Molecular Biochemistry I

Glycogen Metabolism

Contents of this page:
Review of glycogen structure
Glycogen phosphorylase
Debranching enzyme
Fate of glucose-1-P in relation to other pathways
Glycogen synthesis
Regulation of glycogen metabolism
Genetic diseases of glycogen metabolism

Glycogen is a polymer of glucose residues linked mainly by a(14) glycosidic linkages. There are a(16) linkages at branch points. The chains and branches are longer than shown. Glucose is stored as glycogen predominantly in liver and muscle cells.

Glycogen catabolism (breakdown)

Glycogen Phosphorylase catalyzes phosphorolytic cleavage of the a(14) glycosidic linkages of glycogen, releasing glucose-1-phosphate as the reaction product.

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

This phosphorolysis reaction may be compared to cleavage by water during hydrolysis:

Hydrolysis: R-O-R' + HOH R-OH + R'-OH

Phosphorolysis: R-O-R' + HO-PO32- R-OH + R'-O-PO32-

Pyridoxal phosphate (PLP), a derivative of vitamin B6, serves as prosthetic group for Glycogen Phosphorylase. 

Pyridoxal phosphate is held at the active site of Phosphorylase enzyme by a Schiff base linkage, formed by reaction of the aldehyde of PLP with the e-amino group of a lysine residue. 

In contrast to the role of this cofactor in other enzymes (e.g., see section on amino acid catabolism), the phosphate moiety of PLP is involved in acid/base catalysis by Phosphorylase. 

The Pi substrate binds between the phosphate of PLP and the glycosidic oxygen linking the terminal glucose residue of the glycogen substrate.

After the phosphate substrate donates a proton during cleavage of the glycosidic bond, it receives a proton from the phosphate moiety of PLP. PLP then takes back the proton as the phosphate oxygen attacks C1 of the cleaved glucose to yield glucose-1-phosphate. (See diagram in Voet & Voet, Biochemistry, 3rd Edition, p. 630.) 

Glycogen Phosphorylase, a homodimeric enzyme subject to allosteric control, exhibits transitions between "relaxed" (active) and "tense" (inhibited) conformations.

A diagram comparing these conformations is included in an Protein Data Bank Molecule of the Month article by David Goodsell.

A glucose analog, N-acetylglucosamine (GlcNAc), is present at the active site in the crystal structure shown.

A class of drugs developed for treating the hyperglycemia of diabetes (chloroindole-carboxamides) inhibit liver Glycogen Phosphorylase allosterically.  These inhibitors bind at the dimer interface, as shown at right, stabilizing the inactive (tense) conformation.

A glycogen storage site on the surface of the Phosphorylase enzyme binds the glycogen particle. Given the distance between the glycogen storage site and the active site, Phosphorylase can cleave a(14) linkages only to within 4 residues of an a(16) branch point. This is called a "limit branch."

Explore at right the structure of muscle Glycogen Phosphorylase.

Glycogen Phosphorylase

Debranching enzyme has two independent active sites, consisting of residues in different segments of a single polypeptide chain, that catalyze a(16) glucosidase and transferase (transglycosylase) reactions. (See p. 631.)

The transferase of the debranching enzyme transfers three 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-1-phosphate, arising from Phosphorylase activity.

of Glycogen Debranching 

Fate of glucose-1-phosphate in relation to other pathways:

Phosphoglucomutase catalyzes the reversible reaction:

Glucose-1-phosphate Glucose-6-phosphate

A serine hydroxyl at the active site donates and accepts phosphate. The enzyme-bound bisphosphate intermediate is not released. This is similar to the mechanism of Phosphoglycerate Mutase of Glycolysis, except that a serine hydroxyl donates and receives the phosphate, rather than a histidine. 

Phosphoglucomutase Reaction


The glucose-6-phosphate product may enter Glycolysis or (mainly in liver) be dephosphorylated for release to the blood. 

The liver enzyme Glucose-6-phosphatase catalyzes the following reaction, essential to the liver's role in maintaining blood glucose:

        Glucose-6-phosphate + H2O glucose + Pi.
Most other tissues lack this enzyme.

Glycogen Synthesis

Uridine diphosphate glucose (UDP-glucose) is the immediate precursor for glycogen synthesis. As glucose residues are added to glycogen, UDP-glucose is the substrate and UDP is released as a reaction product. Nucleotide diphosphate sugars are precursors also for synthesis of other complex carbohydrates, including oligosaccharide chains of glycoproteins, etc.

UDP-glucose is formed from glucose-1-phosphate and uridine triphosphate (UTP), as summarized at right.

