Pentose phosphate pathway

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.

Uses
The primary functions of the 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.

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.

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.



The entire set of reactions can be summarized as follows:

The overall reaction for this process is:
 * Glucose 6-phosphate + 2 NADP+ + H2O &rarr; ribulose 5-phosphate + 2 NADPH + 2 H+ + CO2

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.

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.