Glycogen metabolism is regulated by hormones through reciprocal control of glycogen breakdown and synthesis. The key enzymes involved are glycogen phosphorylase, which degrades glycogen, and glycogen synthase, which synthesizes glycogen. Epinephrine and glucagon activate phosphorylase through cAMP signaling, while insulin activates protein phosphatase 1, inactivating phosphorylase and activating synthase to stimulate glycogen synthesis. Liver glycogen phosphorylase is directly regulated by glucose levels, sensing glucose to control glycogen breakdown and maintain blood glucose homeostasis.
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*images use in this ppt is only for educational purpose
In this presentation, i tell about substrate level phosphorylation
Phosphorylation involves the transfer of phosphate
group from one compound to other.
➢ Substrate level phosphorylation is a direct
phosphorylation of ADP with a phosphatase group by
using the energy obtain from a coupled reaction.
➢ Occurs in cytoplasm ( glycolysis – due to aerobic and
anaerobic condition) and in mitochondrial matrix ( krebs
cycle – anaerobic condition)
Metabolism of glycogen and its clinical significance final.pptxrohini sane
A comprehensive presentation on Metabolism of Glycogen and its clinical significance MBBS , BDS, B Pharm & Biotechnology students to facilitate self- study.
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- Energetics of gluconeogenesis
-Substrates of gluconeogenesis (each substrate and pathway explained)
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Substrate level phosphorylation and it's mechanism || Biochemistry || B Pharmacy || Project || slideshare || biology || chemistry
*images use in this ppt is only for educational purpose
In this presentation, i tell about substrate level phosphorylation
Phosphorylation involves the transfer of phosphate
group from one compound to other.
➢ Substrate level phosphorylation is a direct
phosphorylation of ADP with a phosphatase group by
using the energy obtain from a coupled reaction.
➢ Occurs in cytoplasm ( glycolysis – due to aerobic and
anaerobic condition) and in mitochondrial matrix ( krebs
cycle – anaerobic condition)
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The glucuronic acid pathway is a quantitatively minor route of glucose metabolism. Like the pentose phosphate pathway, it provides biosynthetic precursors and inter-converts some less common sugars to ones that can be metabolized.
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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.
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2. Glycogen Metabolism
OUTLINE
• Glycogen breakdown requires the interplay of several enzymes
• Phosphorylase is regulated by allosteric interactions and reversible
phosphorylation
• Epinephrine and glucagon signal the need for glycogen breakdown
• Glycogen is synthesized and degraded by different pathways
• Glycogen breakdown and synthesis are reciprocally regulated
Glycogen synthesis: glycogenesis
Degradation of glycogen: glycogenolysis.
3. Glycogen
Glycogen is a highly branched, very large polymer of
glyc mols linked 1 4
Branches arise by 1 6 at about every 8-10th residue
It is found in the cytosol.
It is the storage form of Glc.
Liver and muscle are the major sites for the storage of
glycogen.
10. Degradation of Glycogen
Is not a simple reversal of the synthetic pathway
Other enzymes involved
Glycogen G-1-P
Shortening of chains:
– Glycogen phosphorylase ( -1 4)
– It is an exoglucosidase
– Degrades the gly. chains at their non-reducing ends
until four glucosyl units remain on each chain before
the branch point
– The resulting structure a limit dextrin
– Phosphorylase cannot degrade this any further!
11. Degradation of Glycogen continued
Removal of branches:
Branches are removed through two enzymatic activities
of the debranching enzyme
a. Glucosyl 4:4 transferase removes the outer 3 of 4 glucosyl
residues
b. Single glucose residue attached in an 16 linkage is then
removed by the -amylo (1:6) glucosidase activity of the
debranching enzyme, releasing free glucose
12.
13.
14.
15.
16. Regulation phosphorylase
Regulation of glycogen metabolism is different in muscle
and liver.
