Download - 8 glycogen metabolism (6)
Glycogen Metabolism
Glycogenolysis: catabolism of glycogen
Glycogenesis: anabolism or biosynthesis of glycogen
•Glycogen represent a stored form of glucose and energy that is
quickly mobilized by hormones.
• Total glucose in body fluids has an energy content of ~ 40 kcal
•Total body glycogen has an energy content of ~ 600 kcal.
•Stored in liver (5-6%) by weight and muscle (1-2%) by weight.
•Since muscle mass is >> liver mass, quantity of muscle glycogen
is greater.
•Stored in the cytosol in the form of glycogen granules which contain
the enzyme that catalyzed glycogenolysis, glycogenesis, plus
regulatory enzymes.
Structure of Two Outer Branches of a Glycogen Particle
1 44
The C-1 aldehyde in the open-chain form of glucose reacts with the C-5 hydroxyl
group to form an intramolecular hemiacetal resulting in a 6-membered pyranose
ring.
1
2
3
4
5
6
1
6
Reducing Group
δ+
δ-
1 Reducing end
Reducing End: contains a free keto- or aldehyde group in the straight
chain representation of the sugar.
Glycogenolysis
Glycogen phosphorylase: an α-1,4 glycosidic bond linking 2 glucose
residues by inorganic phosphate removing the terminal glucose
residues as glucose 1-phosphate.
•Phosphorylase stops when it reaches a residue that is 4 positions
away from a branch point.
•A glycogen molecule that has been degraded by phosphorylase to the
limit caused by the branches is called a phosphorylase-limit dextrin.
1 4
•α-1,6 glycosidic linkages at the branch points are not degraded by
phosphorylase.
•When phosphorylase reaches a point 4 residues away from a branch
point it stops.
Further degradation occurs via the action of debranching enzyme.
Debranching enzyme is bifunctional (it catalyzes 2 different reactions).
(1) A transferase activity in which a block of 3 glycosyl residues are
transferred from one outer branch to the other.
The result is a longer amylose chain with only one glucosyl remaining
in α-1,6 glycosidic linkage in the other chain.
Debranching
Enzyme
The remaining α-1,6 linkage is hydrolyzed by the second enzymatic
activity of debranching enzyme, namely its α-1,6-glucosidase activity
wherein an α-1,6 glycosidic bond between two residues is hydrolyzed.
Thus, the sum of the transferase and the glucosidase activities of debranching
enzyme convert a branched structure into a linear one.
Net Result: mainly glucose 1-phosphate + some glucose (from the branch points).
Debranching
Enzyme
Debranching
Enzyme***
Phosphoglucomutase: converts glucose 1-phosphate to glucose
6-phosphate via shifting a phosphoryl group.
The glucose 6-phosphate can then enter the metabolic mainstream.
The Fate of Glucose 6-Phosphate
Tissues which have glucose 6-phosphatase
can generate free glucose.
Liver, kidneys, intestine
HAVE THE ENZYMEThe resulting free glucose is then transporter
into the bloodstream thereby providing a
supply of glucose where needed.
Muscle, brain,adipose tissue,
DO NOT HAVE THE ENZYMEThus glucose is effectively trapped within these
cells where it is used as a fuel to generate ATP
via Glycolysis and the Citric Acid Cycle.
muscle
brain
adipose
tissue
liver
kidney
intesine
Regulation of Glycogen Phosphorylase
Regulated by both allosteric effectors and by reversible phosphorylation.
In skeletal muscle the phosphorylase exists in 2 interconvertible forms:
Phosphorylase a: usually active form
Phosphorylase b: usually (but not always) inactive form.
Phosphorylase b can be allosterically activated by AMP.
ATP and glucose 6-phosphate can prevent this activation.
Thus, the b form is usually inactive (because ATP and glucose 6-
phosphate are plentiful).
The b form is active only when the energy charge of the cell is very low.
Allosteric
regulation
Regulation by
phosphorylation
The a form is active regardless of the cell’s energy charge.
At rest, most of the enzyme exists in the b form. During exercise,
elevated AMP activates the b form.
(in response to epinephrine
in muscle cells)
In the liver, allosteric regulation differs in two respects:
First, AMP does not activate the liver phosphorylase b.
Second, liver phosphorylase a is deactivated by glucose.
Thus when blood glucose is sufficiently high to supply other
tissues, and glycogen breakdown is not needed, phosphorylase a
is inhibited.
Glycogen phosphorylase a acts as a glucose sensor in liver,
slowing glycogen breakdown when blood glucose is high.
Superimposed on this regulation, is the fact that phosphorylase kinase
can be regulated by reversible phosphorylation and by Ca2+.
Phosphorylase kinase is activated by
phosphorylation via protein kinase A (PKA).
PKA is turned on by cAMP.
