This powerpoint gives detailed description and clear view about Glycogenesis and glycogenolysis . these two metabolic actions are very important for regulating blood glucose levels. it also explains about the glycogen storage
2. WHAT IS GLYCOGEN ?
Storage glucan in animals- glycogen
Branching occurs after 8 to 14 residues differing from
amylopectin of plants.
Present in cytoplasmic granules having 100-400 consisting of
12,000 glucose units
These granules endorse enzymes for glycogen synthesis and
degradation along with enzymes for regulation.
They have non- reducing ends which facilitates easy release
of glucose for utilization.
Liver and Muscle are the major storage organ for glycogen.
4. WHY GLYCOGEN IS ENERGY STORAGE
RATHER THAN FAT ?
Although fat is present abundantly and serves
the similar purpose of glycogen our body is
metabollically tuned to make glycogen for energy
storage , due to 3 reasons:-
Muscles cannot mobilize fat as rapidly as they can
glycogen.
The fatty acid residues of fat cannot be
metabolized anaerobically .
Animals cannot convert fatty acids to glucose so
fat metabolism alone cannot adequately maintain
essential blood glucose levels.
5. GLYCOGENESIS
Glycogen is synthesized from molecules of α-D-glucose. The
process occurs in the cytosol, and requires energy supplied
by ATP (for the phosphorylation of glucose) and uridine
triphosphate (UTP).
It occurs in 4 STEPS :
1. ACTIVATION- SYNTHESIS
OF UDP GLUCOSE
2. INITIATION- SYNTHESIS OF
PRIMER TO INITIATE
GLYCOGEN SYNTHESIS
3. ELONGATION-
ELONGATION OF GLYCOGEN
CHAINS
BRANCHING OF GLYCOGEN
GLYCOGENESIS
6. STEP 1 – SYNTHESIS OF UDP
GLUCOSE
In this process the Glucose -6-phosphate gets
converted to Glucose -1-phosphate which is
catalysed by phosphoglucomutase .
From this glucose -1-phosphate and with UTP ,
UDP-Glucose is synthesized catalysed by UDP-
glucose pyrophosphorylase
The reaction takes place in the controlled path by
the high energy pyrophosphate bond (PPi) , the
second product of the reaction.
Cleavage of PPi is the only energy cost for
glycogen synthesis (one ~P bond per glucose
residue).
7. STEP 2- SYNTHESIS OF PRIMER AND
INITIATIATION
The enzyme employed in this process is glycogen
synthase. It is responsible for making
α(1→4)linkages in glycogen.
This enzymes cannot directly act on the UDP-
glucose and thus a primer is required to initiate its
synthesis.
A fragment of glycogen serves this purpose,which
is not depleted known as glycogenin. This acts as
acceptor of glucosyl residues from UDP-glucose .
This performs the priming function . It is a protein
composed of two identical 37-kd subunits, each
bearing an oligosaccharide of α -1,4-glucose
8. STEP 3- ELONGATION OF THE GLYCOGEN
CHAINS.
This process involves transfer of UDP-glucose to
non-reducing end of growing chain.
A new glycosidic bond is formed between anomeric
hydroxyl of carbon1 of the activated glucose and
carbon 4 of accepting glucosyl residue
The enzyme responsible for this process is
glycogen synthase.
The UDP released is converted to UTP by
nucleoside diphosphate kinase enzyme
[UDP + ATP → UTP + ADP]
Glycogen synthase enzyme has the primary
function.
9. STEP 4- BRANCHING OF GLYCOGEN
Branches are made by the action of branching
enzyme or else they are known as amylopectin
compounds of plant energy storage.
The branching enzyme amylo-α(1→4) → α(1→6)-
transglucosidase removes a chain of six to eight
glucosyl residues , breaking an α(1→4) bond to
another residue on the chain, and attaches it to a
non-terminal glucosyl residue by an α(1→6)
linkage . So they are referred as 4:6 transferases.
A branch is created by the breaking of an α-1,4 link
and the formation of an α-1,6 link.
10. STEP 4- BRANCHING OF GLYCOGEN
When the chain is lengthened to 11–12 glucose
residues, the branching enzyme will transfer block
of 6 to 8 glucose residues from this chain to another
site on the growing molecule. The enzyme amylo-
[1, 4]→[1, 6]-transglucosidase (branching
enzyme) forms this alpha-1, 6 linkage.
