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.