Biosynthesis of Carbohydrates-2

Doç. Dr. İncilay Lay

Tıbbi Biyokimya Anabilim Dalı
 Synthesis of Glycogen
• Glycogen is the storage
polysaccharide in mammals
• It is a more highly branched
structure than amylopectin. Chains
of α-D-glucopyranose residues in
α1→4-glucosidic linkage with
branching by α1→6-glucosidic
Each chain is containing
bonds. 12-14 glucose
• Glycogen occurs mainly in LIVER
(%6) and MUSCLE (%1)
Because of the greater mass of
muscle, Muscle contains about 3
to 4 times as much glycogen as
does liver
 Synthesis of Glycogen: GLYCOGENESIS
• Glycogenesis occurs mainly in LIVER and
SKELETAL MUSCLE
1) The starting point for glycogen synthesis is
glucose 6-phosphate.
• As in glycolysis, glucose is phosphorylated to
glucose 6-phosphate, catalyzed by hexokinase
I and II in muscle and hexokinase IV
(glucokinase) in liver.
2) Glucose 6-phosphate is
converted to glucose 1-
phosphate by
phosphoglucomutase
• The enzyme itself is
phosphorylated, and
the phospho -group
takes part in a
reversible reaction in
which glucose 1,6-
bisphosphate is an
intermediate.
3) Glucose 1-phosphate reacts with uridine triphosphate (UTP)
to form the active nucleotide uridine diphosphate glucose
(UDPGlc) and pyrophosphate by UDPGlc pyrophosphorylase
• Sugar nucleotide
UDP-Glucose donates
glucose for glycogen synthesis
• Sugar nucleotides
are substrates for
glycogenesis

Anomeric C of a sugar is
activated by attachment of
a nucleotide through a
phosphate ester linkage .
• The role of UDP-glucose in glycogenesis:
-Formation of UDP-glucose is metabolically irreversible:
makes the metabolic pathway irreversible. The reaction
releases PPi which is rapidly hydrolyzed by inorganic
pyrophosphatase that is strongly exergonic.
- By tagging glucose with
nucleotide permits
the seperation of this
glucose for
glycogenesis. (glucose
phosphates destined
for other purposes
such as glycolysis)
4) UDP-Glc is immediate donor of glucose in the reaction
catalyzed by glycogen synthase
• Glycogen synthase transfers the glucose residue from
UDP-glucose to a nonreducing end of a branched glycogen
molecule.

α1→4 glucosidic bond

5) Glycogen synthase cannot make the α1→6-
glucosidic bonds which are found at the branch
points of glycogen
• Glycogen-branching enzyme (also called amylo
α1→4 to α1→6 transglycosylase or glycosyl 4
→6-transferase) catalyzes transfer of a terminal
fragment of 6 or 7 glucose from the nonreducing
end of a glycogen branch having at least 11
residues to the C-6 hydroxyl group of a glucose at
a more interior position of the same or another
glycogen chain, thus creating a new branch
Glycogen-branching enzyme catalyzes transfer of a
terminal fragment of 6 or 7 glucose from the nonreducing
end of a glycogen branch having at least 11 residues to
the C-6 hydroxyl group of a glucose at a more interior
position of the same or another glycogen chain, thus
creating a new branch
6) Further glucose residues may be added to the
new branch by glycogen synthase.

• Biological effect of branching

is to make the glycogen
molecule more soluble and to
increase the number of
nonreducing ends: This
increases the number of sites
accessible to glycogen
phosphorylase and glycogen
synthase
 Glycogenin
• Glycogen synthase cannot initiate a new
glycogen chain de novo.
• How is a new glycogen molecule initiated?
• It requires a primer.
• A preexisting glycogen molecule, or “glycogen
primer’’ named: Glycogenin
• 37-kDa protein that is glycosylated on a
specific tyrosine residue by UDPGlc.
• Glycogenin is both the
primer on which new
chains are assembled and
the enzyme that catalyzes
their assembly.
• The first step in the
synthesis of a new
glycogen molecule: the
transfer of a glucose from
UDPGlc to the hydroxyl
group of Tyrosine of
glycogenin
• It is catalyzed by the
protein’s intrinsic
glucosyltransferase activity
• The nascent chain is extended by the
sequential addition of 7 more glucose, each
derived from UDPGlc.
• The reactions are catalyzed by the chain-
extending activity of glycogenin.

• Then, glycogen synthase takes over, further

extending the glycogen chain.
• Glycogenin remains
buried within the
particle, covalently
attached to the
single reducing end
of the glycogen
molecule
 Regulation of Glycogen Synthesis
• Glycogen Synthase is regulated by
Phosphorylation and Dephosphorylation
• Active form of glycogen synthase a, is
unphosphorylated
• Inactive form of glycogen synthase b, is
phosphorylated
• Glycogen synthase is phosphorylated on various
residues by at least 11 different protein kinases
• Most important
regulatory kinase is
glycogen synthase kinase
3 (GSK3), which adds
phosphoryl groups to
glycogen synthase,
strongly inactivating it.
• GSK3 cannot
phosphorylate glycogen
synthase until another
protein kinase, casein
kinase II (CKII), has first
phosphorylated the
glycogen synthase on a
nearby residue, an event
called priming
• In liver, conversion of
glycogen synthase b
to the active form is
promoted by protein
phosphatase 1 (PP1),
which is bound to
the glycogen
particle.
• PP1 removes the
phosphoryl groups
from the glycogen
synthase
• 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
• Insulin activates a protein
kinase (protein kinase B,
or PKB) that in turn
phosphorylates and
inactivates GSK3
• PP1, can remove
phosphoryl groups in
response to insülin

• PP1 is itself subject to

covalent and allosteric
regulation; it is inactivated
when phosphorylated by
PKA and is allosterically
activated by glucose 6-
phosphate.
• After ingestion of a carbohydrate-rich meal, the
elevation of blood glucose triggers insulin
release
• In a hepatocyte, insulin has two immediate
effects: it inactivates GSK3 and activates PP1.
These two actions fully activate glycogen
synthase.
• Under these conditions, hepatocytes use the
excess glucose in the blood to synthesize
glycogen, up to the limit of about 10% of the
total weight of the liver
• The physiology of skeletal muscle differs from that of
liver in three ways
(1) - Muscle uses its stored glycogen only for its own needs;
- Liver uses its stored glycogen for supplying adequate
glucose to blood (mostly important for the brain,
erytrocytes)

(2) as it goes from rest to vigorous contraction, muscle

undergoes very large changes in its demand for ATP,
which is supported by glycolysis;
(3) - Muscle lacks the enzymatic machinery for
gluconeogenesis.
- Gluconeogenesis takes place in liver