The Pentose Phosphate Pathway

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The Pentose Phosphate Pathway
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Learning Objectives
Describe the function and the net result of the
pentose phosphate pathway.
Describe the symptoms and underlying metabolic
consequences of a glucose-6-phosphate deficiency
(include the role of NADPH in protecting cells
from reactive oxygen species).
Describe the test for thiamine deficiency.
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NAD (NADH) and NADP (NADPH)
NAD is usually associated with reactions that
involve oxidation of substrates (catabolic
processes) and transfer of electrons (and
protons) to NAD to form NADH.
NADPH, on the other hand, is almost always the
coenzyme in reductions (anabolic processes), in
which the electrons (and proton) are donated by
NADPH to form NADP.
A few enzymes can use either coenzyme, but most
show a strong preference for one or the other.
This functional specialization allows a cell to
maintain two distinct pools of electron carriers
(with distinct functions) in the same cellular
compartment.
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The pentose phosphate pathway is used to produce
NADPH and ribose-5-phosphate.
Since NADPH is used primarily in anabolic
reactions, this pathway is especially prominent
in tissues actively synthesizing fatty acids and
steroids, such as the mammary gland, adrenal
cortex, liver, and adipose tissue.
Skeletal muscle, which is much less active in
synthesizing fatty acids, is virtually lacking in
the pentose phosphate pathway.
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The Pentose Phosphate Pathway of Glucose Oxidation
NADP is the electron acceptor, and the
equilibrium lies far in the direction of NADPH
production.
An intramolecular ester
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The lactone is hydrolyzed to the free acid.
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Dehydrogenation and decarboxylation to form the
ketopentose ribulose-5-phosphate. A second
molecule of NADPH is produced here.
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The ketopentose is converted to its aldose
isomer, ribose-5-phosphate.
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Overall reaction of the pentose phosphate pathway
Glucose-6-phosphate 2 NADP H2O
ribose-5-phosphate CO2 2 NADPH 2 H
The net result is the production of NADPH, a
reductant for biosynthetic reactions, and
ribose-5-phosphate, a precursor for nucleotide
synthesis.
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Glucose-6-phosphate dehydrogenase deficiency
Fava beans, an important food source in the
Mediterranean and Middle East, can make many
people sick with a condition called favism. In
favism, erythrocytes begin to lyse 24 to 48 hours
after ingestion of the beans, releasing free
hemoglobin into the blood. Jaundice and
sometimes kidney failure can result. Similar
symptoms can occur with ingestion of the
antimalarial drug primaquine or sulfa antibiotics
or following exposure to certain herbicides.
These symptoms have a genetic basis deficiency
of glucose-6-phosphate dehydrogenase (G6PD) which
affects about 400 million people.
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A deficiency in G6PD (not a total absence)
reduces the amount of NADPH available to the
cell. Aside from its biosynthetic role, NADPH is
involved in recycling glutathione between its
oxidized and reduced states. Glutathione helps
protect cells from oxidative damage from H2O2 via
glutathionine peroxidase. In G6PD-deficient
individuals, NADPH production is diminished and
detoxification of H2O2 is inhibited. Cellular
damage results lipid peroxidation leading to
erythrocyte membrane breakdown, and protein and
DNA oxidation.
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Role of NADPH and glutathionine peroxidase in
protecting cells against reactive oxygen species
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Only under sever oxidative stress, caused by
drugs, herbicides, or divicine (the toxic
ingredient of fava beans), does G6PG deficiency
cause serious medical problems.
The antimalarial drug, primaquine, is believed to
act by causing oxidative stress to the parasite.
The growth of one such parasite, Plasmodium
falciparum, is inhibited in G6PD-deficient
erythrocytes. This parasite is very sensitive to
oxidative damage and is killed by a level of
oxidative stress that is tolerable to a
G6PD-deficient host.
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The non-oxidative reactions of the pentose
phosphate pathway
In tissues that require primarily NADPH rather
than ribose-5-phosphate (erythrocytes), the
pentose phosphates are recycled into
glucose-6-phosphate.
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These reactions convert pentose phosphates back
to hexose phosphates allowing the oxidative
reactions to continue.
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The enzymes transketolase and transaldolase are
specific to this pathway. Transketolase is a
thiamine pyrophosphate (TPP) dependent enzyme.
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Two sets of interconversions are required.
fructose-6-phosphate
Extra 3 carbon fragment
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Six pentose phosphates are converted to five
hexose phosphates.
Two sets of interconversions take care of the
extra 3 carbon fragments.