Glycogen is the storage form of Glucose which maintain the blood glucose level under various condition. Glycogen Metabolism is the important pathway of carbohydrate metabolism which gives the information about the glycogen synthesis (Glycogenesis), Glycogen breakdown (Glucogenolysis). Glycogen metabolism also gives the information how this pathway is regulated. Their are various diseases which are associated with this metabolism, commonly known as Glycogen storage diseases.
2. GLYCOGEN- INTRODUCTION
Glycogen is a readily mobilized storage form of
glucose.
It is a very large, branched polymer of glucose
residues that can be broken down to yield glucose
molecules when energy is needed.
Most of the glucose residues in glycogen are
linked by α-1,4-glycosidic bonds.
Branches created by α-1,6-glycosidic bonds.
4. GLYCOGEN STORAGE SITES
It is stored mainly in liver and muscle
The liver content of glycogen is greater than that
of muscle,
Since the muscle mass of the body is considerably
greater than that of the liver, about three-quarters
of total body glycogen is in muscle
5. Reasons for storing glycogen as a fuel
Glycogen serves as a buffer to maintain blood-
glucose levels.
Glucose is virtually the only fuel used by the
brain, except during prolonged starvation.
The glucose from glycogen is readily mobilized
and is therefore a good source of energy for
sudden, strenuous activity.
Unlike fatty acids, the released glucose can
provide energy in the absence of oxygen and can
thus supply energy for anaerobic activity.
6. GLYCOGENESIS
Glycogenesis is the synthesis of glycogen from
glucose.
Glycogenesis mainly occurs in muscle and liver.
Takes place in cytosol and require ATP and UTP.
Liver glycogen functions to store and export
glucose to maintain blood glucose between meals.
7. STEPS OF GLYCOGENESIS
A. Synthesis of UDP-glucose
B. Synthesis of a primer to initiate glycogen synthesis
C. Elongation of chain by glycogen synthase
D. Formation of branches
8. A. Synthesis of UDP-glucose
Glucose-1-phosphate reacts with uridine tri-
phosphate (UTP) to form uridine diphosphate
glucose (UDPG)
This reaction is catalysed by UDPG pyro-
phosphorylase
Glucose-1-phosphate + UTP UDP-glucose + PPi
UDP-glucose
pyrophosphorylase
9. B. Synthesis of a primer to initiate
glycogen synthesis
Glucose moiety from UDP-glucose is transferred to a
glycogen primer (Glycogenin) molecule.
Primer is made up of protein-carbohydrate complex.
It a dimeric protein, having two identical monomers to which
an oligosaccharide chain of 7 glucose units is added.
UDP is released and glucose is added to the glycogen primer
Glycogen primer having n glucose units would have n+1
glucose units after the reaction
10. B. Synthesis of a primer to initiate
glycogen synthesis
Carbon 1 of the new glucose unit forms a
glycosidic bond with carbon 4 of the last glucose
unit
The reaction is catalysedby glycogen synthase
Glycogen primer(n) + UDP-glucose Glycogen (n+1) + UDP
Glycogen synthase
11. C. Elongation of chain by glycogen
synthase
Glycogen synthase responsible for formation of
1,4-glycosidic linkages.
This enzyme transfers the glucose from UDP-
glucose to the non-reducing end of glycogen to
from α-1,4 linkages.
