Glycogen breakdown & Synthesis

Carbohydrates
Simple Sugars Simple Sugars (Mono and Disaccharides) Complex sugars

Complex sugars/carbohydrates
Oligosaccharides: Raffinose

(galactose, fructose, and glucose)

Polysaccharides: Starch,Glycogen

Starch
Major storage carbohydrate in higher plants Amylose long straight glucose chains (a1-4) Amylopectin branched every 24-30 glc residues (a 1-6) Provides 80% of dietary calories in humans worldwide

Glycogen

-(1>4) Linkages -(1>6) Linkage

-(1>4) Linkages

Major storage carbohydrate in animals & serves as the secondary long-term energy storage. Glycogen is a polymer of glucose molecules with (14) glycosidic bonds linked, with (16)-linked branches (every 4-8 glucose residues ). More branched than starch Less osmotic pressure & Easily mobilized

Storage Tissues
Primary storage sites: Liver and Muscle. Glycogen is made primarily by the liver and the muscle, but can also be made by glycogenesis within the brain and stomach. Glycogen is found in the form of granules in the cytosol/cytoplasm in many cell types, and plays an important role in the glucose cycle. Glycogen forms an energy reserve that can be quickly mobilized to meet a sudden need for glucose, but it is less compact than the energy reserves of triglycerides (lipids).

In the liver hepatocytes, glycogen can compose up to 8% of the fresh weight (100120 g in an adult) soon after a meal.

Only the glycogen stored in the liver can be made accessible to other organs.
In the muscles, glycogen is found in a low concentration (12% of the muscle mass). The amount of glycogen stored in the bodyespecially within the muscles, liver, and RBCs mostly depends on physical activity, BMR, and eating habits. Small amounts of glycogen are found in the kidneys, and even smaller amounts in certain glial cells in the brain and WBCs.

Glycogen Metabolism
PPi
Pyrophosphatase

2 Pi Glycogen (Glucose)n UDP

UDP-Glucose UTP
UDP-Glucose Pyrophosphorylase Glycogen Synthase

Glucose-6-P

Glucose-1-P

Glycogen (Glucose)n+1

Phosphoglucomutase

Glycogen Phosphorylase
Glycogen (Glucose)n Pi

When the glycogen synthesis or breakdown starts?

After a meal, blood glucose levels rise, and the pancreas secretes insulin. Glucose from the portal vein enters liver cells (hepatocytes).

Insulin acts on the hepatocytes to stimulate the action of several enzymes, including glycogen synthase.
Glycogen synthesis takes place as long as both insulin and glucose remain plentiful. In this postprandial or "fed" state, the liver takes in more glucose from the blood than it releases. After completed digestion, glucose levels begin to fall, insulin secretion is reduced, and glycogen synthesis stops.

When it is needed for energy, or low glucose levels in the blood, glycogen is broken down will be takes place.

Glycogen catabolism (breakdown):

Glycogen phosphorylase catalyzes cleavage of the a(14) glycosidic linkages of glycogen from the non-reducing ends to releasing glucose-1-phosphate as reaction product.
glycogen(n residues) + Pi glycogen (n1 residues) + glucose-1-phosphate
Pyridoxal phosphate Phosphorylase. (PLP), serves as prosthetic group for Glycogen

Phosphorylase can cleave a(14) linkages only to within 4 residues of an a(16) branch point. This is called a "limit branch".

Glycogen Debranching Enzyme

The transferase of the debranching enzyme 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 a(16) glucosidase moiety of the debranching enzyme then catalyzes hydrolysis of the a(16) linkage, yielding free glucose. This is a minor fraction of glucose released from glycogen. The major product of glycogen breakdown is glucose-1phosphate, from Phosphorylase activity.
Limit Branch (4 residues)

-(1>4) transglycosylase
(group transfer reaction)

-(1>6) glucosidase

Glucose

When mutations in the glycogen debranching enzyme, metabolic diseases such as Glycogen storage disease type III can result.

Phosphoglucomutase: Catalyzes the reversible reaction:

Enzyme-Ser-OPO32 CH2OH H OH H OH O H OH H H OPO32 Enzyme-Ser-OH CH2OPO32 O H H H H OH OPO32 OH H OH Enzyme-Ser-OPO32 CH2OPO32 O H H H H OH OH OH H OH

glucose-1-phosphate

glucose-6-phosphate

Phosphoglucomutase

glucose-1-phosphate

glucose-6-phosphate

Phosphoglucomutase transfers a phosphate group on an -Dglucose monomer from the 1' to the 6' position in the forward direction or the 6' to the 1' position in the reverse direction.

Glycogen

Glucose-1-P

Glucose Hexokinase or Glucokinase Glucose-6-Pase Glucose-6-P Glucose + Pi Glycolysis Pathway

Pyruvate Glucose metabolism in liver.

