CLINICAL CASES
183
activity. The enzyme’s transferase activity removes an oligosaccharide com-
posed of the terminal three glucosyl residues from the four residue branch and
transfers it to a free 4-hydroxyl group of the terminal glucosyl residue of
another branch. The remaining glucosyl residue that is in an a-1,6-glucosidic
linkage is then hydrolyzed by the glucosidase activity to release free glucose.
Glucose 1-phosphate released from glycogen by phosphorylase is converted
to glucose 6-phosphate by phosphoglucomutase. Glucose-6-phosphatase,
which is only present in liver and other gluconeogenic tissues, hydrolyzes the
phosphate to produce free glucose. Glucose is then exported from the liver via
the GLUT 2 transporter to increase the blood glucose concentration.
Following a meal, glycogen concentrations within the liver rise rapidly to
high levels; this can be up to 10 percent of the wet weight of the liver. Glucose
in the blood is transported into the hepatocyte by the GLUT 2 transporter and
is converted to glucose 6-phosphate by glucokinase. Phosphoglucomutase
then catalyzes the readily reversible reaction that converts glucose 6-phosphate
to glucose 1-phosphate. The glucose 1-phosphate is further activated to UDP-
glucose by glucose 1-phosphate uridylyltransferase in a reaction that con-
sumes UTP and produces inorganic pyrophosphate. This reaction is
thermodynamically favored by the hydrolysis of pyrophosphate by pyrophos-
phatase, which also makes the formation of UDP-glucose an irreversible reaction.
Glycogen synthase catalyzes the addition of a glucosyl residue to a glycogen
molecule using UDP-glucose as the substrate, forming an a(1^4) glycosidic
bond and releasing UDP. Since glycogen synthase cannot create an a(1^6)
linkage, an additional enzyme is required to form branches. When a chain of
at least 11 glucosyl residues has been synthesized, 1,4-a-glucan branching
enzyme removes a chain of about seven glucosyl residues and transfers it to
another chain, creating an a(1^6) glycosidic bond. This new branch point
must be at least four glucosyl residues away from another branch point.
Since the synthesis and mobilization of glycogen together form a poten-
tial futile cycle, the competing processes must be regulated to prevent waste
of ATP/UTP. This is accomplished by hormonal as well as allosteric controls.
The enzymatic cascade, that is promulgated when glucagon or epinephrine bind
to their respective receptors on the liver cells, is presented in Figure 20-2. The
cAMP that is produced by activation of adenylate cyclase binds to PKA and
activates it so that it can phosphorylate its target proteins. These include phos-
phorylase kinase, glycogen synthase, and inhibitor 1. Phosphorylation of
glycogen synthase converts it to an inactive form, whereas phosphorylation of
phosphorylase kinase and inhibitor 1 activate them. The phosphorylated
inhibitor 1 is then able to bind strongly to protein phosphatase 1, but it is a
poor substrate and is hydrolyzed slowly. Although the phosphorylated
inhibitor 1 is bound to the phosphatase, it will inhibit it from acting on other
phosphorylated proteins. Thus, while protein phosphatase 1 is inhibited, those
proteins that are activated by phosphorylation remain active, and those that are
inhibited by phosphorylation stay in their inactive form.
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