Introduction
The pentose phosphate pathway is primarily an anabolic pathway that utilizes
the 6 carbons of glucose to generate 5 carbon sugars and reducing equivalents.
However, this pathway does oxidize glucose and under certain conditions can
completely oxidize glucose to CO2 and water. The primary functions of
this pathway are:
- To generate reducing equivalents, in the form of NADPH, for
reductive biosynthesis reactions within cells.
- To provide the cell with ribose-5-phosphate (R5P) for the
synthesis of the nucleotides and nucleic acids.
- Although not a significant function of the PPP, it can operate
to metabolize dietary pentose sugars derived from the digestion of nucleic
acids as well as to rearrange the carbon skeletons of dietary carbohydrates
into glycolytic/gluconeogenic intermediates
Enzymes that function primarily in the reductive direction utilize the
NADP+/NADPH cofactor pair as co-factors as opposed to oxidative
enzymes that utilize the NAD+/NADH cofactor pair. The reactions of
fatty acid biosynthesis and steroid biosynthesis utilize large amounts of NADPH.
As a consequence, cells of the liver, adipose tissue, adrenal
cortex, testis and lactating mammary gland have high levels of the PPP
enzymes. In fact 30% of the oxidation of glucose in the liver occurs via the
PPP. Additionally, erythrocytes utilize the
reactions of the PPP to generate large amounts of NADPH used in the reduction of
glutathione (see below). The conversion of ribonucleotides to
deoxyribonucleotides (through the action of ribonucleotide
reductase) requires NADPH as the electron source, therefore, any rapidly
proliferating cell needs large quantities of NADPH. back
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Reactions of the Pentose Phosphate Pathway
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The reactions of oxidative portion of the
pentose phosphate pathway are shown. The enzymes are in green.
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The reactions of the non-oxidative portion of
the pentose phosphate pathway are shown. Enzymes are in green. Relevant
carbohydrate intermediates of this portion of the pathway are in red.
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The reactions of the PPP operate exclusively in the cytoplasm. From this
perspective it is understandable that fatty acid synthesis (as opposed to
oxidation) takes place in the cytoplasm. The pentose phosphate pathway has both
an oxidative and a non-oxidative arm. The oxidation steps, utilizing
glucose-6-phosphate (G6P) as the substrate, occur at the beginning of the
pathway and are the reactions that generate NADPH. The reactions catalyzed by
glucose-6-phosphate dehydrogenase and 6-phosphogluconate
dehydrogenase generate one mole of NADPH each for every mole of
glucose-6-phosphate (G6P) that enters the PPP.
The non-oxidative reactions of the PPP are primarily designed to generate
R5P. Equally important reactions of the PPP are to convert dietary 5 carbon
sugars into both 6 (fructose-6-phosphate) and 3
(glyceraldehyde-3-phosphate) carbon sugars which
can then be utilized by the pathways of glycolysis.
The primary enzymes involved in the non-oxidative steps of the PPP are
transaldolase and transketolase.
- Transketolase functions to transfer 2 carbon groups from substrates of the
PPP, thus rearranging the carbon atoms that enter this pathway.
Like other enzymes that transfer 2 carbon groups, transketolase requires thiamine
pyrophosphate (TPP) as a co-factor in the
transfer reaction.
- Transaldolase transfers 3 carbon groups and thus is also involved in a
rearrangement of the carbon skeletons of the substrates of the PPP. The
transaldolase reaction involves Schiff base
formation between the substrate and a lysine residue in the enzyme.
The net result of the PPP, if not used solely for R5P production, is the
oxidation of G6P, a 6 carbon sugar, into a 5 carbon sugar. In turn, 3 moles of 5
carbon sugar are converted, via the enzymes of the PPP, back into two moles of 6
carbon sugars and one mole of 3 carbon sugar. The 6 carbon sugars can be
recycled into the pathway in the form of G6P, generating more NADPH. The 3
carbon sugar generated is glyceraldehyde-3-phsphate which can be shunted to
glycolysis and oxidized to pyruvate. Alternatively, it can be utilized by the
gluconeogenic enzymes to generate more 6 carbon sugars (fructose-6-phosphate or
glucose-6-phosphate). back
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Metabolic Disorders Associated with the Pentose Phosphate
Pathway
Oxidative stress within cells is controlled primarily by the action of the
peptide, glutathione, GSH. See Specialized
Products of Amino Acids for the synthesis of GSH.
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Glutathione (GSH) is a tripeptide composed of
g-glutamate, cysteine and glycine. The sulfhydryl
side chains of the cysteine residues of two glutathione molecules form a
disulfide bond (GSSG) during the course of being oxidized in reactions
with various oxides and peroxides in cells. Reduction of GSSG to two moles
of GSH is the function of glutathione reductase, an enzyme
that requires coupled oxidation of NADPH.
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Glutathione is the tripeptide g-glutamylcysteinylglycine. The cysteine thiol
plays the role in reducing oxidized thiols in other proteins. Oxidation of 2
cysteine thiols forms a disulfide bond. Although this bond plays a very
important role in protein structure and function, inappropriately introduced
disulfides can be detrimental. Glutathione can reduce disulfides
nonenzymatically. Oxidative stress also generates peroxides that in turn can be
reduced by glutathione to generate water and an alcohol, or 2 waters if the
peroxide were hydrogen peroxide.
Regeneration of reduced glutathione is carried out by the enzyme,
glutathione reductase. This enzyme requires the co-factor NADPH
when operating in the direction of glutathione reduction which is the
thermodynamically favored direction of the reaction.
It should be clear that any disruption in the level of NADPH may have a
profound effect upon a cells ability to deal with oxidative stress. No other
cell than the erythrocyte is exposed to greater oxidizing conditions. After all
it is the oxygen carrier of the body. back
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Erythrocytes and the Pentose Phosphate Pathway
The predominant pathways of carbohydrate metabolism in the red blood cell
(RBC) are glycolysis, the PPP and 2,3-bisphosphoglycerate
(2,3-BPG) metabolism (refer to discussion of hemoglobin
for review of role of 2,3-BPG). Glycolysis provides ATP for membrane ion pumps
and NADH for re-oxidation of methemoglobin. The PPP supplies the RBC with NADPH
to maintain the reduced state of glutathione. The inability to maintain reduced
glutathione in RBCs leads to increased accumulation of peroxides, predominantly
H2O2, that in turn results in a weakening of the cell wall
and concomitant hemolysis. Accumulation of H2O2 also leads
to increased rates of oxidation of hemoglobin to methemoglobin that also weakens
the cell wall. Glutathione removes peroxides via the action of glutathione
peroxidase. The PPP in erythrocytes is essentially the only pathway for
these cells to produce NADPH. Any defect in the production of NADPH could,
therefore, have profound effects on erythrocyte survival.
Several deficiencies in the level of activity (not function) of
glucose-6-phosphate dehydrogenase have been observed to be
associated with resistance to the malarial parasite, Plasmodium
falciparum, among individuals of Mediterranean and African descent. The
basis for this resistance is the weakening of the red cell membrane (the
erythrocyte is the host cell for the parasite) such that it cannot sustain the
parasitic life cycle long enough for productive growth. back
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This article has been modified by Dr. M. Javed Abbas. If you have any comments please do not hesitate to sign my Guest Book.
20:41 21/12/2002
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