Transcript Studing of biosynthesis and catabolism of glycogen. Regulati

Studing of biosynthesis and
catabolism of glycogen. Regulation
of glycogen metabolism.
GLYCOGEN SYNTHESIS AND DEGRADATION
In the well-fed state the glucose after absorption is taken
by liver and deposited as a glycogen
Glycogen is a very large, branched polymer of glucose
residues that can be broken down to yields glucose
molecules when energy is needed
Most glucose residues in glycogen are linked
by a-1,4-glyco-sidic bonds, branches are
created by a-1,6-glycosidic bonds
Glycogen serves as a buffer to maintain blood-glucose level.
Stable blood glucose level is especially important for brain
where it is the only fuel.
The glucose from glycogen is readily mobilized and is
therefore a good source of energy for sudden, strenuous
activity.
Liver (10 % of weight)
and skeletal muscles
(2 %) – two major
sites of glycogen
storage
Glycogen is stored in
cytosolic granules in
muscle and liver cells
of vertebrates
Glucose-6-phosphate is
the central metabolite in
the synthesis and
decomposition of
glycogen.
In the well-fed state
glucose is converted to
glucose-6-phosphate,
which is the precursor
for the glycogen
synthesis.
The glucose-6-phosphate
derived from the
breakdown of glycogen
has three fates: (1)
glycolysis; (2) pentosephosphate pathway; (3)
convertion to free
glucose for transport to
another organs.
DEGRADATION OF GLYCOGEN
Glycogenolysis - degradation of glycogen
The reaction to release glucose from polysaccharide is not
simple hydrolysis as with dietary polysaccharides but
cleavage by inorganic phosphate – phosphorolytic
cleavage
Phosphorolytic cleavage or phosphorolysis is catalyzed
by enzyme glycogen phosphorylase
There are two ends on the molecules of starch or glycogen:
a nonreducing end (the end glucose has free hydroxyl
group on C4) and a reducing end (the end glucose has an
anomeric carbon center (free hydroxyl group on C1)
Glycogen phosphorylase removes glucose residues
from the nonreducing ends of glycogen
Acts only on a-1-4 linkages of glycogen polymer
Product is a-D-glucose 1-phosphate (G1P)
Cleavage of a glucose
residue from the
nonreducing end of
glycogen
Structure of glycogen phosphorylase (GP)
• GP is a dimer of identical
subunits (97kD each)
• Catalytic sites are in clefts
between the two domains of
each subunit
• Binding sites for glycogen,
allosteric effectors and a
phosphorylation site
• Two forms of GP
Phosphorylase a (phosphorylated) active form
Phosphorylase b (dephosphorylated) less active
• GP catalyzes the
sequential removal of
glucose residues from the
nonreducing ends of
glycogen
• GP stops 4 residues from
an a 1-6 branch point
• Tranferase shifts a block
of three residues from
one outer branch to the
other
• A glycogen-debranching
enzyme or 1,6glucosidase hydrolyzes
the 1-6-glycosidic bond
• The products are a free
glucose-1-phosphate
molecule and an elongated
unbranched chain
Metabolism of Glucose 1-Phosphate (G1P)
• Phosphoglucomutase catalyzes the conversion
of G1P to glucose 6-phosphate (G6P)
Glycogen Synthesis
• Synthesis and degradation
of glycogen require
separate enzymatic steps
• Cellular glucose converted
to G6P by hexokinase
• Three separate enzymatic
steps are required to
incorporate one G6P into
glycogen
• Glycogen synthase is the
major regulatory step
Glucose 1-Phosphate formation
• Phosphoglucomutase catalyzes the conversion
of glucose 6-phosphate (G6P) to glucose 1phosphate (G1P).
UDP-glucose is activated
form of glucose.
UDP-glucose is
synthesized from glucose1-phosphate and uridine
triphosphate (UTP) in a
reaction catalized by
UDP-glucose
pyrophosphorylase
Glycogen synthase adds glucose to
the nonreducing end of glycogen
A branching enzyme forms -1,6-linkages
Glycogen synthase
catalyzes only -1,4linkages.
The branching enzyme
is required to form
-1,6-linkages.
Branching is important
because it increases
the solubility of
glycogen.
Branching creates a
large number of
terminal residues, the
sites of action of
glycogen phosphorylase
and synthase.
Regulation of Glycogen Metabolism
• Muscle glycogen is fuel for muscle contraction
• Liver glycogen is mostly converted to glucose
for bloodstream transport to other tissues
• Both mobilization and synthesis of glycogen
are regulated by hormones
• Insulin, glucagon and epinephrine regulate
mammalian glycogen metabolism
Hormones Regulate Glycogen Metabolism
Insulin
• Insulin is produced by b-cells of the pancreas
(high levels are associated with the fed state)
• Insulin increases rate of glucose transport
into muscle, adipose tissue via GluT4
transporter
• Insulin stimulates glycogen synthesis in the
liver via the second messenger
phosphatidylinositol
3,4,5-triphosphate (PIP3)
Glucagon
• Secreted by the a cells of the pancreas in
response to low blood glucose (elevated
glucagon is associated with the fasted state)
• Stimulates glycogen degradation to restore
blood glucose to steady-state levels
• Only liver cells are rich in glucagon receptors
and therefore respond to this hormone
Epinephrine (Adrenalin)
• Released from the adrenal glands in response
to sudden energy requirement (“fight or
flight”)
• Stimulates the breakdown of glycogen to G1P
(which is converted to G6P)
• Increased G6P levels increase both the rate
of glycolysis in muscle and glucose release to
the bloodstream from the liver and muscles
• Both liver and muscle cells have receptors to
epinephrine
Effects of hormones on glycogen metabolism
Reciprocal Regulation of Glycogen
Phosphorylase and Glycogen Synthase
• Glycogen phosphorylase (GP) and glycogen
synthase (GS) control glycogen metabolism in
liver and muscle cells
• GP and GS are reciprocally regulated both
covalently and allosterically (when one is active
the other is inactive)
• Covalent regulation by phosphorylation (-P) and
dephosphorylation (-OH)
• Allosteric regulation by glucose-6-phosphate
(G6P)
Reciprocal Regulation of GP and GS
COVALENT REGULATION
Active form “a”
Glycogen phosphorylase
Glycogen synthase
-P
-OH
Inactive form “b”
-OH
-P
ALLOSTERIC REGULATION by
G6P
GP a (active form) - inhibited by
G6P
Activation of GP and inactivation of GS by
Epinephrine and Glucagone
Activation of GS and inactivation of GP by Insulin