Glycogen Metabolism

BCH 340 lecture 9

Glycogen is homopolysaccharide formed of branched D-glucose

units

The primary glycosidic bond is 1-4-linkage

Each branch is made of 6-12 glucose units. At the branching

point, the chain is attached by 1-6 linkage

Structure of glycogen

Glucose is stored as glycogen predominantly in liver and

muscle cells.

Liver glycogen is about 120 grams (about 6 % of liver

weight).

Muscle glycogen is about 350 grams (about 1 % of

total muscles weight).

Location of glycogen

Liver glycogen: It maintains normal blood glucose

concentration especially during the early stage of fast

(between meals). After 12-18 hours fasting, liver glycogen is

depleted.

Muscle glycogen: It acts as a source of energy within the

muscle itself especially during muscle contractions.

Functions of glycogen

Glycogenesis: It is the formation of glycogen in liver andmuscles

Substrates for glycogen synthesis:

1. In liver:

o Blood glucose

o Other hexoses: fructose and galactose

o Non-carbohydrate sources: (gluconeogenesis) e.g.lactic acid, glycerol and lactate. These are convertedfirst to glucose, then to glycogen

2. In muscles:

o Blood glucose only

OO

OHOH

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H

CH2

H

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N

O

O

OP

O

O

P

O

O

H O

OH

H

OHH

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CH2OH

H

O

H

O

P

O

O

H O

OH

H

OHH

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CH2OH

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OHOH

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H

CH2

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N

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O

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P

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OPO

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PPi

+

UDP-glucose

glucose-1-phosphate UTP

UDP-Glucose Pyrophosphorylase

Uridine diphosphate glucose (UDP-glucose) is the

immediate precursor for glycogen synthesis

OO

OHOH

HH

H

CH2

H

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N

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P

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H O

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UDP-glucose

glucose-1-phosphate UTP

UDP-Glucose Pyrophosphorylase

UDP-glucose is formed from glucose-1-phosphate:

glucose-1-phosphate + UTP UDP-glucose + 2 Pi

Cleavage of PPi is the only energy cost for glycogen

synthesis

H O

OH

H

OHH

OH

CH2OH

H

O H

H

OHH

OH

CH2OH

H

O

HHC

CH

NH

CH2

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5

4

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6

H O

OH

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P O P O Uridine

O

O

O

O

C

CH

NH

CH2

HO

O

tyrosine residue of Glycogenin

O-linked glucose residue

+ UDP

UDP-glucose

Glycogenin (dimer) initiates glycogen synthesis

Glycogenin is an enzyme that catalyzes attachment of a glucose molecule to one of its own tyrosine residues.

UDP is released as a product

Glycogenin then catalyzes glucosylation at C4 of the attached

glucose (UDP-glucose again the donor), to yield an O-linked

disaccharide with α(14) glycosidic linkage

This is repeated until a short linear glucose polymer (glycogen

primer) with α(14) glycosidic linkages is built up

on Glycogenin

H O

OH

H

OHH

OH

CH2OH

H

O H

H

OHH

OH

CH2OH

H

O

HHC

CH

NH

CH2

O

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H O

OH

H

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CH2OH

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C

CH

NH

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5

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H O

OH

H

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OH

CH2OH

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5

4

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P O P O Uridine

O

O

O

O

C

CH

NH

CH2

HO

O

UDP-glucose

O-linked glucose residue

(14) linkage

+ UDP

+ UDP

Glycogen Synthase then catalyzes

elongation of glycogen chains initiated by

Glycogenin.

By the action of Glycogen Synthase (key enzyme of

glycogenesis) UDP-G molecules are added to glycogen

primer causing elongation of the α1-4, branches up to 11

glucose units.

glycogen(n residues) + UDP-glucose glycogen(n +1 residues) + UDP

A branching enzyme transfers a segment (minimum 6 Glc

residues) from the end of a glycogen chain to the C6

hydroxyl of a glucose residue of glycogen to yield a

branch with an α(16) linkage. The new branches are

elongated by the glycogen synthase and the process is

repeated.

Glycogen catabolismIt is the breakdown of glycogen into glucose

(in liver) and lactic acid (in muscles)

Two major enzymes participate in all glycogen degradation:

Glycogen phosphorylase

and

Glycogen debranching enzyme

Glycogen Phosphorylase (the key enzyme of glycogenolysis)

catalyzes phosphorolytic cleavage (addition of Pi) of the α(14)

glycosidic linkages of glycogen, releasing glucose-1-phosphate as

reaction product

glycogen(n residues) + Pi glycogen (n–1 residues) + glucose-1-phosphate

Always acts at nonreducing end, stops at fourth

glucose from α 1,6 branch point

Debranching enzyme has 2 independent active sites,

consisting of residues in different segments of a single

polypeptide chain:

1. The transferase

2. The α (16) glucosidase

The transferase transfers 3 glucose residues from a 4-residue limit branch to the end of another branch, diminishing

the limit branch to a single glucose residue.

