86
Chapter 3
the evolution of aerobic metabolic pathways greatly increases
the amount of energy available to a cell from glucose catabo-
lism. For example, if a muscle consumed 38 molecules of ATP
during a contraction, this amount of ATP could be supplied
by the breakdown of one molecule of glucose in the pres-
ence of oxygen or 19 molecules of glucose under anaerobic
conditions.
It is important to note, however, that although only two
molecules of ATP are formed per molecule of glucose under
anaerobic conditions, large amounts of ATP can still be sup-
plied by the glycolytic pathway if large amounts of glucose are
broken down to lactate. This is not an effi
cient utilization of
nutrients, but it does permit continued ATP production under
anaerobic conditions, such as occur during intense exercise.
Glycogen Storage
A small amount of glucose can be stored in the body to provide
a reserve supply for use when glucose is not being absorbed
into the blood from the intestinal tract. Recall from Chapter
2 that it is stored as the polysaccharide
glycogen,
mostly in
skeletal muscles and the liver.
Glycogen is synthesized from glucose by the pathway
illustrated in
Figure 3–47
. The enzymes for both glycogen syn-
thesis and glycogen breakdown are located in the cytosol. The
fi rst step in glycogen synthesis, the transfer of phosphate from
a molecule of ATP to glucose, forming glucose 6-phosphate,
is the same as the fi rst step in glycolysis. Thus, glucose
6-phosphate can either be broken down to pyruvate or used
to form glycogen.
As indicated in Figure 3–47, different enzymes are used to
synthesize and break down glycogen. The existence of two path-
ways containing enzymes that are subject to both covalent and
allosteric modulation provides a mechanism for regulating the
fl ow between glucose and glycogen. When an excess of glucose
is available to a liver or muscle cell, the enzymes in the glyco-
gen synthesis pathway are activated, and the enzyme that breaks
down glycogen is simultaneously inhibited. This combination
leads to the net storage of glucose in the form of glycogen.
When less glucose is available, the reverse combination
of enzyme stimulation and inhibition occurs, and net break-
down of glycogen to glucose 6-phosphate (known as
glyco-
genolysis
) ensues. Two paths are available to this glucose
6-phosphate: (1) In most cells, including skeletal muscle, it
enters the glycolytic pathway where it is catabolized to pro-
vide the energy for ATP formation; (2) in liver (and kidney)
cells, glucose 6-phosphate can be converted to free glucose by
removal of the phosphate group, and the glucose is then able
to pass out of the cell into the blood to fuel other cells.
Glucose Synthesis
In addition to being formed in the liver from the breakdown of
glycogen, glucose can be synthesized in the liver and kidneys
from intermediates derived from the catabolism of glycerol (a
so-called sugar alcohol) and some amino acids. This process of
generating new molecules of glucose from noncarbohydrate pre-
cursors is known as
gluconeogenesis.
The major substrate in
gluconeogenesis is pyruvate, formed from lactate and from sev-
eral amino acids during protein breakdown. In addition, glycerol
derived from the hydrolysis of triglycerides can be converted into
glucose via a pathway that does not involve pyruvate.
The pathway for gluconeogenesis in the liver and kid-
neys (
Figure 3–48
) makes use of many but not all of the
enzymes used in glycolysis because most of these reactions
are reversible. However, reactions 1, 3, and 10 (see Figure
3–41) are irreversible, and additional enzymes are required,
therefore, to form glucose from pyruvate. Pyruvate is con-
verted to phosphoenolpyruvate by a series of mitochondrial
reactions in which CO
2
is added to pyruvate to form the four-
carbon Krebs-cycle intermediate oxaloacetate. An additional
series of reactions leads to the transfer of a four-carbon inter-
mediate derived from oxaloacetate out of the mitochondria
and its conversion to phosphoenolpyruvate in the cytosol.
Phosphoenolpyruvate then reverses the steps of glycolysis back
to the level of reaction 3, in which a different enzyme from
that used in glycolysis is required to convert fructose 1,6-
bisphosphate to fructose 6-phosphate. From this point on, the
reactions are again reversible, leading to glucose 6-phosphate,
which can be converted to glucose in the liver and kidneys or
stored as glycogen. Because energy in the form of heat and
ATP generation is released during the glycolytic breakdown
of glucose to pyruvate, energy must be added to reverse this
pathway. A total of six ATP are consumed in the reactions of
gluconeogenesis per molecule of glucose formed.
Many of the same enzymes are used in glycolysis and
gluconeogenesis, so the question arises: What controls the
direction of the reactions in these pathways? What conditions
determine whether glucose is broken down to pyruvate or
whether pyruvate is converted into glucose? The answer lies in
Glucose 6-phosphate
Pyruvate
(all tissues)
(liver and
kidneys)
Glucose
P
i
P
i
Glycogen
Figure 3–47
Pathways for glycogen synthesis and breakdown. Each bowed
arrow indicates one or more irreversible reactions that requires
different enzymes to catalyze the reaction in the forward and reverse
directions.
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