section 15.2
Glycogen Metabolism
283
C H ,
n h
2
x
I
•CH— C H
2
— C H — C O O H
H y p o g ly cin A
- a-Ketoglutarate
Transmination
H
2
C = = C H -----------C H — C H
2
— C — C O O H
M eth y le n e c y c lo p ro p y l a -k e to p ro p io n ic a c id
Oxidative
decarboxylation
NADH + H*
C02
0
«,
H
2
C = C ----------- C H C H
2
C — S — C oA
M e th y len e c y clo p ro p y l a-k eto p ro p rio n y l-C o A
Overactivity of gluconeogenesis due to increased secre-
tion of catecholamines, cortisol, or growth hormone or an
increase in the glucagon/insulin ratio (Chapter 22) leads
to hyperglycemia and causes many metabolic problems.
15.2 Glycogen Metabolism
Animals have developed a method of storing glucose that
reduces the need to catabolize protein as a source of gluco-
neogenic precursors between meals. The principal storage
form of glucose in mammals is glycogen. Storage of glu-
cose as a polymer reduces the intracellular osmotic load,
thereby decreasing the amount of water of hydration and
increasing the energy density of the stored glucose.
In muscle, glycogen is stored in the cytosol and endo-
plasmic reticulum as granules, called
/3-particles,
each of
which is an individual glycogen molecule. In the liver,
the ^-particles aggregate, forming larger, rosette-shaped
u-particles
that can be seen with the electron microscope.
The average molecular weight of glycogen is several mil-
lion (10,000-50,000 glucose residues per molecule). The
storage granules also contain the enzymes needed for
glycogen synthesis and degradation and for regulation of
these two pathways.
Glycogen is present in virtually every cell in the body,
but it is especially abundant in liver and skeletal muscle.
The amount stored in tissues varies greatly in response
to metabolic and physiological demands, but in a resting
individual after a meal, liver usually contains roughly 4—
7% of its wet weight as glycogen and muscle about
1
%.
Since the body contains 10 times more muscle than hepatic
tissue, the total amount of glycogen stored in muscle is
greater than that in liver.
Muscle needs a rapidly available supply of glucose
to provide fuel for anaerobic glycolysis when, as dur-
ing bursts of muscle contraction, blood may provide
inadequate supplies of oxygen and fuel. The liver, un-
der most conditions, oxidizes fatty acids for this purpose;
however, liver is responsible for maintaining blood glu-
cose levels during short fasts, and it integrates the supply
of available fuels with the metabolic requirements of other
tissues in different physiological states. Liver glycogen
content changes primarily in response to the availability
of glucose and gluconeogenic precursors. Muscle glyco-
gen stores vary less in response to dietary signals, but they
depend on the rate of muscular contraction and of oxida-
tive metabolism (tissue respiration).
Glycogenesis (glycogen synthesis and storage) and
glycogenolysis
(glycogen
breakdown)
are
separate
metabolic pathways having only one enzyme in com-
mon, namely, phosphoglucomutase. Glycogen synthesis
and breakdown are often reciprocally regulated, so that
stimulation of one inhibits the other. The control mecha-
nisms are more closely interrelated than are those for gly-
colysis and gluconeogenesis, perhaps because the glyco-
gen pathways ensure the availability of only one substrate,
whereas intermediates of several other metabolic path-
ways are produced and metabolized in glycolysis and glu-
coneogenesis (Chapter 13).
Glycogen Synthesis
Glycogenesis begins with the phosphorylation of glucose
by glucokinase in liver and by hexokinase in muscle and
other tissues (Chapter 13):
M g2+
Glucose + ATP4-
— >
glucose-6-phosphate2~ + ADP3~ + H+
The second step in glycogenesis is conversion of glucose-
6
-phosphate to glucose-
1
-phosphate by phosphoglucomu-
tase in a reaction similar to that catalyzed by phospho-
glyceromutase. The phosphoryl group of the enzyme par-
ticipates in this reversible reaction in which glucose-
1
,
6
-
bisphosphate serves as an intermediate:
E-P + glucose-6-phosphate
E + glucose-1,6-bisphosphate
E-P + glucose-1-phosphate
In the third step, glucose-1-phosphate is converted to uri-
dine diphosphate (UDP) glucose, the immediate precursor
of glycogen synthesis, by reaction with uridine triphos-
phate (UTP). This reaction is catalyzed by glucose-1-
phosphate uridylyltransferase (or UDP-glucose pyrophos-
phorylase):