Thus hormones such as glucagon and
epinephrine induce the breakdown of
glycogen in liver and muscle by activating
the cAMP cascade.
Phosphorylase kinase is also activated by
Ca2+.
The enzyme phosphoprotein phosphatase
dephosphorylates and inactivates
both phosphorylase kinase and
phosphorylase converting them from the
a to the b forms.
cAMP decreases the activity of the
phosphatase.
Insulin increases the phosphatase activity.
Activated by
phosphorylation
Activated by
phosphorylation
Inactivated by
dephosphorylation.
Inactivated by
dephosphorylation.
This cascade of reactions results in a tremendous amplification of a hormonal
signal which stimulates liver glycogenolysis in order to increase blood glucose.
For example: 10-9 M epinephrine can result in blood glucose concentration of
5 mM, for ~ 3 million fold amplification.
b a
or Glucagon
Glycogenesis
Glycogen synthesis occurs in virtually all animal tissues, but is most
prominent in the liver and skeletal muscle.
1) The first reaction is catalyzed by hexokinase (or glucokinase in liver):
D-Glucose + ATP D-glucose 6-phosphate + ADP
2) The second reaction is catalyzed by phosphoglucomutase:
Glucose 6 phosphate glucose 1-phosphate
3) UDP-glucose pyrophosphorylase catalyzes the formation of
UDP-glucose which will serve as a glucose donor in subsequent
reactions.
Thus, UDP glucose can be considered as an activated form of glucose.
Glucose 1-phosphate + UTP UDP-glucose + PPi
Glucose donor
PPi is rapidly hydrolyzed to 2 Pi driving the
above reaction to completion.
4) Glycogen synthase catalyzes the transfer of glucose from
UDP-glucose to a growing chain.
Glucosyl units are added to the non-reducing terminal residue of
glycogen (i.e., at the C-4 terminus) to form an α-1,4-glycosidic bond.
•The reaction requires at least 4 residues of glucose as a primer.
•Thus a tetrasaccharide primer is elongated by one residue.
•This process is repeated many times to form a long, unbranched glycogen
molecule.
4 1
Nonreducing
end
1 4
5) Glycogen synthase requires a primer. This priming function is carried
out by glycogenin, a 37 kDa protein to which the first glucose residue is
attached.
Glycogenin acts as a catalyst for synthesis of the nascent glycogen
molecule by attaching a glucose to the hydroxyl group of a specific
tyrosine residue within its structure.
Glycogenin then autocatalyzes the addition of up to 8 glucose units in
α-1,4 glycosidic linkages with UDP-glucose being the glucose donor.
Glycogen synthase then takes over.
6) Branching enzyme forms the α-1,6 linkages that make glycogen a
branched polymer.
Transfers a terminal fragment, 6-7 glucosyl residues in number, from
the non-reducing end of a glycogen branch having at least 11 residues,
to the C-6 hydroxyl group of a glucose residue of the same or another
glycogen chain at a more interior point, thereby creating a branch.
1 2 3 4 5 6 7 8 9 10 11
1
6
Branching: increases the solubility of glycogen (by increasing the number
of hydroxyl groups); AND
increases the rate of glycogen synthesis and degradation by creating a large
number of terminal residues at which the appropriate enzymes can act.
Hormonal Control of Glycogenesis
The activity of glycogen synthase is regulated by BOTH covalent
modification and allosterically.
The active a form of glycogen synthase
is converted to the inactive b form
by phosphorylation via a variety of
kinases.
The synthase is reactivated by
dephosphorylation by phosphoprotein
phosphatase.
Hence the phosphatase accelerates
glycogen synthesis.
Finally, the inactive b form can be
allosterically activated by glucose
6-phosphate.
Phosphorylation
inactivates.
Dephosphorylation
activates.
ActiveInactive
Cooridinated Regulation of Glycogen Synthesis/ Breakdown
Low blood glucose:
glucagon, insulin, PKA,
phosphorylase kinase
glycogen phosphorylase
glycogen synthase
glycogen breakdown, synthesis
High blood glucose:
insulin, glucagon,
phosphoprotein phosphatase
phosphorylase kinase
glycogen phosphorylase
glycogen synthase
glycogen breakdown, glycogen synthesis
Epinephrine has an effect similar to
that of glucagon.
Glycogen Storage Diseases
Result from a defect in an enzyme required for either synthesis or
degradation.
In general:
•affected organs either contain more glycogen or have abnormally
structured glycogen;
•liver is usually the tissue most affected; heart and muscle can also
be affected;
•abnormally structured glycogen due to defects in either debranching
enzyme or branching enzyme;
•depending on the disease type, prognosis varies from poor to easily
manageable;
•most of the defective enzymes are involved in glycogenolysis.
Know types I – V, defective enzyme and effect on glycogen.