Glucose-6-phosphate may enter Glycolysis or (mainly in liver) dephosphorylated for release to the blood. G6P can enter the pentose phosphate pathway via the enzyme G-6-p-d to produce NADPH and 5-carbon sugars. In the liver and kidney, G6P can be dephosphorylated back to Glucose by the enzyme Glucose 6-phosphatase. This is the final step in the gluconeogenesis pathway. Liver Glucose-6-phosphatase catalyzes the following, essential to the liver's role in maintaining blood glucose: glucose-6-phosphate + H2O glucose + Pi Most other tissues lack this enzyme.

In muscle
Muscle cell glycogen appears to function as an immediate reserve source of available glucose for muscle cells.

Muscle cells lack the enzyme glucose-6-phosphatase, which is required to pass glucose into the blood, so the glycogen they store is for internal use and is not shared with other cells. (This is in contrast to liver cells, which, on demand, readily do break down their stored glycogen into glucose and send it through the blood stream as fuel for the brain or muscles).

Glycogen synthesis

CH2OH H H OH OH H OH O H O H O P O O O P O H OH O CH2 H O

HN N

O H H OH

UDP-glucose

Uridine diphosphate glucose (UDP-glucose) is the immediate precursor for glycogen synthesis. As glucose residues are added to glycogen, UDPglucose is the substrate and UDP is released as a reaction product.

UDP-Glucose Pyrophosphorylase
CH2OH H H OH OH H OH O H O H O P O

O HN O O CH2 H H OH N

O O

O O

O O

P O

P O

P O

O H H OH

glucose-1-phosphate
PPi
CH2OH H H OH OH H OH O H O H O P O

UTP
O HN O O

O O P O CH2 H H OH

O H H OH

UDP-glucose

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

Glycogenin initiates glycogen synthesis.

Glycogenin is an enzyme that catalyzes attachment of a glucose molecule to one of its own tyrosine residues.
Glycogenin is a dimer, and evidence indicates that the 2 copies of the enzyme glucosylate one another.

Tyr active site

active site Tyr

Glycogenin dimer

6 CH

2OH

H
4

O H OH H
2

UDP-glucose
H O
1

tyrosine residue of Glycogenin

O C O Uridine HO C CH H2 NH O P O

OH

O H OH

P O
6 CH

2OH

O-linked glucose H residue 4

OH

O H OH H
2

H C
1

O H OH

C CH H2 NH

+ UDP

CH2OH H O H H

CH2OH O H

A glycosidic bond is formed Hbetween the anomeric C1 of the H H C O H OH OH O C glucose moiety derived from UDP-glucose andCH hydroxyl the O OH H2 NH H OH H OH oxygen of a tyrosine side-chain of Glycogenin. UDP is released as a product.

O-linked glucose H residue 4

OH

6 CH 5

2OH

O H OH H
2

H C
1

O H OH

C H2

CH NH

+ UDP

UDP-glucose
CH2OH H H OH OH H OH O H O H

CH2OH H H OH O H O H OH C H2 H C CH NH O

+ UDP

(1 4) linkage

Glycogenin then catalyzes glucosylation at C4 of the attached glucose (UDP-glucose again the donor), to yield an O-linked disaccharide with a(14) glycosidic linkage. This is repeated until a short linear glucose polymer with a(14) glycosidic linkages is built up on Glycogenin. Glycogen Synthase then catalyzes elongation of glycogen chains initiated by Glycogenin.

Glycogen Synthase catalyzes transfer of the glucose moiety of UDP-glucose to the hydroxyl at C4 of the terminal residue of a glycogen chain to form an a(14) glycosidic linkage:
glycogen(n residues) + UDP-glucose glycogen(n +1 residues) + UDP
~7 Glucosyl Residues

A branching enzyme transfers a segment from the end of a glycogen chain to the C6 hydroxyl of a glucose residue of glycogen to yield a branch with an a(16) linkage.
Amylo-(1,4>1,6)-Transglycosylase 4 Residues from
(Branching Enzyme) existing branch

Regulation of glycogen metabolism

Both synthesis & breakdown of glycogen are spontaneous. If both pathways were active simultaneously in a cell, there would be a "futile cycle" with cleavage of one ~P bond per cycle (in forming UDP-glucose). To prevent such a futile cycle, Glycogen Synthase and Glycogen Phosphorylase are reciprocally regulated, by allosteric effectors and by phosphorylation.

Glycogen Phosphorylase in muscle is subject to allosteric regulation by AMP, ATP, and glucose-6-phosphate.
AMP (present significantly when ATP is depleted) activates Phosphorylase. ATP & glucose-6-phosphate, which both have binding sites that overlap that of AMP, inhibit Phosphorylase. Thus glycogen breakdown is inhibited when ATP and glucose-6-phosphate are plentiful.

