Glycogen Synthesis

Animals synthesize and store glycogen when glucose levels are high, but the synthetic pathway is not merely a reversal of the glycogen phosphorylase reaction. High levels of phosphate in the cell favor glycogen breakdown and prevent the phosphorylase reaction from synthesizing glycogen in vivo, in spite of the fact that ?G°' for the phosphorylase reaction actually favors glycogen synthesis. Hence, another reaction pathway must be employed in the cell for the net synthesis of glycogen. In essence, this pathway must activate glucose units for transfer to glycogen chains.

Glucose Units Are Activated for Transfer by Formation of Sugar Nucleotides

Acetyl-CoA is an activated form of acetate, biotin and tetrahydrofolate activate one-carbon groups for transfer, and ATP is an activated form of phosphate. Luis Leloir,a biochemist in Argentina, showed in the 1950s that glycogen synthesis depended upon sugar nucleotides, which may be thought of as activated forms of sugar units. For example, formation of an ester linkage between the C-1 hydroxyl group and the ?-phosphate of UDP activates the glucose moiety of UDP-glucose.

UDP-Glucose Synthesis Is Driven by Pyrophosphate Hydrolysis

Sugar nucleotides are formed from sugar-1-phosphates and nucleoside triphosphates by specific pyrophosphorylase enzymes. For example, UDP-glucose pyrophosphorylase catalyzes the formation of UDP-glucose from glucose-1-phosphate and uridine 5'-triphosphate:

Glucose-1-P + UTP ? UDP-glucose + pyrophosphate

The reaction proceeds via attack by a phosphate oxygen of glucose-1-phosphate on the ?-phosphorus of UTP, with departure of the pyrophosphate anion. The reaction is a reversible one, but—as is the case for many biosynthetic reactions—it is driven forward by subsequent hydrolysis of pyrophosphate:

Pyrophosphate + H2O ? 2 Pi

The net reaction for sugar nucleotide formation (combining the preceding two equations) is thus

Glucose-1-P + UTP + H2O ? UDP-glucose + 2 Pi

Sugar nucleotides of this type act as donors of sugar units in the biosynthesis of oligo- and polysaccharides. In animals, UDP-glucose is the donor of glucose units for glycogen synthesis, but ADP-glucose is the glucose source for starch synthesis in plants.

Glycogen Synthase Catalyzes Formation of ?-(1 ? 4) Glycosidic Bonds in Glycogen

The very large glycogen polymer is built around a tiny protein core. The first glucose residue is covalently joined to the protein glycogenin via an acetal linkage to a tyrosine-OH group on the protein. Sugar units are added to the glycogen polymer by the action of glycogen synthase. The reaction involves transfer of a glucosyl unit from UDP-glucose to the C-4 hydroxyl group at a nonreducing end of a glycogen strand. The mechanism proceeds by cleavage of the C-O bond between the glucose moiety and the Gr-beta-phosphate of UDP-glucose, leaving an oxonium ion intermediate, which is rapidly attacked by the C-4 hydroxyl oxygen of a terminal glucose unit on glycogen.

Glycogen Branching Occurs by Transfer of Terminal Chain Segments

Glycogen is a branched polymer of glucose units. The branches arise from ?-(1 ? 6) linkages which occur every 8 to 12 residues. The branches provide multiple sites for rapid degradation or elongation of the polymer and also increase its solubility. Glycogen branches are formed by amylo-(1,4 ? 1,6)-transglycosylase, also known as branching enzyme. The reaction involves the transfer of a six- or seven-residue segment from the nonreducing end of a linear chain at least 11 residues in length to the C-6 hydroxyl of a glucose residue of the same chain or another chain. For each branching reaction, the resulting polymer has gained a new terminus at which growth can occur.

Control of Glycogen Metabolism

Glycogen Metabolism Is Highly Regulated

Synthesis and degradation of glycogen is important to reserve the energy and serve the metabolic needs of the organism. Glucose is the principal metabolic fuel for the brain, and the concentration of glucose in circulating blood must be maintained at about 5 mM for this purpose. Glucose derived from glycogen breakdown is also a primary