A common theme for the biosynthetic pathways that we will encounter in our study of biochemistry is the requirement for an activated precursor. This axiom holds true for glycogen synthesis. Glycogen is synthesized by a pathway that utilizes uridine diphosphate glucose (UDP-glucose) rather than glucose 1-phosphate as the activated glucose donor. Recall that glucose 1-phosphate is also the product of glycogen phosphorylase. We have already encountered UDP-glucose in our consideration of galactose metabolism. The C-1 carbon atom of the glucosyl unit of UDP-glucose is activated because its hydroxyl group is esterified to the diphosphate of UDP:

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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. UDP-glucose is synthesized from glucose 1-phosphate and the nucleotide 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 within a chain of glycogen 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 isozymic forms of glycogen synthase: one is specific to the liver while the other is expressed in muscle and other tissues.

Glycogen synthase can add glucosyl residues only to a polysaccharide chain already containing more than four residues. Thus, glycogen synthesis requires a primer. This priming function is carried out by glycogenin, an enzyme 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, on its partner subunit. The glucosyl units are covalently attached to the hydroxyl group of a specific tyrosine residue. UDP-glucose is the donor in this reaction. At this point, glycogen synthase takes over to extend the glycogen molecule. Thus, buried deeply inside each glycogen molecule lies a kernel of glycogenin (Figure 25.1).

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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. 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 is quite exacting (Figure 25.2). The block of 7 or so residues must include the nonreducing terminus and 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.

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 25.1). 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.

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What is the cost of converting dietary glucose into glycogen and then into glucose 6-phosphate? Before we make this calculation, we need to introduce another enzyme, nucleoside diphosphokinase. This enzyme catalyzes the regeneration of UTP from UDP, a product released when glycogen grows by the addition of glucose from UDP-glucose. ATP is used by the diphosphokinase to phosphorylate UDP. The summation of the reactions in glycogen synthesis and degradation is

Thus, 2 molecules of ATP are hydrolyzed to incorporate dietary glucose into glycogen. The energy yield from the breakdown of glycogen formed from dietary glucose is highly efficient. About 90% of the residues are cleaved by phosphorolysis to glucose 1-phosphate, which is converted into glucose 6-phosphate without expending an ATP molecule. The other 10% are branch residues that are hydrolytically cleaved. One molecule of ATP is then used to phosphorylate each of these glucose molecules to glucose 6-phosphate. As we saw in Chapters 16 through 21, the complete oxidation of glucose 6-phosphate yields about 31 molecules of ATP, and storage consumes slightly more than 2 molecules of ATP per molecule of glucose 6-phosphate; thus, only 2 molecules of ATP are required to store glucose as glycogen, but glycogen-derived glucose generates 31 molecules of ATP; so the overall efficiency of storage is nearly 94%.