Pentose phosphate pathway

The pentose phosphate pathway (also called the phosphogluconate pathway and the hexose monophosphate shunt) is a process that generates NADPH and pentoses (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.

Outcome
The primary results of the Pathway are:


 * The generation of reducing equivalents, in the form of NADPH, used in reductive biosynthesis reactions within cells. (e.g. fatty acid synthesis)
 * Production of ribose-5-phosphate (R5P), used in the synthesis of nucleotides and nucleic acids.
 * Production of erythrose-4-phosphate (E4P), used in the synthesis of aromatic amino acids.

Aromatic amino acids, in turn, are precursors for many biosynthetic pathways, notably including the lignin in wood.

Dietary pentose sugars derived from the digestion of nucleic acids may be metabolized through the pentose phosphate pathway, and the carbon skeletons of dietary carbohydrates may be converted into glycolytic/gluconeogenic intermediates.

In mammals, the PPP occurs exclusively in the cytoplasm, and is found to be most active in the liver, mammary gland and adrenal cortex in the human. However, the pathway is absent in skeletal muscle tissue. The PPP 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 glutathione via glutathione reductase, which converts reactive H2O2 into H2O by glutathione peroxidase. If absent, the H2O2 would be converted to hydroxyl free radicals by Fenton chemistry, which can attack the cell.

In a significant step, erythrocytes generate, through the pentose phosphate pathway, a large amount of NADPH used in the reduction of glutathione.

Hydrogen peroxide is also generated for phagocytes in a process often referred to as a respiratory burst.

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

Non-oxidative phase


Net reaction: 3 ribulose-5-phosphate → 1 ribose-5-phosphate + 2 xylulose-5-phosphate → 2 fructose-6-phosphate + glyceraldehyde-3-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. An NADPH-utilizing pathway forms NADP+, which stimulates Glucose-6-phosphate dehydrogenase to produce more NADPH.

Erythrocytes and the pentose phosphate pathway
Carbohydrates are metabolized in red blood cells mainly by glycolysis, the pentose phosphate pathway (PPP), and 2,3-bisphosphoglycerate (2,3-BPG) metabolism (refer to discussion of hemoglobin for the role of 2,3-BPG). Glycolysis provides ATP for membrane ion pumps and NADH for reduction of methemoglobin. The PPP supplies the red blood cell with NADPH, which in turn maintains the reduced state of glutathione. The inability to maintain reduced glutathione in red blood cells 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, in essence, 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 may be a 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.