Spontaneous hydrolysis of the ~ bond in PPi (P~P) drives the overall reaction. 

Cleavage of PPi is the only energy cost for glycogen synthesis (one ~P bond per glucose residue).

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 two copies of the enzyme glucosylate one another.

A glycosidic bond is formed between the anomeric C1 of the glucose moiety derived from UDP-glucose and the hydroxyl oxygen of a tyrosine side-chain of Glycogenin.

UDP is released as a product.

Glycogenin then catalyzes glucosylation at C4 of the attached glucose, with UDP-glucose again being the glucose donor. The product is an O-linked disaccharide with an a(14) glycosidic linkage (diagram above). This process is repeated until a short linear glucose polymer with a(14) glycosidic linkages is built up on the Glycogenin.

Glycogen Synthase catalyzes elongation of glycogen chains. 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(1 4) glycosidic linkage (diagrams p. 633):

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

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 (p. 634).

Physiological regulation of glycogen metabolism

Both synthesis and breakdown of glycogen are spontaneous. If glycogen synthesis and phosphorolysis were active simultaneously in a cell, there would be a "futile cycle" with cleavage of one ~P bond per cycle (in formation of UDP-glucose). 

To prevent such a futile cycle, Glycogen Synthase and Glycogen Phosphorylase are reciprocally regulated, both by allosteric effectors and by covalent modification (phosphorylation).

Reciprocal allosteric controls:

Glycogen Phosphorylase in muscle is subject to allosteric regulation by AMP, ATP, and glucose-6-phosphate, as summarized in Fig. 18-9, p. 635. A separate isozyme of Phosphorylase expressed in liver is less sensitive to these allosteric controls.

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

It is useful to a cell to store glucose as glycogen when the input to Glycolysis (glucose-6-phosphate), 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. (cAMP is discussed in the section on cell signals). 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 activates cAMP formation in muscle.

The cAMP cascade results in phosphorylation of a serine hydroxyl of the Glycogen Phosphorylase enzyme, which promotes transition to the active (relaxed) state. The phosphorylated enzyme is less sensitive to allosteric inhibitors. Thus even if cellular ATP and 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. With this hormone-activated regulation by covalent modification, the needs of the organism take precedence over the needs of the cell.  

Commonly used terminology: 

  • "a" is the form of the enzyme that tends to be active, and independent of allosteric regulators (in the case of Glycogen Phosphorylase, when phosphorylated);
  • "b" is the form of the enzyme that is dependent on local allosteric controls (in the case of Glycogen Phosphorylase when dephosphorylated).
The signal cascade by which Glycogen Phosphorylase is activated is summarized in the diagram at right. A more complex diagram is on p. 639.

The cAMP cascade 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) conformation. The cAMP cascade thus inhibits glycogen synthesis. Instead of being converted to glycogen, glucose-1-phosphate in liver may be converted to glucose-6-phosphate, and dephosphorylated for release to the blood.

High cytosolic glucose-6-phosphate, which would result when blood glucose is high, turns off the signal with regard to glycogen synthesis. The conformation of Glycogen Synthase induced by the allosteric activator glucose-6-phosphate is susceptible to dephosphorylation by Protein Phosphatase.

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, and Glycogen Synthase enzymes. Thus insulin antagonizes effects of the cAMP cascade induced by glucagon and epinephrine.

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. (See information on calcium-release channels.)

The released Ca++ also activates Phosphorylase Kinase, which in muscle includes calmodulin as its d subunit. Phosphorylase Kinase is partially activated by binding of Ca++ to this subunit.

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. (Fat metabolism is discussed elsewhere.)

An inborn error of glycogen metabolism:

A genetic defect in the isoform of the Glycogen Synthase enzyme expressed in liver causes a disease with symptoms that include:

Treatment of this disease consists of frequent meals of complex carbohydrates (avoiding simple sugars that would lead to a rapid rise in blood glucose) and meals high in protein to provide substrates for gluconeogenesis.

Glycogen storage diseases are genetic enzyme deficiencies associated with excessive glycogen accumulation within cells. Some enzymes whose deficiency leads to glycogen accumulation are part of the interconnected pathways shown at right.

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 (low blood glucose), relating to impaired mobilization of glucose for release to the blood during fasting.
  • When the defect is in muscle tissue, weakness and difficulty with exercise result from inability to increase glucose entry into Glycolysis during exercise.
  • Additional symptoms depend on the particular enzyme that is deficient. 

See Studio Exercise on glycogen storage diseases.

Copyright 1998-2007 by Joyce J. Diwan. All rights reserved.

Additional material on Glycogen Metabolism:
Readings, Test Questions, Tutorial, & Studio Exercise

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