Glycogen Metabolism
Glycogenesis and glycogenolysis occur in the cytoplasm of cells
P~Pi
UDP-glucose pyrophosphorylase
Glycogen synthase
Branching enzyme
Glycogenesis &
Glycogenolysis
Step 2
Step 3
Step 4
Glycogen Structure
Activation of Glucose
UTP
Glucose
Activation
of Glucose
Glycogen synthase enzyme catalyses the transfer of
glucose units of UDPG to a pre–existing glycogen
molecule or primer
C1 of UDPG forms a glycosidic bond with C4 of a
terminal glucose residue of glycogen, liberating UDP
When the chain has been lengthened to between 8 and
12 glucose residues, the branching enzyme transfers a
part of the 1,4–chain to a neighboring chain to form a
1,6–linkage, thus establishing a branching point in the
molecule
Glycogen Synthase Enzyme
& Branching Enzyme
Glycogenin (Glycogen primer)
Glycogen primer synthase
autocatalysis
Glycogen primer
Glycogen primer synthase
Regulation of Glycogenesis Glycogen synthase is the key enzyme of glycogenesis
It is present in two inter-convertible forms:
Synthase D, inactive (Dependent), phosphorylated
It is dependent on the presence of G6P
Synthase I, active (Independent), which is
dephosphorylated and independent on the
presence of glucose 6–phosphate
Synthase I is converted to the inactive synthase D by
phosphorylation by protein kinase enzyme, with ATP
as phosphate donor
The protein kinase only acts in the presence of cAMP
Glycogenesis
Stimulated after carbohydrate meal, due to
increased insulin
Glycogen synthase activated allosterically
by Glucose–6–phosphate & ATP
Inhibited during fasting, due to increased
secretion of adrenaline & glucagon
Inhibited also by thyroxin
cAMP (3', 5'-cylic AMP) is
sterically constrained by having
a phosphate with ester linkages
to 2 hydroxyls of the same ribose.
Hydrolysis of one of these
linkages (in red), converting
cAMP to 5'-AMP is highly
spontaneous.
The lability of cAMP to
hydrolysis makes it an excellent
transient signal.
Explore cAMP with Chime.
N
N N
N
NH2
O
OHO
HH
H
H2C
HO
PO
O-
1'
3'
5' 4'
2'
cAMP 3',5'–Cyclic AMP ( )
The conversion of ATP to cyclic
AMP releases pyrophosphate
((P~Pi
3′,5′-cAMP
+
Adrenaline
&/or
Glucagon
Insulin Decomposes cAMP
3′-
+Insulin
Activation of cAMP-dependent
protein kinase A (PKA)
Glucagon activates it's cell-surface receptor
This activation is coupled to the activation of a
receptor-coupled G–protein (GTP–binding and
hydrolyzing protein)
G–protein is composed of 3 subunits (, , )
Upon activation the alpha subunit dissociates
and binds to and activates adenylate cyclase
Adenylate cyclase then converts ATP to cAMP
PKA is cAMP-dependent protein kinase
PKA is composed of 2 catalytic & 2 regulatory subunits
The cAMP binds to the regulatory subunits of PKA
leading to dissociation of the catalytic subunits, so the
catalytic subunits become active
The dissociated catalytic subunits phosphorylate
numerous substrate using ATP as phosphate donor
Activation of cAMP-dependent
protein kinase A (PKA)
2 Catalytic & 2 Regulatory subunits
RC
CR
Activation of
Protein kinase A
R
CC
R
cAMP
Structural formulas of four common
intracellular Second messengers
cAMP cGMP DAG IP3
Regulation of Glycogen Synthesis
Briefly, glycogen synthase I (active form)
when phosphorylated, becomes much less
active and requires glucose–6–phosphate to
restore its activity
PKA also phosphorylates glycogen synthase
directly
Regulation of Glycogen Synthesis
Glycogen synthase is directly phosphorylated by:
Protein kinase A (PKA), which activated by cAMP
Protein kinase C (PKC) or Calmodulin–dependent
protein kinase, which activated by Ca2+ ions or DAG
DAG is formed by receptor–mediated hydrolysis of
membrane phosphatidylinositol disphosphate (PIP2)
• Phosphorylation of Glycogen Synthase
leads to:
1. Decreased affinity of synthase for UDP–glucose
2. Decreased affinity of synthase for glucose–6–
phosphate
3. Increased affinity of synthase for ATP and Pi
Glycogenolysis It is the breakdown of glycogen into glucose in
liver or into lactic acid in muscles
In liver, glycogenolysis maintains the blood
glucose level during fasting for less then 18
hours
In muscles, glycogenolysis followed by
