As with glycolysis and gluconeogenesis, biosynthetic and degradative pathways rarely operate by precisely the same reactions in the forward and reverse directions. Glycogen metabolism provided the first known example of this important principle. Separate pathways afford much greater flexibility, both in energetics and in control.

Glycogen is synthesized by a pathway that utilizes uridine diphosphate glucose (UDP-glucose) as the activated glucose donor.

UDP-glucose, the glucose donor in the biosynthesis of glycogen, is an activated form of glucose, just as ATP and acetyl CoA are activated forms of orthophosphate and acetate, respectively. The C-1 carbon atom of the glucosyl unit of UDP-glucose is activated because its hydroxyl group is esterified to the diphosphate moiety of UDP.

UDP-glucose is synthesized from glucose 1-phosphate and uridine triphosphate (UTP) in a reaction catalyzed by UDP-glucose pyrophosphorylase. This reaction liberates the outer two phosphoryl residues of UTP as pyrophosphate.

This reaction is readily reversible. However, pyrophosphate is rapidly hydrolyzed in vivo to orthophosphate by an inorganic pyrophosphatase. The essentially irreversible hydrolysis of pyrophosphate drives the synthesis of UDP-glucose.

The synthesis of UDP-glucose exemplifies another recurring theme in biochemistry: Many biosynthetic reactions are driven by the hydrolysis of pyrophosphate.

New glucosyl units are added to the nonreducing terminal residues of glycogen. The activated glucosyl unit of UDP-glucose is transferred to the hydroxyl group at C-4 of a terminal residue to form an α-1,4-glycosidic linkage. UDP is displaced by the terminal hydroxyl group of the growing glycogen molecule. This reaction is catalyzed by glycogen synthase, the key regulatory enzyme in glycogen synthesis. Humans have two isozymes of glycogen synthase: one is specific to the liver while the other is expressed in muscle and other tissues.

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Glycogen synthase, a member of the large glycosyltransferase family (Section 11.3), can add glucosyl residues only to a polysaccharide chain already containing at least four residues. Thus, glycogen synthesis requires a primer. This priming function is carried out by glycogenin, a Mn²⁺-requiring glycosyltransferase composed of two identical 37-kDa subunits. Each subunit of glycogenin catalyzes the formation of α-1,4-glucose polymers, 10 to 20 glucosyl units in length, which are covalently attached to the phenolic hydroxyl group of a specific tyrosine residue in each glycogenin subunit. UDP-glucose is the donor in this autoglycosylation. At this point, glycogen synthase takes over to extend the glycogen molecule. Thus, every glycogen molecule has a glycogenin molecule at its core (Figure 21.1).

Despite no detectable sequence similarity, structural studies have revealed that glycogen synthase is homologous to glycogen phosphorylase. The binding site for UDP-glucose in glycogen synthase corresponds in position to the pyridoxal phosphate in glycogen phosphorylase.

Glycogen synthase catalyzes only the synthesis of α-1,4 linkages. Another enzyme is required to form the α-1,6 linkages that make glycogen a branched polymer. Branching takes place after a number of glucosyl residues are joined in α-1,4 linkages by glycogen synthase (Figure 21.17). A branch is created by the breaking of an α-1,4 link and the formation of an α-1,6 link. A block of residues, typically 7 in number, is transferred to a more interior site. The branching enzyme that catalyzes this reaction requires that the block of 7 or so residues must include the nonreducing terminus, and must come from a chain at least 11 residues long. In addition, the new branch point must be at least 4 residues away from a preexisting one.

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Branching is important because it increases the solubility of glycogen. Furthermore, branching creates a large number of terminal residues, the sites of action of glycogen phosphorylase and synthase (Figure 21.18). Thus, branching increases the rate of glycogen synthesis and degradation.

Glycogen synthase, like phosphorylase, exists in two forms: an active nonphosphorylated a form and a usually inactive phosphorylated b form. Again, like the phosphorylase, the interconversion of the two forms is regulated by covalent modification. However, the key means of regulating glycogen synthase is by allosteric regulation of the phosphorylated form of the enzyme, glycogen synthase b. Glucose 6-phosphate is a powerful activator of the enzyme, stabilizing the R state of the enzyme relative to the T state.

The covalent modification of glycogen synthase appears to play more of a fine-tuning role. The synthase is phosphorylated at multiple sites by several protein kinases—notably, glycogen synthase kinase (GSK), which is under the control of insulin, and protein kinase A. The function of the multiple phosphorylation sites is still under investigation. Note that phosphorylation has opposite effects on the enzymatic activities of glycogen synthase and glycogen phosphorylase.

What is the cost of converting glucose 6-phosphate into glycogen and back into glucose 6-phosphate? The pertinent reactions have already been described, except for reaction 5, which is the regeneration of UTP. ATP phosphorylates UDP in a reaction catalyzed by nucleoside diphosphokinase.

Thus, 1 molecule of ATP is hydrolyzed to incorporate glucose 6-phosphate into glycogen. The energy yield from the breakdown of glycogen is highly efficient. About 90% of the residues are phosphorolytically cleaved to glucose 1-phosphate, which is converted at no cost into glucose 6-phosphate. The other residues are branch residues, which are hydrolytically cleaved. One molecule of ATP is then used to phosphorylate each of these glucose molecules to glucose 6-phosphate. The complete oxidation of glucose 6-phosphate yields about 31 molecules of ATP, and storage consumes slightly more than 1 molecule of ATP per molecule of glucose 6-phosphate; so the overall efficiency of storage is nearly 97%.