A comprehensive presentation on Metabolism of Glycogen and its clinical significance MBBS , BDS, B Pharm & Biotechnology students to facilitate self- study.
3. Functions of Glycogens
Glycogen is stored in Liver and skeletal muscles as energy reserve.
Muscle Glycogen is to provide energy for prolonged muscles
contraction
Liver Glycogen is to maintain blood sugar levels in human body.
4. Glycogen is the storage form of Glucose in animals.
It is stored in cytosol of cells of Liver (6-8% )and muscles (1-2%) in a granular
form.
GlycogenMetabolism
5. Stored Glycogen serves as a fuel reserve
Stored Glycogen serves as a fuel reserve for following reasons
a) Glycogen can be rapidly metabolized.
b) Glycogen can generate energy in absence of oxygen.
c) Brain depends on continuous glucose supply
Fat mobilization is slow and depends on oxygen for energy generation
and cannot produce glucose ( to significant extent) in human body .
• Fat = fixed deposit of bank
• Glycogen = saving /current account of bank
6.
7.
8. Glycogenesis
Glycogenesis : Synthesis of Glycogen from Glucose
a) Site of Glycogenesis : cytosol of Muscle (250gms/day),Liver (75gm/day) cells
b) Initiation of glycogen synthesis by Glycogenin :A protein can accept glucose from
UDPG in absence of Glycogen primer initiation of Glycogen synthesis
c) Glycogen synthase : uses UDP-glucose as a substrate for Glycogenesis ,adding
one residue of Glucose at a time to non reducing end of Glycogen .It forms α1 4
bonds between neighboring glucosyl residues.
d) Branching enzyme of Glycogenesis : Glucosyl α 4,6 transferase/ Amylo α1,4
1,6 transglucosidase).This enzyme transfers a small fragment of 5-8 residues from
non reducing end of Glycogen chain (by breaking α1,4 linkages) to another
glucose residue where it is linked by α1,6 bond
e) Cofactors required in Glycogenesis : ATP and UDP
f) Glycogen elongation & branching :by repeated action of Glycogen synthase and
Glucosyl α 4,6 transferase
g) Reaction involved in Glycogenesis
9. Glycogenesis
Reaction involved in Glycogenesis
( Glucose )n + Glucose + 2ATP ( Glucose )n+1 + 2ADP + 2 Pi
Of 2 ATP utilized one required for the phosphorylation of Glucose
while other is needed for conversion of UDP to UTP.
10. Initiation of glycogen synthesis by Glycogenin
The hydroxyl group of the amino acid
Tyrosine of Glycogenin is site
at which the initial glucose residue
gets attached.
The enzyme Glycogen synthase transfers
the first Glucose molecule to
Glycogenin.
Glycogenin, itself takes up glucose
molecules subsequently to form a
glycogen primer.
15. Glycogenolysis
Glycogenolysis : is a degradation of stored Glycogen
Site of Glycogenolysis : cytosol of Muscle & Liver cells
Enzymes involved in Glycogenolysis: Glycogen Phosphorylase and debranching
enzymes
Liver Glycogenolysis
1. Glycogen Phosphorylase : Glycogen Glucose1-P
2. Phosphoglucomutase: Glucose 1-P + Mg2+ Glucose 6-P
3. Glucose 6 Phosphatase : Glucose 6-P Glucose
Muscle Glycogenolysis
I. Glycogen Phosphorylase : Glycogen Glucose 1-p
II. Phosphoglucomutase : Glucose 1-P + Mg2+ Glucose 6-P
III. Glycolysis :Glucose 6-P Lactate
Muscle lacks enzyme –Glucose 6 phosphatase
16.
17. Glycogen Phosphorylase
• Glycogen Phosphorylase :
• It removes glucose residues sequentially from non reducing ends of
Glycogen molecule ,producing Glucose 1 phosphate as the first
product of Glycogenolysis.
• It breaks α 1 4 glycosidic bonds and cannot break α 1 6
glycosidic branch points/bonds .
21. Fates of Glucose 6-phosphate as an intermediate of Glycogenolysis
Glucose 6-phosphate enters
Glycolysis and is oxidized to yield
energy for muscle contraction
The ratio of Glucose 1-phosphate to
Glucose 6-phosphate is 8:1
23. Regulation of Glycogenesis and Glycogenolysis
Regulation of Glycogenesis and Glycogenolysis and their good
coordination is essential to maintain blood glucose levels .
Glycogen synthase regulates Glycogenesis.
Glycogen phosphorylase regulates Glycogenolysis.
24. Regulation of Glycogenesis and Glycogenolysis
Regulation of Glycogenesis and Glycogenolysis and their good
coordination is accomplished by three mechanisms.
a) Hormonal regulation
b) Allosteric regulation
c) Influence of Calcium
25. Hormonal Regulation of Glycogenesis
/ Glycogenolysis
The hormones through complex series of reactions bring about covalent
modifications ,namely phosphorylation and dephosphorylation of
enzymes which ultimately control Glycogen synthesis (Glycogenesis)
and or its degradation (Glycogenolysis).
26.
