chapter 15
Carbohydrate Metabolism II: Gluconeogenesis, Glycogen Synthesis and Breakdown, and Alternative Pathways
Glucose-1-phosphate is next converted by phosphoglu-
comutase to glucose-
-phosphate. The latter may then
enter the glycolytic pathway, but if glucose-
is present, free glucose can be formed.
Glycogen phosphorylase sequentially removes the glu-
cosyl residues from a glycogen branch until further action
is sterically hindered by a branch point. This occurs when
the branch is four residues long from the branch point. De-
branching enzyme, a multifunctional protein, first removes
the trisaccharide “stump” on the branch and then removes
the branch point itself. The a (1 —> 4) glycosidic bond link-
ing the trisaccharide to the branch point residue is first
cleaved, and the trisaccharide is transferred to the nonre-
ducing end of an adjacent branch. This elongated branch
can now be cleaved, one residue at a time, by glycogen
phosphorylase. The glucose residue that remains, linked
by an a(
) glycosidic bond, is then cleaved by hydrol-
ysis to yield free glucose. Thus, one molecule of glucose
is released for each branch point removed, even in mus-
cle, which lacks glucose-
-phosphatase. Roughly 7% of
the glycosidic bonds in glycogen are a(l —»•
) linkages.
Under normal conditions, glycogen phosphorylase and
debranching enzyme act simultaneously at different re-
gions of the glycogen molecule. Deficiency of either en-
zyme prevents complete glycogen degradation. Glyco-
gen phosphorylase deficiency leaves the original glycogen
molecule untouched. Deficiency of debranching enzyme
results in a glycogen molecule smaller than the original,
with very short chains on the outer branches but with the
inner core unchanged (a limit dextrin).
Regulation of Glycogen Metabolism
Metabolism of glycogen in muscle and liver is regulated
primarily through control of glycogen synthase and glyco-
gen phosphorylase. The activities of these enzymes vary
according to the metabolic needs of the tissue (as in mus-
cle) or of other tissues that use glucose as a fuel (as in
liver). Proximal control is exerted on synthase and phos-
phorylase by phosphorylation/dephosphorylation and by
allosteric effectors such as glucose, glucose-
and several nucleotides (ATP, ADP, AMP, and UDP).
The concept that allosteric effectors are of primary im-
portance in regulating synthase and phosphorylase activ-
ities was based mostly on
in vitro
experiments. For ex-
ample, inactive (phosphorylated) glycogen synthase can
be activated, without dephosphorylation, by glucose-
phosphate. For this reason, the active and inactive forms
of this enzyme were formerly called glycogen synthase
I (glucose-
-phosphate independent) and glycogen syn-
thase D (glucose-
-phosphate dependent). It now appears
that the concentration of glucose-
-phosphate may not
vary widely enough, particularly in muscle, to change syn-
thase activity significantly, although glucose-
binding may help determine the basal activity of the en-
zyme. The two forms are now known as glycogen synthase
a (dephosphorylated) and b (phosphorylated). The same
type of nomenclature is used for glycogen phosphorylase,
except that phosphorylase a, the active form, is phospho-
rylated, while phosphorylase b is dephosphorylated. The
regulation of glycogen metabolism in liver and in muscle
differs in several ways. Although the control mechanisms
are not completely understood, particularly in liver, the
differences probably are due to the receptors in each tis-
sue and to the presence of glucose-
-phosphatase in liver
rather than to differences in the intrinsic regulatory prop-
erties of the enzymes involved. This aspect of tissue differ-
ences in glycogen metabolism between muscle and liver
probably also applies to that in brain, myocardium, and
other tissues. In all tissues, the rate of glycogen synthesis
must be inversely proportional to the rate of glycogenoly-
sis to avoid futile cycling.
In muscle, glycogen is used as a fuel for anaerobic
metabolism during brief periods of high-energy output
(e.g., sprinting). Glycogenolysis is initiated and glycoge-
nesis inhibited by the onset of muscle contraction and by
factors such as epinephrine that signal a need for muscular
activity. Since muscle glycogen is not a source of glucose
for other tissues, it is not sensitive to blood glucose levels.
Control o f Glycogen Synthase
Muscle glycogen synthase
(M.W. ~340,000) is a
tetramer of identical subunits that exists in several forms,
which differ in catalytic activity and degree of covalent
modification. Glycogen synthase a, an active dephospho-
rylated form, can interconvert with several less active,
phosphorylated forms, collectively called glycogen syn-
thase b. The enzyme contains at least nine serine residues
located near the extremities of the molecule, which can be
phosphorylated by protein kinases (Figure 15-9). For the
most part, the sites can be phosphorylated in any order.
An exception is site C42, which undergoes phosphoryla-
tion by glycogen synthase kinase-3 only after phospho-
rylation at site C46 by casein kinase-2. Once C46 and
C42 are phosphorylated in that order, glycogen synthase
kinase-3 phosphorylates at sites C38, C34, and C30. In
general, phosphorylation reduces synthase activity, and an
increase in the number of phosphorylated sites additively
decreases the activity. Reduced synthase activity may be
manifested as increased
for UDP-glucose, increased
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