2. Glycogen
• Glycogen is the major storage
carbohydrate in animals
• It is a rapidly mobilizable form of glucose
storage
• Glycogen guarantees a quick supply of
glucose to the body in response to falling
blood glucose levels
3. Glycogen
• The main stores of glycogen in the body
are found in skeletal muscle and the liver
• Glycogen makes up to 10% of the fresh
weight of a well fed adult liver and 1-2% of
the fresh weight of a resting muscle.
4. Glycogen
• It is a highly branched polymer of α-D-
glucose
• Linked linearly by (1→4) glycosidic
linkages with numerous (1→6) linkages
at branch points
• The molecules of glycogen exists in
discrete cytoplasmic granules that
contain most of enzymes necessary for
glycogen synthesis and degradation
5. Glycogen
• Glycogen is stored in large cytosolic granules
• The elementary (single) particle of glycogen,
the β-particle, about 21 nm (10-40nm) in
diameter, consists of up to 55,000 glucose
residues with about 2,000 non-reducing ends
• Twenty to 40 of these particles cluster together
to form α-rosettes, especially in hepatocytes
6. Glycogen
• Muscle glycogen is a source of glucose for the
muscle itself. This is because muscle cells lack
the glucose-6-phosphatase enzyme needed for
liberating glucose from G-6-P
• Liver glycogen can be used to produce free
glucose for export to blood to maintain blood
glucose level between meals
• After 12-18 hrs of fasting liver glycogen is
almost totally depleted
9. Glycogenesis
• Glycogen synthesis occurs in the cytoplasm,
and requires a supply of ATP and uridine
triphosphate (UTP)
•
• Glucose is phosphorylated to G-6-P
• Glucose + ATP G-6-P by hexokinase in the
muscle and glucokinase in the liver
• G-6-P is isomerized to G-1-P by
phosphoglucomutase
10. Glycogenesis cont…
• G-1-P reacts with uridine triphosphate (UTP) to
form UDP-glucose
• UDP-glucose is the source of glucosyl residues
that are added to the growing glycogen
molecule
– UDP-glucose is the substrate of glycogen synthase
• G-1-P +UTP → UDP-Glucose + PPi
11. Glycogenesis cont…
• Synthesis of UDP-Glc is catalysed by enzyme:
UDP-glucose pyrophosphorylase
• The high energy pyrophosphate (PPi) group is
hydrolyzed to two inorganic phosphates (2Pi)
ΔG=-25kJ/mol
• Pyrophosphatase catalyses this reaction to
release 2moles of inorganic phosphate and this
helps to drive the previous reaction forward
12. Glycogenesis cont…
• Glucose residues are added to glycogen at the
non-reducing ends of the branched glycogen
molecule
• UDP is released as a reaction product
• Glycogen synthase is responsible for
polymerization of glucose residues into the
glycogen polymer
• It catalyzes transfer of the glucose from UDP-
glucose to the hydroxyl at C4 of the terminal
residue (non-reducing end) of a glycogen chain
13. Glycogenesis cont…
• This forms an (1→4) glycosidic linkage
• The enzyme cannot initiate a glucose chain
synthesis using free glucose as an acceptor of
a molecule of glucose from UDP-glucose
• An (1→4) glucose chain primer having at
least four glucose residues must be present for
the enzyme to work
• A fragment of glycogen remaining in a cell can
serve as a primer in cells whose glycogen
stores are not completely depleted.
14. Glycogenesis cont…
• In the absence of glycogen fragment, to act as
a primer
• The primer is usually formed on and by the
protein gycogenin
• Glycogenin acts as a glucose acceptor and
catalyzes the transfer of the first few (7)
glucose residues from UDP-glucose
• Glycogenin stays associated with and is found
in the center of the completed molecule of
glycogen
15. Glycogenesis cont…
• At this point glycogen synthase takes over,
further extending the glycogen chain
• Glycogen synthase can not catalyze the
branching that is seen in glycogen molecules
because it can not make the (α1→6) bond
found at branch points
• Branching is done by the glycogen-branching
enzyme.
– also called amylo (1→4) to (1→6)
transglycosylase or glycosyl-(4→6)-transferase
16. Glycogenesis cont…
• The branching enzyme catalyses the transfer of
a terminal fragment of about 6-8 glucose
residues from the non reducing end of a
glycogen branch having atleast 11 residues
• The enzyme will attach it to the OH group of C-
6 at a more interior position on the same
chain it was broken off from or at a different
chain
• This fragment will constitute the initial chain of a
new branch
17. Glycogenesis cont…
• Then elongation continues at the non reducing
ends of the old and new branches
• Elongation and branching continues throughout
the macromolecule as described above
increasing its size.