27. Hormonal Regulation of Glycogenesis / Glycogenolysis by Epinephrine and
Insulin
Cyclic AMP ( c AMP)
acts as a second messenger during hormonal regulation of Glycogenesis /
Glycogenolysis by Epinephrine , nonepinephrine ,Glucagon and Insulin.
binds to cell membrane and brings changes inside the cell.
Regulates activities of Glycogen synthase and phosphorylase (
involved in Glycogenesis / Glycogenolysis respectively ).
Hormones like epinephrine and nonepinephrine and Glucagon ( in
Liver) activate adenylate cyclase to increase the production of Cyclic AMP ( c
AMP) .
Insulin increases phosphodiesterase activity in liver and lowers C-AMP
levels.(Enzyme phosphodiesterase breaks down C-AMP).
28.
29. Hormonal Regulation of Glycogenesis / Glycogenolysis by Epinephrine and
Insulin
Cyclic AMP ( c AMP) during Starvation
High levels of Cyclic AMP ( c AMP) causes activation of inactive
Glycogen phosphorylase enhancing Glycogenolysis ( through protein
kinases ).
High levels of Cyclic AMP ( c AMP) inactivates an active Glycogen
synthase leading to inhibition of Glycogenesis .
Glucagon and Adrenalin(Epinephrine )stimulate Glycogenolysis
through High levels of Cyclic AMP
30. Regulation of Glycogenolysis by Epinephrine,
Norepinephrine and Glucagon -through C-Amp
Glycogenolysis is regulated by a enzyme Glycogen Phosphorylase
Glycogen Phosphorylase exist in two forms :
1) a form of Glycogen Phosphorylase ( Phosphorylated and most active )
2) b form of Glycogen Phosphorylase ( dephosphorylated and inactive )
C-Amp is formed due to hormonal (Epinephrine and Glucagon ) stimulation
C-Amp activates dependent on protein Kinase
Conversion of b form(inactive ) to a form (active ) of Glycogen Phosphorylase kinase :
phosphorylation catalyzed by active form of protein Kinase
Conversion of b form(inactive ) to a form (active ) of Glycogen Phosphorylase : phosphorylation
catalyzed by a form (active ) of Glycogen Phosphorylase kinase.
a form (active ) of Glycogen Phosphorylase degrades Glycogen ( Glycogenolysis )
Conversion of a form to b form of Glycogen Phosphorylase kinase : de phosphorylation by protein
phosphatase . (removes phosphate for inactivation of Glycogen Phosphorylase kinase )
Conversion of a form to b form of Glycogen Phosphorylase : de phosphorylation by protein
phosphatase I. (removes phosphate for inactivation of Glycogen Phosphorylase )
Inhibition of Glycogenolysis (Glycogen Phosphorylase ) : by epinephrine , norepinephrine and
Glucagon by Conversion of a form(active ) to b form (inactive ) of Glycogen Phosphorylase - De
phosphorylation
31. Regulation of Glycogenesis by Epinephrine,
Norepinephrine and Glucagon -through C-Amp
Glycogenesis is regulated by Glycogen synthase
Glycogen synthase exist in two forms :
1) a form of Glycogen synthase ( Not Phosphorylated and most active )
2) b form of Glycogen synthase( Phosphorylated and inactive )
Conversion of a form(active ) to b form (inactive ) of Glycogen synthase : phosphorylation
catalyzed by C-Amp dependent on protein Kinase
Conversion of b form to a form of Glycogen synthase : de phosphorylation by protein
phosphatase I.
Inhibition of Glycogenesis (Glycogen synthase ) : by epinephrine , norepinephrine and Glucagon
through C-Amp (Conversion of a form(active ) to b form (inactive ) of Glycogen synthase by
phosphorylation
32. Hormonal regulation of Glycogenolysis by Epinephrine/Glucagon through ,C-AMP and Protein kinase
a form of Glycogen
synthase ( Not
Phosphorylated and most
active )
b form of Glycogen synthase
( Phosphorylated and inactive )
Conversion of a form to b form by phosphorylation
catalyzed by C-Amp dependent on protein Kinase
34. Hormonal regulation of Glycogenolysis by Epinephrine/Glucagon through
G –protein ,C-AMP and Protein kinase
Signal transduction
35.
36.
37. Allosteric regulation of Glycogen Metabolism
Allosteric regulation of Glycogen Metabolism by Metabolites that
allosterically regulate the activities of Glycogen Synthase and
Glycogen phosphorylase .
Glycogen synthesis is increased when substrate availability and
energy levels are high.
Glycogen breakdown is increased Glucose concentration is low.
