Glycogenin Primes the Initial Sugar Residues in Glycogen

Glycogen synthase cannot initiate a new glycogen chain de novo. It requires a primer, usually a preformed (a1n4) polyglucose chain or branch having at least eight glucose residues. How is a new glycogen molecule initiated? The intriguing protein glycogenin (Fig. 15-10) is both the primer on which new chains are assembled and the enzyme that catalyzes their assembly. The first step in the synthesis of a new glycogen mole cule is the transfer of a glucose residue from UDP-glucose to the hydroxyl group of Tyr194 of glycogenin, catalyzed by the protein's intrinsic glucosyltransferase activity (Fig. 15-11a). The nascent chain is extended by the sequential addition of seven more glucose residues, each derived from UDP-glucose; the reactions are catalyzed by the chain-extending activity of glycogenin. At this point, glycogen synthase takes over, further extending the glycogen chain. Glycogenin remains buried within the particle, covalently attached to the single reducing end of the glycogen molecule (Fig. 15-11b).

FIGURE 15-10 Glycogenin structure. (PDB 1D 1 772) Muscle glycogenin (Mr 37,000) forms dimers in solution. Humans have a second isoform in liver, glycogenin-2. The substrate, UDP-glucose (shown as a red ball-and-stick structure), is bound to a Rossman fold near the amino terminus and is some distance from the Tyr194 residues (turquoise)—15 A from that in the same monomer, 12 A from that in the dimeric partner. Each UDP-glucose is bound through its phosphates to a Mn2+ ion (green) that is essential to catalysis. Mn2+ is believed to function as an electron-pair acceptor (Lewis acid) to stabilize the leaving group, UDP. The glycosidic bond in the product has the same configuration about the C-1 of glucose as the substrate UDP-glucose, suggesting that the transfer of glucose from UDP to Tyr194 occurs in two steps. The first step is probably a nucleophilic attack by Asp162 (orange), forming a temporary intermediate with inverted configuration. A second nucleophilic attack by Tyr194 then restores the starting configuration.

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