In muscle, the end served by glycolysis is ATP
production and the rate of glycolysis increases as
muscle works more, demanding more ATP.
The liver has a different role in whole-body metabolism
and glucose metabolism in the liver is different. The
liver makes sure that glucose level is constant in the
blood, producing and exporting Glc.
17. Regulation of Glycogen Breakdown
Glycogen represents the most immediately available large-scale
source of metabolic energy. Therefore, it is important that
animals be able to activate glycogen mobilization very rapidly.
Glycogen breakdown is an hormone-controlled process.
Structure of glycogen phosphorylase:
Dimer; exists in two forms.
– Active phosphorylase a
– Inactive phosphorylase b
Activation by phosphorylase kinase
Deactivation phosphorylase phosphatase
Control of phosphorylase activity:
Phosphorylase kinase is activated by c-AMP protein kinase
18. Muscle phosphorylase
In muscle, phosphorylase has 2 forms.
1. Phosphorylase a:
– active form
– 2 subunits, in each Ser residue at position 14 is Plated (Phosphorylase kinase
does this)
2. Phosphorylase b:
– inactive form
– in resting muscle, all enzyme is its inactive form
– structurally identical except that Ser residues are not Plated. It is active when
AMP is high! It is inactive when ATP and Glc 6-P are high! So, muscle
phosphorylase b is active only when the energy charge of the muscle is low.
The rate of glycogen breakdown is due to the a/b which is controlled by
hormones especially by epinephrine.
Phosphorylase a phosphorylase b by dephosphorylation catalyzed by
phosphorylase a phosphatase.
26. Muscle phosphorylase regulation
Both phosphorylase b and phosphorylase a exist
as equilibria between an active R state and a less
active T state.
Phosphorylase b is usually inactive because the
equilibrium favors the T state.
Phosphorylase a is usually active because the
equilibrium favors the R state.
27.
28. AMP dependency of phosphorylase b
Phosphorylase a is AMP-independent
Phosphorylase b is AMP-dependent.
– The stimulation of phosphorylase b by AMP can be prevented by
high ATP concentrations.
AMP binds its allosteric site and stabilizes the conformation of
phosphyrylase b in the R state.
ATP acts as a negative allosteric modulator by competing with AMP
and so favors the T state.
Intensive exercise AMP/ATP goes up, Phosphorylase b (active)
In resting muscle AMP/ATP goes down, Phosphorylase b (inactive)
Exercise will also result in hormone release (epinephrine)
that generates the phosphorylated a form of the enzyme.
29.
30. Liver phosphorylase
Liver phosphorylase and muscle phosphorylase are 90%
identical in amino acid sequence.
Liver phosphorylase a, but not b, has the most responsive
T-to-R transition.
The binding of Glc shifts the allosteric equilibrium of the
a form from the R to the T state, deactivating the enzyme.
Why would Glc function as a negative regulator of liver
phosphorylase a?
– When there is plenty of Glc, no need to breakdown liver
glycogen!
31. Liver Glycogen phosphorylase
is regulated by hormones and blood glucose.
Liver glycogen has a different role in our system.
– When blood glucose is low (lower than 4-5 mM)
Glycogen Glc-1-P Glc-6-P Glc
– So, when blood glucose is low, glucose is released into the blood
stream and carried to the needy tissues.
Glycogen phosphorylase of liver is under hormonal control.
– Glucagon is the hormone.
– When glucose is low, glucagon is released.
– Liver phosphorylase is allosterically regulated by Glc not AMP.
• When Glc is high in the blood, it enters hepatocytes and binds regulatory
sites of the enzyme, causing conformational changes (favoring the T
state).
• Therefore, glycogen phosphorylase is a glucose sensor.
• When Glc is high, it stops its own FORMATION.
32.
33. Phosphorylase kinase
is activated by phosphorylation and calcium ions
The phosphorylase enzyme.
Has a fully active form and an inactive form
Has a mass of 1200 kd
Consist of 4 subunits ( )
– The subunit is the source of catalytic activity.