The α(16) glucosidase

moiety of the debranching

enzyme then catalyzes

hydrolysis of the α(16)

Linkage by adding H2O, yielding free glucose

This is a minor fraction of glucose released from glycogen

The major product of glycogen breakdown is

glucose-1-phosphate, from Phosphorylase activity.

Glucose-1-P formed by phosphorolytic cleavage of

glycogen is converted into glucose-6-P by

Phosphoglucomutase (catalyzes the reversible reaction):

glucose-1-phosphate glucose-6-phosphate

• Glucose 6-phosphate derived from glycogen can be:

o used as a fuel for anaerobic or aerobic metabolism as in, for instance, muscle;

o converted into free glucose in the liver and subsequently released into the blood to maintain a relatively level of blood glucose;

o processed by the pentose phosphate pathway to generate NADPH or ribose in a variety of tissues

Regulation of Glycogen Metabolism

Glycogen reserves are the most immediately available

large source of metabolic energy for mammals

Storage and utilization are under dietary and

hormonal control

Glycogen synthase and glycogen phosphorylase are

the targets of allosteric modulators and of covalent,

reversible modification (phosphorylation)

Allosteric regulation of phosphorylase activity

Glycogen Phosphorylase in muscle is subject to allostericregulation by AMP, ATP, and glucose-6-phosphate. A separate isozyme of Phosphorylase expressed in liver is less sensitive to these allosteric controls

o AMP (present significantly when ATP is depleted) activates Phosphorylase

o ATP & glucose-6-phosphate inhibit Phosphorylase

Thus glycogen breakdown is inhibited when ATP and glucose-6-phosphate are plentiful

Glycogen Synthase is allosterically activated by glucose-6-phosphate (opposite of the effect on Phosphorylase)

Thus, glycogen synthesis is activated when glucose-6-phosphate is plentiful

These controls benefit the cell because it is more useful to a cell to store glucose as glycogen when the input to Glycolysis (glucose-6-P), and the main product of Glycolysis (ATP), are adequate.

Primary hormones :

1. epinephrine (adrenaline)

2. glucagon

3. insulin

The actions of these hormones on glycogen phosphorylase and glycogen synthase are indirect

Regulation by covalent modification

(phosphorylation)

Glucagon

Low levels of glucose induce release of glucagon

Acts primarily on liver cells.

Detected by receptors on surface of liver cells.

Stimulates glycogen breakdown & inhibits glycogenesis.

Glucagon also blocks glycolysis & stimulates

gluconeogenesis.

Epinephrine

Low levels of glucose induce release of Epinephrine

Acts primarily on skeletal muscle.

Detected by receptors at surface of cells.

Stimulates glycogen breakdown & inhibits glycogenesis.

Glucagon and epinephrine both stimulate intracellular pathway via increasing

levels of cAMP

Insulin

High levels of glucose induce release of insulin from β-

cells of islets of Langerhan in the pancreas.

Detected by receptors at surface of muscle and liver

cells.

Increases glycogenesis in muscle.

Intracellular signal pathway involvescomplex sequential phosphorylations

and dephosphorylations

Epinephrine and glucagon inhibit glycogen synthesis

1. protein kinase A phosphorylates glycogen synthase, decreasing its activity.

How is Glycogenesis Inhibited?

2. also phosphorylase kinase can phosphorylate glycogen synthase, inactivating it.

Complex process stimulated by Insulin

dephosphorylation is the major pathway for stimulation of

glycogenesis in liver and resting muscles

Insulin indirectly activates a phosphoprotein phosphatase:

How is Glycogenesis Activated?

glycogen synthase b glycogen synthase a

phosphorylated dephosphorylated

less active active

Differences between liver glycogen

and muscle glycogen

Muscle glycogenLiver glycogen

Blood glucose only 1. Blood glucose:

2. Other hexoses

3. Non-CHO sources

Source

400 grams maximum120 grams maximumAmount

1%6%Concentration

Private source of energy for

muscles only

General store of glucose for all body

cells

Functions

Lactate (due to the absence of

G6Pase)

Glucose End product

Same

Same

No effect

Stimulate glycogenesis

Stimulate glycogenolysis

Stimulate glycogenolysis

Effect of hormones

1. Insulin

2. Epinephrine

3. Glucagon