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HMP SHUNT
The pentose phosphate pathway (also called Phosphogluconate Pathway, or Hexose
Monophosphate Shunt [HMP shunt]) is a process that serves to generate NADPH and the
synthesis of pentose (5-carbon) sugars. There are two distinct phases in the pathway. The first
is the oxidative phase, in which NADPH is generated, and the second is the non-oxidative
synthesis of 5-carbon sugars. This pathway is an alternative to glycolysis. While it does
involve oxidation of glucose, its primary role is anabolic rather than catabolic. For most
organisms it takes place in the cytosol; in plants most steps take place in plastids.
Functions
The primary functions of the pathway are:
1.To generate reducing equivalents, in the form of NADPH, for reductive biosynthesis
reactions within cells.
2.To provide the cell with ribose-5-phosphate (R5P) for the synthesis of the nucleotides and
nucleic acids.
3.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.
Located exclusively in the cytoplasm, the pathway is one of the three main ways the body
creates molecules with reducing power, accounting for approximately 60% of NADPH
production in humans. One of the uses of NADPH in the cell is to prevent oxidative stress. It
reduces the coenzyme glutathione, which converts reactive H2O2 into H2O. If absent, the
H2O2 would be converted to hydroxyl free radicals, which can attack the cell. Significantly,
erythrocytes utilize the reactions of the PPP to generate large amounts of NADPH used in the
reduction of glutathione It is also used to generate hydrogen peroxide for phagocytes
Phases of HMP shunt
Oxidative phase
In this phase, two molecules of NADP+ are reduced to NADPH, utilizing the energy from the
conversion of glucose-6-phosphate into ribulose 5-phosphate.
Regulation
Glucose-6-phosphate dehydrogenase is the rate-controlling enzyme of this pathway. It is
allosterically stimulated by NADP+. The ratio of NADPH:NADP+ is normally about 100:1 in
liver cytosol. This makes the cytosol a highly-reducing environment. Formation of NADP+
by a NADPH-utilizing pathway, thus, stimulates production of more NADPH.
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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 membrane 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.
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