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The component labeled G is glycogenin.
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View this media module to better understand how glycogen metabolism fits in with other energy storage and utilization pathways (glycolysis, citric acid cycle, pentose phosphate pathway, and fatty acid metabolism).
As we have seen in 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.
In 1957, Luis Leloir and his coworkers showed that glycogen is synthesized by a pathway that utilizes uridine diphosphate glucose (UDP-glucose) rather than glucose 1-phosphate 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. The pyrophosphate liberated in this reaction comes from the outer two phosphoryl residues of UTP.
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 a C-4 terminus of glycogen to form an α-1,4-glycosidic linkage. In elongation, 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.
Glycogen synthase can add glucosyl residues only if the polysaccharide chain already contains more than four residues. Thus, glycogen synthesis requires a primer. This priming function is carried out by glycogenin, a protein composed of two identical 37-kd subunits, each bearing an oligosaccharide of α-1,4-glucose units. Carbon 1 of the first unit of this chain, the reducing end, is covalently attached to the phenolic hydroxyl group of a specific tyrosine in each glycogenin subunit. How is this chain formed? Each subunit of glycogenin catalyzes the addition of eight glucose units to its partner in the glycogenin dimer. UDP-glucose is the donor in this autoglycosylation. At this point, glycogen synthase takes over to extend the glycogen molecule.
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 occurs after a number of glucosyl residues are joined in α-1,4 linkage 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: this reaction is different from debranching. 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. 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.
The component labeled G is glycogenin.
). Thus, branching increases the rate of glycogen synthesis and degradation.
A conserved aspartate residue forms a covalent intermediate with a chain of glucose molecules.
Glycogen branching requires a single transferase activity. Glycogen debranching requires two enzyme activities: a transferase and an α-1,6 glucosidase. Sequence analysis suggests that the two transferases and, perhaps, the α-1,6 glucosidase are members of the same enzyme family, termed the α-amylase family. Such an enzyme catalyzes a reaction by forming a covalent intermediate attached to a conserved aspartate residue (Figure 21.16). Thus, the branching enzyme appears to function through the transfer of a chain of glucose molecules from an α-1,4 linkage to an aspartate residue on the enzyme and then from this site to a more interior location on the glycogen molecule to form an α-1,6 linkage.
Glycogen synthase has a highly asymmetric charge distribution. Phosphorylation markedly changes the net charge of the amino- and carboxyl-terminal regions (yellow) of the enzyme. The net charge of these regions and the interior of the enzyme before and after complete phosphorylation are shown in green and red, respectively. [After M. F. Browner, K. Nakano, A. G. Bang, and R. J. Fletterick. Proc. Natl. Acad. Sci. USA 86(1989):1443.]
). Phosphorylation has opposite effects on the enzymatic activities of glycogen synthase and phosphorylase. Phosphorylation converts the active a form of the synthase into a usually inactive b form. The phosphorylated b form requires a high level of the allosteric activator glucose 6-phosphate for activity, whereas the a form is active whether or not glucose 6-phosphate is present.
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, one ATP is hydrolyed incorporating 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 10% 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 one molecule of ATP per molecule of glucose 6-phosphate; so the overall efficiency of storage is nearly 97%.