glycolysis supply the contracting muscle with
energy during muscular exercise
Site: Cytoplasm of cells
Glycogen Catabolism (Breakdown)
• Glycogen Phosphorylase
catalyzes phosphorolytic
cleavage of the (1 4)
glycosidic linkages of
glycogen, releasing
glucose-1-phosphate
Glycogen (n) + Pi glycogen (n-1) + glucose-1-phosphate
Glycogenolysis
1. Glycogen phosphorylase acts at the 1,4–glycosidic
linkages yielding glucose–1–P. It stops when there are
only four glucose units away from a branch point
2. Glucan transferase transfers a trisaccharide unit from
one side to the other, thus exposing the 1,6–linkage
(branch point)
3. Debranching enzyme acts on the 1,6–linkage to
liberate a free glucose residue
Glycogenolysis
Glycogenolysis
(Absent in Muscles)
Phosphoglucomutase
Regulation of Glycogenolysis
Phosphorylase is the key enzyme of glycogenolysis
There are 2 types of phosphorylase enzyme
Active form: phosphorylase a, which is
phosphorylated, so known as phospho-
phosphorylase
Inactive form: phosphorylase b, which is
dephosphorylated, so known as dephospho-
phosphorylase
Regulation of Glycogenolysis
Phosphorylase b is converted to phosphorylase a
by the enzyme phosphorylase b kinase, with ATP
as phosphate donor
Phosphorylase b kinase is activated by the enzyme
protein kinase which requires cAMP for its activity
cAMP is increased by glucagon (in liver) and
adrenaline (in liver and muscle)
Regulation of Glycogenolysis
Glycogen phosphorylase is also regulated by
allosteric effectors:
Activation by AMP is seen only in muscle cells
under extreme conditions of anoxia and ATP
depletion
G6P inhibits glycogen phosphorylase by binding
to the AMP allosteric site, to ensure that glycogen
is not wasted if the cells have sufficient energy
Regulation of Glycogenolysis
Activation of glycogen degradation during muscle
contraction by calcium
Rapid need of ATP increases nerve impulses,
leading to membrane depolarization, which
promote Ca release from the sarcoplasmic
reticulum into the sarcoplasm of muscle cells
Regulation of Glycogenolysis
Calcium binds to calmodulin (subunit of
phosphorylase kinase)
So Calcium ions activate phosphorylase kinase
even in the absence of the enzyme phosphorylase
kinase
This allows neuromuscular stimulation by
acetylcholine leading to increased glycogenolysis
in the absence of receptor stimulation
Regulation of Glycogen
Phosphorylase
Regulation of Glycogen Phosphorylase
Glycogen phosphorylase is activated by:
• cAMP
• AMP, allosterically
• Ca2+
• Phospholipase C (PLC)
Glycogen phosphorylase is inhibited by:
• G–6–P
• F–1–P, allosterically
Differences Between Liver & Muscle Glycogen
Muscle GlycogenLiver Glycogen
30 Kg1 – 1.5 KgTissue Weight
300 g100 gGlycogen
Amount
1 %10 %Glycogen
Conc.
Blood Glucose onlyBlood Glucose &
GluconeogenesisSource
Blood LactateBlood GlucoseHydrolysis
Product
Used by muscles onlyUsed by all tissuesEnergy
produced
Source of Energy for
muscles only
Maintenance of Blood
GlucoseFunction
Factors Affecting Liver &
Muscle Glycogen
Muscle
Glycogen
Liver
Glycogen
Less Marked IncreaseIncreases greatlyDiet
Little effectDepletionFasting
DepletionLittle effectMuscular
Exercise
Hormonal Regulation of Liver & Muscle Glycogen
Muscle
Glycogen
Liver
Glycogen
GlycogenesisGlycogenesis Insulin
Little increase due to
hyperglycemiaGluconeogenesisGlucocorticoids
Little increase due to
hyperglycemiaGluconeogenesis
Growth
Hormone
GlycogenolysisGlycogenolysisThyroxine
No EffectGlycogenolysisGlucagon
GlycogenolysisGlycogenolysisAdrenaline
Glycogen Storage Diseases (GSD)
• Glycogen storage diseases are inborn errors of
glycogen metabolism (genetic diseases)
• It is characterized by the storage of abnormal
amounts of glycogen in the body
• There are five different types of these diseases
depending on the enzyme missing
Glycogen Storage Diseases (GSD)
• All people who are born with GSD are unable to
properly metabolize or break down glycogen
• People with GSD have the ability to use sugar
stored as glycogen, but are unable to use the
stores to provide the body with energy during
fasting or exercise
Thanks