Metabolism of glycogen following the curriculum of medical biochemistry of MBBS course

1. GLYCOGEN
METABOLISM
DR. FARHANA ATIA
ASSOCIATE PROFESSOR
DEPARTMENT OF BIOCHEMISTRY
NILPHAMARI MEDICAL COLLEGE, NILPHAMARI

2. GLYCOGEN
Glycogen is polymer of
glucose and major storage
carbohydrate in animal
Stored site
Skeletal muscle: Serve fuel
for muscle activity
Liver: maintain blood glucose
concentration in early stage of
fasting (12-18 hours)
Brain: modest amount

3. Liver glycogen Muscle glycogen
1. Amount
90 g [5% of tissue
weight -1.8 kg]
245 g [0.7% of tissue
weight- 35 kg]
2. Source
Dietary carbohydrate
& gluconeogenesis
Blood glucose & muscle
lactic acid
3. Turnover rate Rapid Slow
4. Maintenance of
blood glucose
concentration
Positive role
No role due to absence of
glucose-6-phosphatase
5. Fuel for muscle
activity
No role
Ready source of glucose-1-
phosphate for glycolysis

4. GLYCOGENESIS
Glycogenesis is the formation of glycogen from glucose
Substrate: Glucose as Glucose-1-phosphate
Product: Glycogen
Site: Liver, Muscle
Comp: Cytoplasm
Nature: Anabolic
Rate limiting enzyme: Glycogen synthase

5. Steps of Glycogenesis
Glucose is phosphorylated
to glucose-6-phosphate,
catalyzed by hexokinase
(muscle) and glucokinase
(liver)
Glucose-6-phosphate is
isomerized to glucose-1-
phosphate by
phosphoglucomutase

6. Steps of Glycogenesis
Glucose-1-phosphate reacts
with uridine triphosphate
(UTP) to form the active
nucleotide uridine
diphosphate glucose
(UDPGlc) and pyrophosphate
catalyzed by UDPGlc
pyrophosphorylase

7. Steps of Glycogenesis
Initial steps in glycogen synthesis
involve the protein glycogenin
which is glucosylated on a specific
tyrosine residue by UDPGlc
Glycogenin catalyzes the transfer
of a further 7 glucose residues from
UDPGlc in 14 linkage to form a
glycogen primer that is the
substrate for glycogen synthase

8. Steps of Glycogenesis
Glycogen synthase catalyzes
the formation of a glycosidic
bond between C-1 of the
glucose of UDPGlc & C-4 of a
terminal glucose residue of
glycogen primer, liberating UDP
So the branches of the
glycogen molecule become
elongated as successive 14
linkage are formed

9. Steps of Glycogenesis
When growing chain is at least
11 glucose residues long,
branching enzyme transfers a
part of the 14 chain (at least 6
glucose) to a neighboring chain
to form a 16 linkage
establishing a branch point
The branches grow by further
addition of 14 glucosyl units &
further branching

10. Pathway
of
Glycogenesis
Harper’s Biochemistry 31st edn p-165

11. Glycogenolysis
Substrate: Glycogen
Product: Glucose-1-phosphate [finally glucose in liver,
but in muscle G1P:free glucose = 10:1]
Site: Liver, Muscle, Brain
Comp: Cytoplasm
Nature: Catabolic
Rate limiting enzyme: Glycogen phosphorylase

12. Steps in Glycogenolysis
Glycogenolysis is not the reverse of
glycogenesis, it is a separate pathway
Glycogen phosphorylase catalyzes
the rate limiting step in glycogenolysis-
the phosphorolytic cleavage of the 14
linkages of glycogen to yield glucose-1-
phosphate. The enzyme requires
pyridoxal phosphate as it’s coenzyme

13. Steps in Glycogenolysis
The terminal glucosyl
residues are removed
sequentially until
approximately 4 residues
remain on either side of
16 branch

14. Steps in Glycogenolysis
The debranching enzyme has
2 catalytic sites
Glucan transferase: Transfers a
trisaccharide unit from one
branch to the other, exposing the
16 branch point
A 1,6-glycosidase: Catalyzes
hydrolysis of 16 glycoside bond
to liberate free glucose

15. Steps in Glycogenolysis
Further phosphorylase action
can then proceed
The combined action of
phosphorylase and debranching
enzyme leads to the complete
breakdown of glycogen

16. Steps in Glycogenolysis
Phosphoglucomutase
catalyzes the conversion of
glucose-1-phosphate to glucose-
6-phosphate
In liver (not muscle) glucose-6-
phosphatase catalyzes hydrolysis
of glucose-6-phosphate yielding
glucose

17. Pathway
of
Glycogenolysis
Harper’s Biochemistry 31st edn p-165

18. Regulation
Glycogen metabolism is
regulated by a balance in
activities between
glycogen synthase &
phosphorylase
Cyclic-AMP
simultaneously activate
phosphorylase & inhibit
glycogen synthase
Insulin
Glycogen
synthase
C-AMP
Glycogen
phosphorylase
Glucagon
Epinephrine

19. Regulation
cAMP is stimulated by
epinephrine & glucagon,
which in turn enhances
glycogenolysis
Whereas c-AMP is
inhibited by high
concentration of insulin
which in turn inhibits the
glycogenolysis
Insulin
Glycogen
synthase
c-AMP
Glycogen
phosphorylase
Glucagon
Epinephrine

20. Glycogen storage disease
Inherited deficiencies of enzymes of glycogen
metabolism in both liver & muscle cause glycogen
storage disease
Characterized by deficient mobilization of glycogen or
deposition of abnormal forms of glycogen
Leading to liver damage and muscle weakness; some
result in early death.