2. Glycogen Metabolism
– Glycogen
• Storage form of glucose in animal body specially in
liver & muscles
• Readily mobilized when body needs glucose
– Why body stores glucose as glycogen and not as
glucose itself?
• Reasons:
– Insoluble in water
» Exerts no osmotic pressure
• Does not disturb the intracellular fluid
content
• Does not diffuse from its storage sites
– Higher energy level than glucose
– Readily broken down under the influence of
hormones & enzymes 2
3. Cont…
– Why we need to make glycogen?
• Reasons:
– We are not eating all the time! But our brain needs
glucose continuously
– One of the very important function of glycogen is
to maintain blood glucose level
– Which glycogen is important to maintain blood
glucose level?
• Answer: Liver Glycogen
– Two important tissue sites for glycogen:
• Liver
• Muscle
3
4. Cont…
– What are the most important differences b/n liver
& muscle glycogen?
– Difference no-1:
» Liver glycogen is mobilized for safety of other
tissues during hypoglycemic condition
» Muscle glycogen is mobilized for its private &
personal needs , not for need of other tissues
» Due to absence/ presence of glucose 6-
phosphatase
– Difference no-2:
» In well fed state:
• Around 100gm of glycogen in liver & 400gm of
glycogen in muscle
• However,
• Muscle glycogen makes 1-2 % of muscle mass
• Liver glycogen makes about 10 % of liver
mass 4
5. Cont…
• Difference no-3:
– Glycogen stores in liver & muscle fluctuate
» Liver glycogen stores fluctuate according to
Fed/Fasting state of body
» Muscle glycogen stores fluctuate according to
resting/exercising state of muscle
– Glycogen metabolism can be discussed under two
phases:
• Synthetic phase
– Formation of glycogen (Glycogenesis )
• Catabolic phase
– Breakdown of glycogen (Glycogenolysis)
5
6. Cont…
– Characteristics of two phases:
• Breakdown pathway is not a ‘reversal’ of synthetic
pathway
• When glycogenesis occurs, glycogenolysis does not
take place and vice versa
• Both phases are regulated finally, at substrate level,
by end-products & hormonally
Glycogenesis
– Formation of glycogen from glucose
– Starts with phosphorylation of glucose at C-6 6
7. Cont…
– 1st, glucose is phosphorylated to glucose-6-P by
Glucokinase or Hexokinase
• Common step for EM pathway & glycogenesis
– 2nd, Glucose 6-P Glucose 1-P by
phosphoglucomutase
7
8. Cont…
– 3rd, Glucose-1-P plus UTP UDP-Glucose plus
PPi by UDP-glucose pyrophosphorylase
– Subsequent hydrolysis PPi by inorganic
pyrophosphatase drives the reaction to right
– Then, C-1 of UDP-Glucose reacts with C-4 of
terminal glucose residue in primer, or pre-
existing glycogen liberating UDP by Glycogen
synthase
8
9. – Pre-existing glycogen molecule, or “primer” must
be present to initiate glycogen synthase reaction
– Glycogenin
• Protein primer on which glycogen ‘primer’ is formed
• Glycosylated on a specific tyrosine residue by UDPGlc
• An existing glycogen chain can be repeatedly extended
by one glucose unit
– Librated UDP reacts with ATP UTP
(regenerated) plus ADP by nucleoside
diphosphokinase
– In each extension existing glycogen chain , 2
ATPs are expended:
• 1 ATP: Glucokinase/Hexokinase reaction
• 1 ATP: Nucleoside diphosphokinase reaction 9
10. Cont…
– When a minimum of 11 glucose residues reached,
• Another enzyme called Branching enzyme (Amylo-1, 4
→ 1, 6-transglucosidase)
– Cleaves α-1 → 4 glycosidic linkage on growing
glycogen chain
– Transfers a minimum of 6 glucose residues to
neighboring chain
– Forms α-1 → 6 glycosidic linkage in the neighboring
chain
– Branches grow by further additions of α- (1 → 4)
glucosyl units by glycogen synthase activity &
further branching by branching enzyme activity
10
12. Cont…
Glycogenolysis
– Breakdown of glycogen to glucose or glucose 6- P
– Involves two steps:
• Phosphorolysis
• De-branching
• Phosphorlysis:
– Cleavage of bond by addition of phosphate
groups
– Catalyzed by Glycogen Phosphorylase
• Pyridoxal phosphate (PLP) dependant enzyme
• Removes glycosyl residues from non-reducing end of
glycogen by adding Pi group
12
13. Cont…
– Addition of Pi group:
• Splits glycosidic linkage b/n C-1 of terminal residue &
C-4 of adjacent residue in glycogen molecule
• Phosporylates terminal residue at C-1 Glucose 1-
Phosphate
13
14. Cont…
– Repeated action of glycogen phosphorylase
continues till 4 glucose residues remain before
(α-1,6) branch point
– Glycogen molecule completely sheared by
glycogen phosphorylase up to four residue
remnant Phosphorylase dextrin or Limit
dextrin
• De-branching:
– Next step in glycogenolysis
– Requires de-branching enzyme oligo (α-1,6) to
(α-1,4) glucantransferase