To this newly created branch, further glucose units
can be added in alpha-1, 4 linkage by glycogen
synthase.
11.
12. GLYCOGENOLYSIS - INTRODUCTION
The degradative pathway that mobilizes stored
glycogen in liver and skeletal muscle is not a
reversal of the synthetic reactions.
Instead, a separate set of cytosolic enzymes is
required. When glycogen is degraded, the primary
product is glucose 1-phosphate, obtained by
breaking α(1→4) glycosidic bonds. In addition, free
glucose is released from each α(1→6)-linked
glucosyl residue.
13. STEP 1- SHORTENING OF CHAINS
Glycogen phosphorylase removes glucose as
glucose- 1-phosphate from glycogen . The alpha-1,
4 linkages in the glycogen are cleaved.
It removes glucose units one at a time. Enzyme
sequentially hydrolyzes alpha-1, 4 glycosidic
linkages, till it reaches a glucose residue, 3–4
glucose units away from a branch point It cannot
attack the 1,6 linkage at branch point.
If glycogen phosphorylase alone acts on a
glycogen molecule, the final product is a highly
branched molecule; it is called limit dextrin.
15. STEP 2- DEBRANCHING
Branches are removed by the two enzymatic activities of
a single bifunctional protein, the debranching enzyme.
Now the branch point is free. Then alpha-1, 6-
glucosidase (debranching enzyme) can hydrolyze
the remaining glucose unit held in alpha-1, 6 linkage at
the branch point .
This glucose residue is released as free glucose. At
this stage, the ratio of glucose-1-phosphate to free
glucose is about 8:1.
The transferase and alpha-1, 6-glucosidase will
together convert the branch point to a linear one.
With the removal of the branch point, phosphorylase
enzyme can proceed with its action.
16. STEP 3 -CONVERSION OF GLUCOSE 1-
PHOSPHATE TO GLUCOSE 6-PHOSPHATE
Glucose 1-phosphate, produced by glycogen
phosphorylase, is converted in the cytosol to glucose 6-
phosphate by phosphogluco-mutase—a reaction that
produces glucose 1,6-bisphosphate as a temporary but
essential intermediate
In the liver, glucose 6-phosphate is transported into the
endoplasmic reticulum (ER) by glucose 6-phosphate
translocase.
There it is converted to glucose by glucose 6-
phosphatase—the same enzyme used in the last step of
gluconeogenesis.
The glucose then moves from the ER to the cytosol.
Hepatocytes release glycogen-derived glucose into the
blood to maintain blood glucose levels until the
gluconeogenic pathway is actively producing glucose.
17. FATE OF G-6-P.
The fate of glucose 6-phosphate depends on the tissue.
The liver, kidney and intestine contain the enzyme
glucose 6-phosphatase that cleaves glucose 6-
phosphate to glucose.
This enzyme is absent in muscle and brain, hence free
glucose cannot be produced from glucose 6-phosphate
in these tissues. Therefore, liver is the major glycogen
storage organ to provide glucose into the circulation to
be utilised by various tissues.
In the peripheral tissues, glucose 6-phosphate produced
by glycogenolysis will be used for glycolysis. It may be
noted that though glucose 6-phosphatase is absent in
muscle, some amount of free glucose (8-10% of
glycogen) is produced in glycogenolysis due to the
action of debranching enzyme.
18.
19.
20. REGULATION OF GLYCOGENESIS AND
GLYCOGENOLYSIS.
A good coordination and regulation ofglycogen
synthesis and its degradation are essential to
maintain the blood glucose levels.
Glycogenesis and glycogenolysis are, respectively,
controlled by the enzymes glycogen synthase and
glycogen phosphorylase.
Regulation of these enzymes is accomplished by
three mechanisms:-
1)Allosteric regulation
2)Hormonal regulation
3)Influence of calcium
21. 1. ALLOSTERIC REGULATION
There are certain metabolites that allosterically regulate the
activities of glycogen synthase and glycogen phosphorylase.
The control is carried out in such a way that glycogen
synthesis is increased when substrate availability and energy
levels are high.
