once
it’s converted to glucose-6-P by
phosphoglucomutase

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2. Re-modeling of Glycogen 3. De-branching

• Re-modeling prior to further degradation occurs • α-1,6 glycosidic bond is cleaved by an α -1,6-
near the branch point glucosidase

• Released glucose from de-branching is converted

to glucose-6-P and can enter glycolysis.

4. Further Release of Glc-1-P Fate of Glc-1-P in the Liver

 Glucose-1-P can be converted to glucose
phosphoglucomutase Glc−6−phosphatase
Glc-1-P Glc-6-P Glucose
12Pi
Glycogen
 Glc-6-phosphatase is present in the liver only.
phosphorylase
 Free glucose exits the hepatic cells and goes
into the blood stream for:
• maintaining proper blood glucose levels in
between meals
• transport to other organs (brain and
muscles)

Fate of Glc-1-P in the Muscle Fate of Glc-1-P in the Liver and muscle
• Muscle cells degrade glycogen for its own need.
• Glucose-1-P → Glucose 6-P → glycolysis
• Muscle cells lack glucose-6-phosphatase.

phosphoglucomutase
Glc-1-P Glc-6-P

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Overview
• UDP-Glucose is the
activated form of glucose
that serves as glucose
donor for glycogen
Glycogen Synthesis: synthesis

GLYCOGENESIS • UTP – uridine triphosphate

1. Formation of Glc-6-P 2. Conversion of Glc-6-P to Glc-1-P

CH2OH CH2O PO32-

ATP ADP
O O C
H OPO2-
C
H O H
2 3 2
OH OH O O
hexokinase p
hosp
hog
luco
m u
tase
OH OH OH OH O
H O
H
OH 2-
OH O
H O
H O
H OP
O 3
a -D-glucopyranose a -D-glucopyranose-6- OH OH
phosphate a-D
-glu
copyrano
se-6
- a-D
-glu
copyrano
se-1
-
phosp
h a
te phosp
h a
te

3. Formation of UDP-Glucose 4. Addition of Glc to Glycogen

C
H
O
H
2 C
H
2O
H C
H
2O
H C
H
2O
H
-
D
a-
g
l
u
co
p
y
r
an
o
s
e
-1
-
O p
h
os
p
h
at
e O O O
O
H O
H O
H OH
O
HO2
-
P
O O
H O
UD
PO
H O O
3
O
H OH OH OH
U
T
P U
D
P-
Gl
uco
s
e G
l
yc
og
e
n(
na
tl
eas
tn
=4
)
UD
P
-
g
lu
c
o
s
e
p
y
r
o
p
h
os
p
h
o
ry
l
a
s
e g
l
yc
og
en
s
y
nth
a
se
P
P
H i
C
H
O
2 O
O C
HO
H C
HO
H C
HO
H
2 2 2
O
HOO N
H
O O O
O
HOP
O
PONO O
H O
H OH
O
HO
O O O
O
H O O
U
D
P
-
G
l
u
co
s
e O
H O
H O
H
O
H
O
H G
l
yc
og
e
nn
+1

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5. Branching 5. Branching
• Branching Enzyme • Branching occurs at about every 10th residue
• Breaks the α-1,4 link and forms the α -1,6 • Branching increases solubility of glycogen
branch.

5. Branching Glycogenin
In addition, branching  acts as a primer, by polymerizing the
creates a large number of first few glucose molecules, after which
terminal residues, the sites other enzymes take over
of action of glycogen
phosphorylase and
synthase

Thus, branching increases

the rate of glycogen
synthesis and degradation. Glycogen synthase
Glycogenin and branching enzyme
oregonstate.edu

Reciprocal Regulation
• Glycogenolysis and glycogenesis are
reciprocally regulated
• Conditions that promote synthesis inhibit
degradation and vice versa
HORMONAL REGULATION OF • Regulation is employed in response to the blood
GLYCOGEN METABOLISM glucose level
• Normal blood glucose level: 70-100 mg/100 mL

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Hormones for Regulation Hormonal Regulation

INSULIN After a carbohydrate
rich meal
• Stimulates uptake of glucose from the
bloodstream • Blood glucose level
elevates
• Promotes glycogenesis and inhibits
• Pancreas will secrete
glycogenolysis
insulin
EPINEPHRINE (in muscle) and • Glycogenesis is
GLUCAGON (in liver) promoted
• Stimulates glycogen breakdown to glucose

science.howstuffworks.com

Hormonal Regulation Hormonal Regulation

After not eating for a During stress (strenuous exercise, excitement,
long period of time beating deadlines, cramming for exams etc.)
• Blood glucose level • Adrenal glands secrete epinephrine
decreases
• Glycogenolysis is stimulated in the muscle
• Pancreas secretes
glucagon • The so-called “Adrenaline Rush”
• Glycogenolysis is • Epinephrine is also called adrenaline
promoted in the liver

Lethargic after meals? Diabetes Mellitus Type 1

Why do we feel lethargic after a carbohydrate- • Insulin-dependent diabetes
rich meal?
• Deficiency in insulin may be caused by:
• After such meal, blood glucose level increases.
• Autoimmune destruction of pancreatic cells
• Insulin is secreted by the pancreas and secreting insulin
glycogen synthesis is activated
• Mutation of insulin structure
• No glucose is available for energy production so
the person feels lethargic.

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Diabetes Mellitus Type 2

• Insulin-resistant diabetis
• Patient is non-responsive to insulin
• Due to defect in the structure of the insulin
receptor
• Insulin cannot promote uptake of glucose
from the blood