Glycogen Metabolism CH2OH CH2OH glycogen H O H H O H H H OH H OH H 1 O OH O H OH H OH

CH2OH CH2OH 6CH2 CH2OH CH2OH H O H H O H H 5 O H H O H H O H H H H H H 1 4 OH H OH H 4 OH H OH H OH H O O O O OH OH 3 2 H OH H OH H OH H OH H OH

Glycogen is a polymer of glucose residues linked by  a(14) glycosidic bonds, mainly  a(16) glycosidic bonds, at branch points. Glycogen chains & branches are longer than shown. Glucose is stored as glycogen predominantly in liver and muscle cells.

Glycogen Glucose Hexokinase or Glucokinase Glucose-6-Pase Glucose-1-P Glucose-6-P Glucose + Pi Glycolysis Pathway Pyruvate Glucose metabolism in liver.

Glucose-6-phosphate may enter Glycolysis or (mainly in liver) be dephosphorylated for release to the blood. Glycogenesis Definition: synthesis of glycogen from glucose. Site: cytosol of liver & muscles. Steps:

O

CH2OH HN

H O H Glycogen H O N O O synthesis OH H OH O P O P O CH 2 O   H OH O O H H H H UDP-glucose OH OH

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. UDP-Glucose Pyrophosphorylase O

CH2OH HN

H O H H O N OH H O O O O   OH O P O + O P O P O P O CH2 O     H OH O O O O H H glucose-1-phosphate H H UTP OH OH

PPi O

CH2OH HN

H O H H O N OH H O O OH O P O P O CH 2 O   H OH O O H H H H UDP-glucose OH OH

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:

glycogen(n residues) + UDP-glucose  glycogen(n +1 residues) + UDP Glycogen Synthase then catalyzes elongation of glycogen chains

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(16) linkage. Regulation of glycogenesis

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.

Glycogenolysis Definition: breakdown of glycogen to glucose in liver or G6P in muscles ( due to absence of G6 phosphatase in muscles). Importance: In muscles: source of energy during exercise. In liver: source of blood glucose during 18 hours starvation. Steps:

Glycogen catabolism

Glycogen Phosphorylase catalyzes phosphorolytic cleavage of the a(14) glycosidic linkages of glycogen, releasing glucose-1-phosphate as reaction product. Debranching enzyme has 2 independent active sites, consisting of residues in different segments of a single polypeptide chain:  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(16) glucosidase moiety of the debranching enzyme then catalyzes hydrolysis of the a(16) linkage, 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.

Regulation of glycogenolysis

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 inhibit Phosphorylase  Thus glycogen breakdown is inhibited when ATP and glucose-6- phosphate are plentiful.

SUMMARY The Metabolism of Glycogen in Animals

1. Glycogen is stored in muscle and liver as large particles. Contained within the particles are the enzymes that metabolize glycogen, as well as regulatory enzymes.

2. Glycogen phosphorylase catalyzes phosphorolytic cleavage at the nonreducing ends of glycogen chains, producing glucose 1-phosphate. The debranching enzyme transfers branches onto main chains and releases the residue at the (a1→6) branch as free glucose.

SUMMARY The Metabolism of Glycogen in Animals (cont.)

3. Phosphoglucomutase interconverts glucose 1- phosphate and glucose 6-phosphate. Glucose 6- phosphate can enter glycolysis or, in liver, can be converted to free glucose by glucose 6- phosphatase in the endoplasmic reticulum, then released to replenish blood glucose.

SUMMARY The Metabolism of Glycogen in Animals (cont.)

4. The sugar nucleotide UDP-glucose donates glucose residues to the nonreducing end of glycogen in the reaction catalyzed by glycogen synthase. A separate branching enzyme produces the a(1→6) linkages at branch points.

SUMMARY The Metabolism of Glycogen in Animals (cont.)

5. New glycogen particles begin with the autocatalytic formation of a glycosidic bond between the glucose of UDP-glucose and a Tyr residue in the protein glycogenin, followed by addition of several glucose residues to form a primer that can be acted upon by glycogen synthase.