– The other subunits are regulatory subunits.
Is under dual control
1. Regulated by phosphorylation
– The subunit is phosphorylated by cAMP dependent PKA).
2. Partly activated by calcium levels of the order of 1 mM.
– The subunit is calmodulin, a calsium sensor that stimulates many
enzymes.
Phosphorylase kinase has the highest activity only after both the
phosphorylation of the subunit and the activation of the subunit by
Ca binding.
34.
35. Epi and Glucagon signal the need for glycogen
breakdown
PKA activates phosphorylase kinase
Glycogen phosphorylase activated
Glc 1-P is made
What activates PKA?
– HORMONES
• Glucagon
• Epinephrine
Signal transduction
– Epi
– GTP-bound G proteins
– Increased cAMP
– PKA increases
cAMP amplifies the effects of hormones
36.
37.
38.
39.
40. What shuts off glycogen breakdown?
This signal transduction pathway is shut down
by the same pathway.
How?
• GTP is deactivated by its inherent GTPase
activity
• cAMP is converted to AMP (not a second
messenger) by phosphodiesterase enzyme.
41. Steps in Glycogen Synthesis
A. UDPG synthesis:
G-6-P G-1-P
G-1-P + UTP UDPG + PPi
B. A primer is required for glycogen synthesis:
1. A fragment of glycogen can serve as a primer in cells whose
glycogen stores are not totally depleted.
2. If a glycogen fragment is not present, glycogenin, a
glycosyltransferase, serves as the primer.
42. Steps in Glycogen Synthesis continued
C. Elongation of glycogen chains
– Glucose is transferred from UDPG to the non-reducing end of the
growing chain.
• New glycosidic bond between C-1 of the activated sugar and C-4 of the
accepting glucosyl residue
• Enzyme: glycogen synthase
– If no other enzyme acts on the chain, the resulting structure is a linear
molecule of glucosyl residues attached by 1-4.
• Such a compound, called amylose, is found in fruits.
– The UDP released when the new bond is made can be convert back.
UDP + ATP UTP + ADP
43. Steps in Glycogen Synthesis continued
D. Creating branches in glycogen:
– Amylose unbranched
Glygogen branches (~8)
The branches are made through the “branching enzyme”, glucosyl 4:6
transferase (amylo 1, 4 - 1,6 transglycosylase
– This enzyme transfers 5 to 8 glucosyl residues from the non-
reducing end to another residue by an 1,6 link.
– Further elongation
– Branches have two important functions
a) increases the solubility of the glycogen molecule.
b) The number of non-reducing ends to which new glucosyl residues can
be added and thereby greatly accelerating the rate at which glycongen
synthesis and degradation can occur.
51. Summary of the synthesis
UDP-Glucose synthesis UDP-glucose phosphorylase
A primer is required for glycogen synthesis (glycogenin or
a fragment of glycogen)
Glc units are added to the either the existing glycogen
chains or glycogenin (enzyme glycogen synthase).
• C-4 is the non-reducing end of glycogen chain. New glucose
molecules are always added to this non-reducing terminus.
Elongation of glucose chains
Creating branches in glycogen (enzyme transferase)
Branches have 2 functions:
1. Increase the solubility of the glycogen molecule
2. Increase the rate of glycogen synthesis
52. How Is Glycogen Synthesis Regulated?
Glucagon and Epi promote glycogenolysis, at the same
time they inhibit glycogen synthesis.
– Both effects are mediated by cAMP and cAMP dependent
protein kinase.
– Regulated enzyme: glycogen synthase
• a form: active (not phosphorylated)
• b form: inactive (phosphorylated)
• PKA and other kinases phosphorylate the enzyme.
– Protein kinase (Ser – phosphorylated)
Steps after the binding of the hormones:
– Epi liver cell recep.
– Adenylate cyclase activity
– cAMP
– cAMP Pkinase which phosphorylates and inactivates
glycogen synthase
53.
