Glycogen is the storage form of glucose found in the liver and muscles. It consists of glucose monomers linked together by glycosidic bonds to form a branched polymer. Glycogen serves as a readily available source of glucose through the processes of glycogenolysis and glycogenesis. Glycogenolysis involves the breakdown of glycogen into glucose-1-phosphate through the actions of phosphorylase, phosphoglucomutase, and glucose-6-phosphatase. Glycogenesis is the synthesis of glycogen from glucose-6-phosphate utilizing glycogen synthase and branching enzyme. The activities of these enzymes are regulated by hormonal signals and allosteric effectors to ensure coordinated anabolism and catabol
10. Step 1:Depolymerization
(Release of Glu-1-P)
Enzyme:Phosphorylase
Co Enzyme:Pyridoxal phosphate
Orthophosphate splits between C1 and C4 of adjacent
glucose
Stops 4 units before branching point
11.
12. Step 2: Remodelling &
Debranching
Bifunctional enzyme
Transferase
Alpha-1,6-glucosidase
Release of free glucose residue
Linear Glycogen
13. Step 3:Conversion of
Glu-1-P to Glu-6-P
Enzyme: Phosphoglucomutase
The active site of Mutase has phosphorylated
serine
Glu-1,6-bisP intermediate formed
17. Regulation of
Glycogenolysis
Regulation of enzyme Glycogen Phosphorylase
Hormonal action of Glucagon/Epinephrine
Mechanism is similar in Liver and Muscle
Epinephrine in Muscle
18. Glycogen
Phosphorylase
2 Isozyme Glycogen Phosphorylase a and b
Each exists in R and T state
Dimer with Serine residue
Phosphorylase kinase promotes Phosphorylase
b—>a
21. Regulation of glucose
breakdown in muscles
Low energy state-
1.Epinephrine through Phosphorylase kinase
Phosphorylase b—->a
2.AMP from degradation of ATP as allosteric
activator of Phosphorylase b from T—>R state
Resting state-
1.ATP shift Phophorylase b R—>T state
2.High Glu-6-P favour T state
22. Regulation of glycogen
breakdown in Liver
Liver Phosphorylase sensitive to free Glu
Free Glu binds to active site, causes covalent
modification R—>T state
Low Glu..activate Phosphorylase a
Insulin promotes uptake of Glu and
phosphorylation to Glu-6-P
23. Glucagon signal
pathway
Alpha cells of pancreas secrete Glucagon
Epinephrine by adrenal medulla
Epinephrine bind to alpha adrenergic receptor
Similar cascade of reactions
24.
25. NAMRATA CHHABRA, M.D.
Role of Insulin in Glycogen
degradation
Both Phosphorylase and Phosphorylase kinase are
dephosphorylated and inactivated by protein
phosphatase.
Protein phosphatase is stimulated by Insulin,
Therefore Insulin by inhibiting the activation of
these enzymes inhibits the overall process of
glycogenolysis.
14-Jan-17
27. GLYCOGENESIS
Mainly in Liver and Muscles
Liver Glycogen functions as storage and export of
glucose for maintaining level
Muscle glycogen as readily available source of glucose
36. Initiation
Glycosidic bond between the C1 of the glucose moiety of UDP-
glucose and the hydroxyl oxygen of a tyrosine side-chain of
Glycogenin.
Glucosyl Transferase
UDP is released as a product.
Each subunit of glycogenin catalyzes the addition of eight glucose
units to its partner in the glycogenin dimer.
At this point, glycogen synthase takes over to extend the glycogen
molecule.
37.
38.
39. Elongation
Catalyzed by Glycogen Synthase
New glucosyl units added to nonreducing terminal
residues of glycogen.
Formation of α-1,4-glycosidic linkage.
.
44. NAMRATA CHHABRA, M.D.
Role of Insulin in Glycogenesis
Promotes Glycogenesis
Causes activation of Phosphoprotein Phosphatase
resulting dephosphorylation of Glycogen Synthase
In liver insulin increases the activity of
phosphodiesterase, promoting hydrolysis of cAMP
Insulin thus antagonizes effects of the cAMP
cascade induced by glucagon & epinephrine.
14-Jan-17
46. NAMRATA CHHABRA, M.D.
General mechanisms involved in the
regulation of enzyme activities
Regulation of
enzyme activity
Induction/Repres
sion
Covalent
modification
Allosteric
modification
Substrate/produ
ct concentration
14-Jan-17
47. NAMRATA CHHABRA, M.D.
Key enzymes involved in the regulation
of glycogen metabolism
Glycogen synthase-
For Glycogenesis
Glycogen
Phosphorylase
Both these
enzymes are
reciprocally
regulated.