38. Well fed state
Availability of Glucose6-phosphate high
Allosteric activation
of Glycogen synthase
More Glycogen synthesis
Allosteric regulation of Glycogen Metabolism
39. Starvation /fasting state
Availability of Glucose6-phosphate and ATP low
Allosteric activation of Glycogen
phosphorylase by C- Amp
More Glycogen breakdown
Allosteric regulation of Glycogen Metabolism
40. Allosteric regulation of Glycogen Metabolism
ACTIVATORS INHIBITORS
Glycogen synthase ATP, Glucose 6 P (well fed- concentration
increases )Glycogenesis ON
C –AMP (starvation concentration
increases)Glycogenesis OFF
ACTIVATORS INHIBITORS
Glycogen
phosphorylase
C—AMP
(concentration increases during
starvation) Glycogenolysis ON
In muscles ionic Calcium,C-Amp act as
activators
ATP,
liver free Glucose,
Glucose 6- P
(concentration increases in well fed )
Glycogeniolysis OFF
STARVATION WELL FED
Glucose ,ATP Decreases glucose ,ATP INCREASES
Glycogenolysis ON Glycogenolysis OFF
Glycogen synthesis OFF Glycogen synthesis ON
42. Glycogenesis/Glycogenolysis during starvation and well fed conditions
WELL FED NUTRITIOUS STATUS STARVATION NUTRITIOUS STATUS
1. HIGH LEVELS OF GLUCOSE CONCENTRATION 1. LOW LEVELS OF GLUCOSE CONCENTRATION
2. HIGH LEVELS OF INSULIN CONCENTRATION (induced by Glucose ) 2. LOW LEVELS OF INSULIN CONCENTRATION
3. LOW LEVELS OF GLUCAGON (inhibited by high levels of Glucose )
4. HIGH LEVELS OF ATP
5. LOW LEVELS OF C-AMP
6. INACTIVATION OF GLYCOGEN PHOSPHORYLASE
7. INHIBITION OF GLYCOGENOLYSIS
8. STIMULATION OF GLYCOGEN SYNTHESIS TILL GLUCOSE
CONCENTRATION BROUGHT BACK TO NORMAL
3. HIGH LEVELS OF GLUCAGON (INCREASES )
4. LOW LEVELS OF ATP
5. HIGH LEVELS OF C-AMP
6. ACTIVATION OF GLYCOGEN PHOSPHORYLASE
7. STIMULATION OF GLYCOGENOLYSIS
8. INHIBITION OF IN GLYCOGEN SYNTHESIS TILL
GLUCOSE CONCENTRATION BROUGHT BACK TO
NORMAL
43. REGULATION OF GLYCOGEN METABOLISM
WELL FED NUTRITIOUS STATUS STARVATION NUTRITIOUS STATUS
INCREASE IN GLUCOSE CONCINCREASE IN INSULIN DE CREASE IN GLUCOSE CONCDECREASE IN INSULIN
ATP CONC INCREASES ATP CONC DECREASES
C –AMP LOW C –AMP HIGH
GLYCOGENOLYSIS DECREASES--OFF GLYCOGENOLYSIS INCREASES--ON
GLYCOGEN SYNTHESIS INCREASES --ON GLYCOGEN SYNTHESIS DECREASES --OFF
DEPHOSPHORYLATION OF GLYCOGEN SYNTHASE (ACTIVE)
GLYCOGEN SYNTHESIS CONTINUES TILL GLUCOSE CONC
BROUGHT BACK TO NORMAL
PHOSPHORYLATION OF GLYCOGEN SYNTHASE (INACTIVE)
GLYCOGEN SYNTHESIS DECREASES TILL GLUCOSE CONC
BROUGHT BACK TO NORMAL
44.
45. Regulation of Glycogen Metabolism by Insulin
C-Amp + Phosphodiesterase 5’AMP
Insulin promotes phosphodiesterase decreases C-Amp levels
Insulin converts Glycogen Phosphorylase A (active and phosphorylated form ) Glycogen
Phosphorylase B (inactive )THEREFORE INSULIN INHIBITS GLYCOGENOLYSIS
Glycogen Synthase B (dephosphorylated form and inactive) Glycogen Synthase A ( active and
phosphorylated )THEREFORE INSULIN ENHANCES GLYCOGENESIS
Mechanism : Insulin decreases C-AMP levels (Glycogen synthase remains in active
form)STIMULATES GLYCOGEN SYNTHESIS.
INSULIN PLAYS ANABOLIC ROLE
46.
47. EFFECT OF CALCIUM IONS ON GLYCOGENOLYSIS
1. Need for ATP increases during Muscle Contraction
2. Muscle Contraction induces release Of Calcium From Sarcoplasmic
Reticulum
3. Calcium –Calmodulin Complex formed
4. Direct Activation Of Phosphorylase Kinase without C-amp
Dependent Protein Kinase
5. Muscle Activity Of Glycogen Phosphorylase Increases
6. Increase In Concentration Of ATP
48. Effect of Calcium ions on Glycogenolysis
Muscle Contraction
Need for ATP increases
Release Of Calcium From Sarcoplasmic Reticulum
Calcium –Calmodulin Complex formed
Direct Activation of Phosphorylase Kinase without C-amp Dependent Protein Kinase
Muscle Activity of Glycogen Phosphorylase increases increase In Concentration Of
ATP
51. FUTILE CYCLES
The synthesis and degradative pathways of metabolism ( particularly reactions
involving phosphorylation and de-phosphorylation utilizing ATP ) are well
regulated and subjected to fine tuning to meet body’s demands with minimal
wastage of energy.
Glycogenolysis and Glycogenesis operate in selective fashion to suit cellular
demands.