12. D. Formation of branches
Addition of glucose units to the glycogen primer continues until
the chain contains about eleven glucose units
Then, amylo-1,4 1,6-transglucosidase detaches a fragment of
6-7 glucose units from the growing end
The two branches start growing again by addition of glucose
units by α-1,4-glycosidic bonds catalysed by glycogen synthase
When the branches contain about 11 glucose units, branching
enzyme acts again and creates more branches
The process of lengthening and branching continues until a large
and highly branched glycogen molecule is formed
13. The overall reaction of the glycogen synthesis for the
reaction of each residue is
(Glucose)n + Glucose + 2ATP (Glucose)n+1 + 2ATP + Pi
15. The regulatory enzyme is glycogen synthase
which is regulated by covalent modification
is addition orThe covalent modification
removal of phosphate
The enzyme exists in two forms – glycogen
synthase a and glycogen synthase b
The covalent modification
removal of phosphate
REGULATION
16. Glycogen synthase a is the dephosphorylated
and active form of the enzyme
Glycogen synthase b is the phosphorylated
and inactive form
Addition of phosphate converts glycogen
synthase a into glycogen synthase b
Removal of phosphate converts glycogen
synthase b into glycogen synthase a
17. Phosphate is added to glycogen synthase a by
protein kinase A
Phosphate is removed from glycogen synthase b
by protein phosphatase-1
Protein kinase A and protein phosphatase- 1 are
regulated by cAMP
18. Intracellular concentration Of cAMP is regulated by
some hormones
So, the ultimate regulators of glycogenesis are epinephrine,
glucagon and insulin
Epinephrine and glucagon increase the concentration of cAMP
Insulin decreases the concentration of cAMP
19. cAMP is the regulatorof protein kinase A
(cAMP-dependent protein kinase)
Protein kinase A is a tetramer made up of
two regulatory (R) and two catalytic (C)
subunits
20. GLYCOGENOLYSIS (DEGRADATION
OF GLYCOGEN)
Glycogen is degraded by breaking α-1,4- and α-1,6-
glycosidic bonds
Glycogen degradation consists of three steps:
(1) Action of glycogen phosphorylase.
(2) Action of debranching enzyme.
(3) Formation of glucose-6-phosphate and glucose.
21. 1.Action of glycogen phosphorylase
The α-1,4-glycosidic bonds are cleaved by glycogen
phosphorylase to yield glucose-1-phosphate.
Called phosphorolysis- continues until four glucose
residues remain on either side of branching pont.
The glycogen formed known as Limit dextrin which
cannot further degraded.
22. 2.Action of debranching enzyme
The branches of glycogen cleaved by two enzyme c/d
debranching enzyme, hence it is a bifunctional enzyme.
Glycosyl 4:4 transferase removes a fragment of three or
four glucose residues.
Amylo α-1,6-glucosidase breaks the α-1,6 bond at a
branch and releases a free glucose.
23. 3. Formation of glucose-6-phosphate
and glucose.
Glycogen phosphorylase and debranching enzyme,
glucose 1-phosphate and free glucose are produced.
Glucose 1-phosphate is converted to glucose 6-
phosphate by the enzyme phosphoglucomutase.
Glucose6-phosphatase cleaves glucose 6-phosphate to
glucose.
24.
25. CONVERSION OF GLUCOSE-6-P TO FREE
GLUCOSE
The liver contains a hydrolytic enzyme, glucose 6-
phosphatase, which cleaves the phosphoryl group to form
free glucose and orthophosphate.
Glucose 6-phosphatase is absent in muscles.
Consequently, glucose 6-phosphate is retained for the
generation of ATP.
The liver releases glucose into the blood during muscular
activity and between meals to be taken up primarily by the
brain and skeletal muscle.
26. REGULATION OF GLYCOGEN METABOLISM
The principal enzymes controlling glycogen
metabolism—glycogen phosphorylase and glycogen
synthase—are regulated by three mechanisms
1. Allosteric regulation
2. Hormonal regulation
3. Influence of calcium
27. 1. ALLOSTERIC REGULATION
Glycogen synthesis increase when substrate
availability and energy (ATP) levels high.
Glycogen breakdown increase when glucose conc.
and energy level low
In well-fed state glucose-6-phosphate availability
high which activates glycogen synthase and inhibits
glycogen phosphorylase.
Also free glucose and ATP inhibits glycogen
phosphorylase.
28. 2. HORMONAL REGULATION
Hormones bring covalent modification, phosphorylation
and dephosphorylation of enzyme proteins, thus control
glycogen synthesis and degradation.
Hormones epinephrine and nor-epinephrine, and
glucagon activate adenylate cyclase and increase
production of cAMP.
Enzyme phosphodiesterase breaks down cAMP.
Hormone insulin increase phosphodiesterase activity in
liver
29. CLINICAL SIGNIFICANCE
Glycogen storage diseases
"Glycogen storage disease" is a generic term to
describe a group of inherited disorders
characterized by deposition of an abnormal type or
quantity of glycogen in tissues, or failure to mobilize
glycogen.
32. QUESTIONS
Q1. What is Glycogenesis? Describe briefly the
metabolic pathway involved in glycogenesis.
Q2. Describe the regulation of glycogenesis,
glycogenolysis?
Q3. Short Notes on-
a) Glycogen storage disease
b) Glycogenesis
c) Glycogenolysis