48. NAMRATA CHHABRA, M.D.
Reciprocal regulation of Enzymes
Glycogen Synthase & Phosphorylase activity are
reciprocally regulated
At the same time as phosphorylase is activated by a rise in
concentration of cAMP (via phosphorylase kinase), glycogen
synthase is converted to the inactive form.
Thus, inhibition of glycogenolysis enhances net glycogenesis,
and inhibition of glycogenesis enhances net glycogenolysis
Both processes do not occur at the same time.14-Jan-17
49.
50. NAMRATA CHHABRA, M.D.
Substrate concentration and allosteric
modification
Substrate Glucose-6-P
Glycogen Synthase is allosterically activated by
glucose-6-P.
High blood glucose concentration leads to
elevated intracellular glucose-6-P.
When glycolytic pathway is saturated, excess
glucose-6-P activates Glycogen synthase
14-Jan-17
51. NAMRATA CHHABRA, M.D.
Covalent modification- General
concepts
Reversible phosphorylation and dephosphorylation
Hormone mediated cAMP mediated cascade
Phosphorylation is mediated by Protein kinase A
Dephosphorylation is carried out by Phosphatase
Insulin causes dephosphorylation by stimulating Phosphatase and
Phosphodiesterase (enzyme that breaks down cAMP)
Glucagon causes phosphorylation by stimulating Protein kinase A14-Jan-17
52. NAMRATA CHHABRA, M.D.
Regulation of glycogen synthase by
covalent modification
Glycogen synthase exists in both phosphorylated or
dephosphorylated states
Active glycogen synthase a is dephosphorylated
and inactive glycogen synthase b is phosphorylated
14-Jan-17
53. NAMRATA CHHABRA, M.D.
Covalent modification of glycogen
synthase
Glycogen synthase
a
Glycogen synthase
b
Phosphatase Protein
kinase A
ATPPi
H2O ADP
Active
Inactive14-Jan-17
p
54. NAMRATA CHHABRA, M.D.
Regulation of Glycogenolysis by
Covalent Modification
The cAMP cascade results in phosphorylation of a serine
hydroxyl of Glycogen Phosphorylase, which promotes
transition to the active state.
The phosphorylated enzyme is less sensitive to allosteric
inhibitors.
Thus, even if cellular ATP and glucose-6-phosphate are
high, Phosphorylase will be active.
14-Jan-17
55. NAMRATA CHHABRA, M.D.
Role of cAMP In Glycogen degradation
cAMP activates cAMP dependent Protein Kinase
Phosphorylation of inactive phosphorylase kinase b to a
Phosphorylation of inactive Glycogen Phosphorylase b to a
In the liver, cAMP is formed in response to glucagon, muscle is
insensitive to glucagon.
In muscle, increased cAMP formation is the action of
norepinephrine
14-Jan-17
56. NAMRATA CHHABRA, M.D.
Role of calcium in muscle degradation
Phosphorylase Kinase is partly
activated by binding of Ca++
Further activation is brought by
phosphorylation.
Phosphorylase Kinase
Dephosphorylated (inactive)
Phosphorylase kinase- Ca++
Partly active
Phosphorylase kinase- Ca++
Phosphorylated- active
Ca++
ATP
14-Jan-17
Glycogen granules range in diameter of 20-40nm
Glycogenin, a primer molecule for Glycogen synthesis
Branching provides high no. of sites both for synthesis and degradation of glycogen
It also increases solubility in cytoplasm
Significance of glycogenolysis
Advantages of phosphorylatic cleavage..1.Released sugar is already phosphorylated so it need not be phosphorylated at expense of ATP 2.GluP cant cross Plasma membrane
Phosphory group of serine is transferred to Glu-1-P to form intermediate of Glu-1,6-BisP
C-1 Phosphoryl group of the intermediate is shuttled to same serine residue thus enzyme is regenerated
As fuel for aerobic and anaerobic metabolism as in Muscles
As free Glu to blood maintaining blood sugar level
Into PPP to generate NADPH, Ribose sugar..
Phosphorylase a is phosphorylated form.
R state…active site is available
b isoform predominantly exist in T state
phosphoryl attaches to serine residue
gamma subunit…catalytic site, others are regulatory
delta subunit are calmodulin protein
During muscle contraction, release of Ca ions
Glucagon has no effect
for maintaining glucose level in blood
Glu-6-P inhibit Phosphorylase a
Fate of Glucose 6 P…1.Glycolysis 2.HMP 3.Glycogen synthesis