The Metabolism of Glycogen in Animals:- 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 (α1→4) 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 as sembled and the enzyme that catalyzes their assembly. The first step in the synthesis of a new glycogen molecule 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 cat alyzed by the chain-extending activity of glycogenin. At this point, glycogen synthase takes over, further ex tending 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 1772) 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 Å from that in the same monomer, 12 Å from that in the dimeric partner. Each UDP-glucose is bound through its phosphates to a Mn+2 ion (green) that is essential to catalysis. Mn+2 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.
MECHANISM FIGURE 15–11 Glycogenin and the structure of the glycogen particle. (a) Glycogenin catalyzes two distinct reactions. Initial attack by the hydroxyl group of Tyr194 on C-1 of the glucosyl moiety of UDP-glucose results in a glucosylated Tyr residue. The C-1 of another UDP-glucose molecule is now attacked by the C-4 hydroxyl group of the terminal glucose, and this sequence repeats to form a nascent glycogen molecule of eight glucose residues attached by (α1→4) glycosidic linkages. (b) Structure of the glycogen particle. Starting at a central glycogenin molecule, glycogen chains (12 to 14 residues) extend in tiers. Inner chains have two (α1→6) branches each. Chains in the outer tier are unbranched. There are 12 tiers in a mature glycogen particle (only 5 are shown here), consisting of about 55,000 glucose residues in a molecule of about 21 nm diameter and Mr 107.