54. Coordinate Control of Glycogen Breakdown and Synthesis by cAMP Cascades
Glycogen degradation
Glycogen synthesis
Inactive forms are shown in red, active forms are shown in green.
55. Glycogen
degradation
Inactive forms are shown in red,
active forms are shown in green.
56. Glycogen
synthesis
Inactive forms are shown in red,
active forms are shown in green.
57. Breakdown and synthesis are reciprocally
regulated
Hormone -triggered cAMP cascade acting through PKA
Glycogen breakdown and synthesis are reciprocally
regulated.
• Phosphorylase kinase also inactivates glycogen synthase.
PP1(protein phosphatase 1) reverses the regulatory effects
of glycogen metabolism.
– PKA action is reversed by phosphatases
– PP1 inactivates phosphorylase kinase and phosphorylase a by
dephosphorylating these enzymes.
– PP1 also removes P groups from the glycogen synthase b to the
glycogen synthase a form (more active)
58.
59. PP1 has 3 components:
– P1
– Rgl
– I
How is phosphatase activity of PP1 regulated?
– Rgl phosphorylation by PKA prevents its binding to PP1, therefore
activation of cAMP cascade leads to the inactivation of PP1 because
it cannot bind to its substrate.
– Phosphorylation of inhibitor 1 by protein kinase A blocks catalysis
by PP1.
Thus, Epi increases glycogen breakdown by making
phosphorylase a and decreases glycogen synthesis by
making inactive phosphatase.
60.
61.
62. Insulin stimulates glycogen synthesis
by activating protein phosphatase 1
When blood glucose is high, insulin is stimulated.
Activated insulin-sensitive protein kinase makes activated
protein phosphatase
The consequent dephosphorylation of glycogen
synthase, phosphorylase kinase, and phosphorylase
promotes glycogen synthesis and blocks its
degradation!
63.
64.
65. Phosphorylation of the enzymes is regulated
by hormones
Phosphorylated groups can be removed by
phosphatases; therefore, the action of phosphatases
always opposes kinases.
– If kinases activity is greater than activity of phosphatase, the
enzyme is in the phosphorylated mode.
Insulin, Glucagon, and Epi are three important
hormones which affect glycogen metabolism!
66. Glycogen metabolism in the liver
regulates the blood-glucose level
After a carbohydrate-rich meal blood glucose increases.
Insulin is the primary signal for glycogen synthesis.
Blood glucose level 80-120 mg/dL (4.4-6.7 mM)
The liver senses the concentration of blood glucose and
either release or takes up glucose.
Glucose infusion changes the enzymes involved in
glycogen metabolism
67.
68. Glucose regulation of glycogen metabolism
Phosphorylase a is the glucose sensor in liver cells
Glucose is high
Binding of Glc converts R T
PP1 is released
Inactivation of glycogen breakdown and the activation of
glycogen synthesis take place..
70. Summary of the Regulation of
Glycogen Synthesis and Degradation
Synthesis and degradation are regulated by the same
hormonal signals!
An increase in insulin stimulates glycogen synthesis
An increase in glucagon or Epi stimulates glycogen degradation
cAMP production increases in response to the release ofEpi and
glucogon
cAMP production decreases in the presence of insulin!
Key enzymes are phophorylated by a family of kinases,
some of which are cAMP dependent.
Phosphorylation of an enzyme causes 3D change that
affects the active site. It may either increase or decrease
its activity depending on the type of enzyme.
71. Glycogen storage diseases
Glycogen metabolism is a finely controlled system.
– It is not surprising that genetically determined enzyme deficiencies
result in disease state.
– Genetic diseases are in fact valuable research tools for us.
There are 8 glycogen storage diseases but we will only
cover Type I and Type V
– Type I
• Von Gierke Disease
• Glc 6-phosphatase is missing.
– Type V
• McArdle Disease
• Phosphorylase is missing.