18. Glycogenesis cont…
• The extensive branching makes the molecule
more soluble and increases the number of non
reducing ends
• Thus branching increase the number of sites
accessible to glycogen synthase and glycogen
phosphorylase both of which act only on non
reducing ends
19. Glycogenolysis
• Glycogen breakdown is catalyzed by glycogen
phosphorylase
• The glycogenolytic pathway cleaves off residues of
glucose, one by one, from the outer branches of
glycogen, i.e the non reducing ends
• The enzymes involved are: glycogen
phoshorylase which catalyzes a phosphorolysis
reaction through which the glucose residues in an
(α1→4) linkage are cleaved as glucose-1-
phosphate.
21. Glycogenolysis cont…
• In phosphorolysis reaction some of the energy
released when the glycosidic bond is broken is
conserved in the bond between phosphate and
glucose in the G-1-P molecule that is formed
• Glycogen phosphorylase acts repetitively on the
non reducing ends of glycogen branches until it
reaches a point four glucose residues away from
an (α1→6) branch point where its action stops.
• At this point the second enzyme of glycogenolysis
takes over. This is the debranching enzyme
– Also called oligo (α1→6) to (α1→4) glucantransferase
22. Glycogenolysis cont…
• The debranching enzyme catalyzes two
successive reactions
• A fragment of 3 residues out of the 4 glucose
residues remaining on the branch is hydrolysed
off and reattached at the main chain in an
(α1→4) linkage
23. Glycogenolysis cont…
• The remaining glucosyl residue at the
branching point in an (α1→6) linkage with the
main chain is hydrolysed and released as free
glucose
• After the debranching enzyme has done this,
glycogen phosphorylase activity can continues
until the next branching point is approached.
24. Glycogenolysis cont…
• The produced G-1-P is acted upon by a
third enzyme, the phosphoglucomutase
which isomerizes G-1-P to G-6-P
• The G-6-P can enter glycolysis, in case of
glycogenolysis in muscle cells or be used
for other functions in the same tissue
25. Glycogenolysis cont…
• In the liver cells G-6-P can be converted
to free glucose by glucose-6-phosphatase,
an enzyme found only in the endoplasmic
reticulum of the cells of the liver and
kidney cortex
• This glucose can then be transported into
the blood to maintain blood glucose levels
and supply tissues that preferentially or
exclusively oxidize glucose for energy
26. Regulation of glycogen metabolism
• The synthase and phosphorylase are
reciprocally regulated
• The enzymes are regulated both allosterically
and by covalent modification (hormonal control)
• The synthesis and degradation enzymes can
exist in an active or inactive form
– Phosphorylase b (dephosphorylated)(inactive) and
Phosphorylase a (phosphorylated) (active)
– Glycogen synthase a (active form)
(dephosphorylated) and Glycogen synthase b
(inactive form) (phosphorylated)
27.
28.
29. • In Muscle cells
– Ca2+, the signal for muscle contraction, binds to and
activates phosphorylase b kinase, promoting conversion of
phosphorylase b to the active a form
– AMP, which accumulates in vigorously contracting muscle
as a result of ATP breakdown, binds to and activates
phosphorylase, speeding the release of glucose 1-
phosphate from glycogen
– When ATP levels are adequate, ATP blocks the allosteric
site to which AMP binds, inactivating phosphorylase.
– When the muscle returns to rest, a second enzyme,
phosphorylase a phosphatase, also called
phosphoprotein phosphatase 1 (PP1), removes the
phosphoryl groups from phosphorylase a, converting it to the
less active form, phosphorylase b.
30. • In hepatocytes
– When blood glucose levels return to normal,
glucose enters hepatocytes and binds to an
inhibitory allosteric site on phosphorylase a
– This binding also produces a conformational
change that exposes the phosphorylated Ser
residues to PP1, which catalyzes their
dephosphorylation and inactivates the
phosphorylase
31.
32.
33.
34. • Glycogen synthase is also under hormonal mediated
regulation by covalent modification
– Glucagon/epinephrine causing its phosphorylation and
inactivation
– Insulin causing its dephosphorylation and activation
• Allosteric regulation
• In hepatocytes
– Glucose 6-phosphate binds to an allosteric site on
glycogen synthase b, making the enzyme a better
substrate for dephosphorylation by PP1 and
causing its activation
Notas do Editor
It can only elongate already existing chains of glucose.