Glycogen

Glucose-1-P

Glucose Hexokinase or Glucokinase Glucose-6-Pase Glucose-6-P Glucose + Pi Glycolysis Pathway

Pyruvate Glucose metabolism in liver.

Glycogen Synthase is allosterically activated by glucose-6-P (opposite of effect on Phosphorylase). Thus Glycogen Synthase is active when high blood glucose leads to elevated intracellular glucose-6-P. It is 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.

Regulation by covalent modification (phosphorylation)

The hormones glucagon and epinephrine activate G-protein coupled receptors to trigger cAMP cascades. Both hormones are produced in response to low blood sugar. Glucagon, which is synthesized by a-cells of the pancreas, activates cAMP formation in liver.

Epinephrine (adrenaline) activates cAMP formation in muscle.

The cAMP cascade results in phosphorylation of Glycogen Phosphorylase, which promotes transition to the active state. The phosphorylated enzyme is less sensitive to allosteric inhibitors. Thus, even if cellular ATP & glucose-6-phosphate are high, Phosphorylase will be active.

The glucose-1-phosphate produced from glycogen in liver may be converted to free glucose for release to the blood.

Hormone (epinephrine or glucagon) via G Protein (G-GTP) Adenylate cyclase (inactive) Adenylate cyclase (active) catalysis ATP cyclic AMP + PPi Activation Phosphodiesterase AMP Protein kinase A (inactive) Protein kinase A (active) ATP ADP Phosphorylase kinase (b-inactive) Phosphatase Pi Phosphorylase (b-allosteric) Phosphatase Pi Phosphorylase kinase (P) (a-active) ATP ADP Phosphorylase (P) (a-active)

Signal cascade by which Glycogen Phosphorylase is activated.

The cAMP cascade induced in liver by glucagon or epinephrine has the opposite effect on glycogen synthesis. Glycogen Synthase is phosphorylated by Protein Kinase A as well as by Phosphorylase Kinase.
Phosphorylation of Glycogen Synthase promotes the "b" (less active). The cAMP cascade thus inhibits glycogen synthesis.

Insulin, produced in response to high blood glucose, triggers a separate signal cascade that leads to activation of Phosphoprotein Phosphatase. This phosphatase catalyzes removal of regulatory phosphate residues from Phosphorylase, Phosphorylase Kinase, & Glycogen Synthase enzymes. Thus insulin antagonizes effects of the cAMP cascade induced by glucagon & epinephrine.

Phosphorylase Kinase Phosphorylase Kinase-Ca++ P-Phosphorylase Kinase-Ca++

inactive partly active fully active

Ca++ also regulates glycogen breakdown in muscle.

During activation of contraction in skeletal muscle, Ca++ is released from the sarcoplasmic reticulum to promote actin/myosin interactions. The released Ca++ also activates Phosphorylase Kinase, which in muscle includes calmodulin as its d subunit. Phosphorylase Kinase is partly activated by binding of Ca++ to this subunit.

Phosphorylase Kinase Phosphorylase Kinase-Ca++ P-Phosphorylase Kinase-Ca++

inactive partly active fully active

Phosphorylation of the enzyme, via a cAMP cascade induced by epinephrine, results in further activation. These regulatory processes ensure release of phosphorylated glucose from glycogen, for entry into Glycolysis to provide ATP needed for muscle contraction. During extended exercise, as glycogen stores become depleted, muscle cells rely more on glucose uptake from the blood, and on fatty acid catabolism as a source of ATP.

Regulation of glycogen metabolism by Epinephrine, glucagon and Insulin

Glycogen Storage Diseases

Glycogen Storage Diseases are genetic enzyme deficiencies associated with excessive glycogen accumulation within cells.
glycogen glucose-1-P Glucose-6-Phosphatase glucose-6-P glucose + Pi fructose-6-P Phosphofructokinase fructose-1,6-bisP Glycolysis continued

Some enzymes whose deficiency leads to glycogen accumulation are part of the inter-connected pathways shown here.

Symptoms in addition to excess glycogen storage: When a genetic defect affects mainly an isoform of an enzyme expressed in liver, a common symptom is hypoglycemia, relating to impaired mobilization of glucose for release to the blood during fasting. When the defect is in muscle tissue, weakness & difficulty with exercise result from inability to increase glucose entry into Glycolysis during exercise. Additional symptoms depend on the particular enzyme that is deficient.

Glycogen Storage Disease Type I, liver deficiency of Glucose-6-phosphatase (von Gierke's disease) Type IV, deficiency of branching enzyme in various organs, including liver (Andersen's disease) Type V, muscle deficiency of Glycogen Phosphorylase (McArdle's disease) Type VII, muscle deficiency of Phosphofructokinase.

Symptoms, in addition to glycogen accumulation hypoglycemia (low blood glucose) when fasting, liver enlargement. liver dysfunction and early death.

muscle cramps with exercise.

inability to exercise.

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