• Catalyzes two two successive reactions that transfer
branches 14
15. Cont…
– 1st, transfer of oligosaccharide unit (3 glucose
residue) from limit dextrin of one branch to
neighboring branch (converting from 4 into 7
glucose residues)
• Catalyzed by (α-14) to (α-14)-glucantransferase
activity (Transferase activity)
– 2nd , cleavage of (α-16)-glycosidic linkage
Free glucose residue
• Catalyzed by amylo-(α-16)-glucosidase or de-
branching enzyme activity
• Phosphorylase activity now, continues in the
elongated branch of 7 glucose residues until
limit dextrin 15
17. Cont…
Fate of Glucose-1-P
– Combined action of phosphorylase & de-
branching enzymes convert glycogen to glucose-
1-P mostly
– Glucose-1-P is easily converted to glucose-6-P by
action of Phosphoglucomutase enzyme
– Glucose 6-phosphate
• Enters glycolytic pathway in muscle cells
• Transported into ER lumen by specific transporter
(T1) ER membrane of liver & kidney
– Converted to glucose & Pi by Glucose 6-
phosphatase Released into blood
– Glucose & Pi transported back into cytosol by
specific transporters ( T2 &T3, respectively)
17
19. Regulation of glycogen metabolism
Objectives:
– To store glucose at times of plenty and mobilize
it at times of scarcity
– To prevent the reaction of storage &
mobilization of glucose from occurring at the
same time
• Glycogenesis & glycogenolysis are coordinated
processes
– Glycogen synthase is nearly inactive when glycogen
phosphorlase is fully active and vice versa
19
20. Cont…
• Nature of signals regulating glycogen
metabolism differs from tissues to tissues
– Muscle cells regulate to mobilize glucose for ATP
formation & to store the glucose at rest when
the glucose supply is adequate
• Important muscle signals:
– Intracellular concentration of Ca2+ and AMP Rise
during muscle contraction
– Blood plasma concentration of hormones:
» Adrenalin & insulin
20
21. Cont…
• Adrenalin:
– Concentration in blood increases with decreasing
concentration of blood glucose
– Signals requirement for fuel
– Enhances glycogen degradation in the muscle
• Insulin:
– Concentration in blood increases with increasing
concentration of blood glucose
– Signals availability of fuel
– Enhances glycogen biosynthesis in muscle
21
22. Cont…
– Liver cells regulate to maintain normal blood
glucose concentration
• Important liver signals:
– Blood plasma concentration of hormones:
» Glucagon & Insulin
– Insulin:
• Signals adequate supply of glucose
• Promotes synthesis of glycogen in liver
– Glucagon:
• Signals low blood glucose
• Promotes degradation of glycogen in liver
22
23. Regulation of Glycogen metabolism in muscle cells
– Glycogen phosphorylase & glycogen synthases
• Two principal enzymes in regulating glycogen
metabolism both in muscle and liver cells
• In muscle cells:
– These enzymes are regulated by two means:
• Covalent modification
• Allosteric modulators
• Regulation by covalent modification:
– Phosphorylation activates glycogen phosphorylase
– Dephosphorylation activates glycogen synthases
23
29. Regulation of Glycogen metabolism in liver cells
• Liver Glycogen Phosphorylase Regulation
– Same as in the muscle cells
• Regulated by:
– Covalent modification
– Allosteric modulators
• Deactivated by protein phosphatase
• High conc. of glucose 6-P & ATP deactivate liver
phosphorylase
• Insulin deactivates liver phosphorylase
29
30. Cont…
– Difference is on:
• Effects of hormones in two types of cells
– Glucagon:
» Principal hormone affecting glycogen
metabolism in the liver
– Epinephrine:
» Muscle counterpart hormone to liver glucagon
» Also affects liver glycogen metabolism
• Effects of intracellular Ca2+
– Ca2+ has no effect on liver phosphorylase kinase
• Effects of high conc. of glucose
– High conc. of glucose deactivates liver
phosphorylase
30
31. Cont…
• Liver Glycogen Synthase Regulation:
– Stimulatory Signals of liver glycogen
phosphorylase:
• Glucagon
• Adernalin
– Inhibitory signals of liver glycogen
phosphorylase:
• Insulin
• Glucose
• Glucose 6-P
• ATP
Inhibitory signals for liver glycogen
synthase
Stimulatory signals for liver
glycogen synthase
31
33. Clinical Comments Related to Glycogen Metabolism
– Glycogen Storage Diseases:
• Congenital defects in different enzymes involved in
glycogen metabolism Storage of glycogen in tissues
that lacks a particular enzyme
• Can be three types:
– Hepatic form
» Von Gierke disease (Type-I)
» Cori disease (Type-III)
» Hers disease (Type-VI)
– Myopathic form
» McArdles disease (Type-V)
– Generalized form ( affects liver, muscle, Heart…)
» Pompe disease (Type-II)
» Andersons disease (Type-IV) 33
