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Glycogen Is Synthesized and Degraded by Different Pathways

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Glycogen Is Synthesized and Degraded by Different Pathways
been maintained throughout evolution.
Differences arise, however, when we compare the regulatory sites. The simplest type of regulation would be feedback
inhibition by glucose 6-phosphate. Indeed, the glucose 6-phosphate regulatory site is highly conserved among the
majority of the phosphorylases. The crucial amino acid residues that participate in regulation by phosphorylation and
nucleotide binding are well conserved only in the mammalian enzymes. Thus, this level of regulation was a later
evolutionary acquisition.
II. Transducing and Storing Energy
21. Glycogen Metabolism
21.3. Epinephrine and Glucagon Signal the Need for Glycogen Breakdown
Figure 21.14. Regulatory Cascade for Glycogen Breakdown. Glycogen degradation is stimulated by hormone binding
to 7TM receptors. Hormone binding initiates a G-protein-dependent signal-transduction pathway that results in the
phosphorylation and activation of glycogen phosphorylase.
II. Transducing and Storing Energy
21. Glycogen Metabolism
21.4. Glycogen Is Synthesized and Degraded by Different Pathways
Conceptual Insights, Overview of Carbohydrate and Fatty Acid
Metabolism. 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.
21.4.1. UDP-Glucose Is an Activated Form of Glucose
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 UDPglucose 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 UDPglucose 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.
21.4.2. Glycogen Synthase Catalyzes the Transfer of Glucose from UDP-Glucose to a
Growing Chain
New glucosyl units are added to the nonreducing terminal residues of glycogen. The activated glucosyl unit of UDPglucose 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.
21.4.3. A Branching Enzyme Forms α-1,6 Linkages
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.
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 21.15). Thus, branching increases
the rate of glycogen synthesis and degradation.
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.
21.4.4. Glycogen Synthase Is the Key Regulatory Enzyme in Glycogen Synthesis
The activity of glycogen synthase, like that of phosphorylase, is regulated by covalent modification. Glycogen synthase
is phosphorylated at multiple sites by protein kinase A and several other kinases. The resulting alteration of the charges
in the protein lead to its inactivation (Figure 21.17). 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.
21.4.5. Glycogen Is an Efficient Storage Form of Glucose
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%.
II. Transducing and Storing Energy
21. Glycogen Metabolism
21.4. Glycogen Is Synthesized and Degraded by Different Pathways
Figure 21.15. Cross Section of a Glycogen Molecule. The component labeled G is glycogenin.
II. Transducing and Storing Energy
21. Glycogen Metabolism
21.4. Glycogen Is Synthesized and Degraded by Different Pathways
Figure 21.16. Structure of Glycogen Transferase. A conserved aspartate residue forms a covalent intermediate with a
chain of glucose molecules.
II. Transducing and Storing Energy
21. Glycogen Metabolism
21.4. Glycogen Is Synthesized and Degraded by Different Pathways
Figure 21.17. Charge Distribution of Glycogen Synthase. 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.]
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