matrix that drives the synthesis of ATP by ATP synthase. For this process to
continue, a plentiful supply of oxygen must be supplied to the tissues.
It has been estimated that at the beginning of the marathon, a runner who is
running at a reasonable pace consumes energy in a ratio of 75 percent carbo-
hydrate to 25 percent fatty acids. This ratio will decrease as glycogen stores in
the body diminish. However, as exertion continues and the muscle starts to rely
more on the P-oxidation of fatty acids to provide its energy needs, its oxygen
demand increases, placing a heavier demand on the heart to provide oxy-
genated blood. If the runner does not take steps to replace fluids lost through
sweat, dehydration will occur, resulting in decreased perfusion of the muscle
with adequately oxygenated blood.
If the muscle uses ATP faster than it can be produced by oxidative phos-
phorylation either by overexertion or because O2 uptake is limited, NADH lev-
els increase in the mitochondria and in the cytoplasm. ADP and AMP
concentrations in the cytoplasm will rise as ATP is used by the muscle for con-
traction. This will increase the flux of glucose through the glycolytic pathway
in the muscle, causing pyruvate levels to increase. To regenerate the oxidized
cofactor NAD+ that is required in the conversion of glyceraldehyde 3-phosphate
to 3-phosphoglycerate, pyruvate is reduced by NADH to lactate in a reaction
catalyzed by lactate dehydrogenase. Lactate is transported out of the muscle
cell to the blood.
Lactate in the blood is taken up by the liver and used as a carbon
source in the synthesis of new glucose by the gluconeogenic pathway. The
liver must first reoxidize lactate to pyruvate in a reaction that is catalyzed by
lactate dehydrogenase and generates NADH. Pyruvate cannot be directly con-
verted to phosphoenolpyruvate (PEP) by pyruvate kinase because under phys-
iologic conditions; the reaction is thermodynamically irreversible in favor of
the formation of pyruvate. Instead, pyruvate must enter the mitochondria and
be carboxylated by the enzyme pyruvate carboxylase to form oxaloacetate
in a reaction that requires biotin as a cofactor (Figure 21-1). Oxaloacetate is
then reduced to malate by malate dehydrogenase and malate then exits the
mitochondrion. In the cytosol, malate is reoxidized back to oxaloacetate by
cytoplasmic malate dehydrogenase. The cytoplasmic oxaloacetate is then
converted to PEP by PEP carboxykinase in a reaction that requires GTP.
(In a minor alternate pathway, mitochondrial oxaloacetate can be converted to
PEP by the mitochondrial form of the enzyme PEP carboxykinase. PEP then
exits the mitochondrion to the cytosol.) The pathway from PEP to glucose is
identical to that of glycolysis except for two reactions, as shown in Figure 21-2.
Fructose 1,6-bisphosphate is converted to fructose 6-phosphate by hydrolysis
of phosphate by the enzyme fructose-1,6-bisphosphatase. The final reaction is
hydrolysis of glucose 6-phosphate to glucose by glucose-6-phosphatase.
Hepatic glucose produced via gluconeogenesis is then delivered to the blood for
use by the brain and muscle. This process by which extrahepatic lactate is taken
back to the liver, converted to glucose by gluconeogenesis, and returned to
extrahepatic tissues is called the Cori cycle. When the rate of lactate production
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