On the other hand, glycogen breakdown is enhanced when
glucose concentration and energy levels are low.
In a well-fed state, the availability of glucose 6-phosphate is
high which allosterically activates glycogen synthase for more
glycogen synthesis.
On the other hand, glucose 6-phosphate and ATP
allosterically inhibit glycogen phosphorylase.
Free glucose in liver also acts as an allosteric inhibitor of
glycogen phosphorylase.
22. 2. HORMONAL REGULATION
The hormones, through a complex series of
reactions, bring about covalent modification,
namely phosphorylation and dephosphorylation of
enzyme proteins which, ultimately control glycogen
synthesis or its degradation.
cAMP as secondary messenger for hormones:
Hormones like epinephrine and norepinephrine,
and glucagon (in liver) activate adenylate cyclase to
increase the production of cAMP. The enzyme
phosphodiesterase breaks down cAMP. The
hormone insulin increases the phosphodiesterase
activity in liver and lowers the cAMP levels.
23. REGULATION OF GLYCOGENESIS.
The glycogenesis is regulated by glycogen synthase. This
enzyme exists in two forms— glycogen synthase ‘a’—which is
not phosphorylated and most active, and secondly, glycogen
synthase ‘b’ as phosphorylated inactive form.
Glycogen synthase ‘a’ can be converted to ‘b’ form (inactive)
by phsophorylation.
The degree of phosphorylation is proportional to the inactive
state of enzyme.
The process of phosphorylation is catalysed by a cAMP
dependent protein kinase.
The protein kinase phosphorylates and inactivates glycogen
synthase by converting ‘a’ form to ‘b’ form.
The glycogen synthase ‘b’ can be converted back to synthase
‘a’ by protein phosphatase I.
24.
25. REGULATION OF GLYCOGENOLYSIS
The hormones like epinephrine and glucagon bring about
glycogenolysis by their action on glycogen phosphorylase
through cAMP .
Glycogen phosphorylase exists in two forms, an active ‘a’ form
and inactive form ‘b’.
The cAMP—formed due to hormonal stimulus—activates cAMP
dependent protein kinase. This active protein kinase
phosphorylates inactive form of glycogen phsophorylase kinase
to active form. (The enzyme protein phosphatase removes
phosphate and inactivates phosphorylase kinase).
The active phosphorylase kinase phosphorylates inactive
glycogen phosphorylase ‘b’ to active glycogen phosphorylase ‘a’
which degrades glycogen.
The enzyme protein phosphatase I can dephosphorylate and
convert active glycogen phosphorylase ‘a’ to inactive ‘b’ form.
26.
27. 3. INFLUENCE OF CALCIUM
When the muscle contracts, Ca2+ ions are released
from the sarcoplasmic reticulum. Ca2+ binds to
calmodulin-calcium modulating protein and
directly activates phosphorylase kinase without the
involvement of cAMP-dependent protein kinase.
The overall effect of hormones on glycogen
metabolism is that an elevated glucagon or
epinephrine level increases glycogen degradation
whereas an elevated insulin results in increased
glycogen synthesis.
28. GLYCOGEN STORAGE DISEASES.
These are a group of genetic diseases that result from a
defect in an enzyme required for glycogen synthesis or
degradation.
They result either in formation of glycogen that has an
abnormal structure, or in the accumulation of excessive
amounts of normal glycogen in specific tissues as a
result of impaired degradation.
A particular enzyme may be defective in a single tissue,
such as liver (resulting in hypoglycemia) or muscle
(muscle weakness), or the defect may be more
generalized, affecting liver, muscle, kidney, intestine,
and myocardium.
The severity of the glycogen storage diseases (GSDs)
ranges from fatal in infancy to mild disorders that are not
life-threatening.
29.
30. REFERENCES
Lippincotts_Illustrated_Reviews_Biochemistry 5th
edition
Biochemistry by Dr. U. Satyanarayana
Textbook of Biochemistry 7th edition by D.M.
Vasudevan
Biochemistry 8th edition by Jeremy M. Berg John
L. Tymoczko Gregory J. Gatto, Jr. Lubert Stryer
Biochemistry 4th edition by DONALD VOET
JUDITH G. VOET.
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