Pentose phosphate pathway

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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.

Phases

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.

Oxidative phase of pentose phosphate pathway

The entire set of reactions can be summarized as follows:

Reactants	Products	Enzyme	Description
Glucose 6-phosphate + NADP+	→ 6-phosphoglucono-δ-lactone + NADPH	glucose 6-phosphate dehydrogenase	Dehydrogenation. The hemiacetal hydroxyl group located on carbon 1 of glucose 6-phosphate is converted into a carbonyl group, generating a lactone, and, in the process, NADPH is generated.
6-phosphoglucono-δ-lactone + H2O	→ 6-phosphogluconate + H+	6-phosphogluconolactonase	Hydrolysis
6-phosphogluconate + NADP+	→ ribulose 5-phosphate + NADPH + CO2	6-phosphogluconate dehydrogenase	Oxidative decarboxylation. NADP+ is the electron acceptor, generating another molecule of NADPH, a CO2, and ribulose 5-phosphate.
ribulose 5-phosphate	ribose 5-phosphate	Phosphopentose isomerase	Isomerization. (Can also be considered part of nonoxidative phase)

The overall reaction for this process is:

Glucose 6-phosphate + 2 NADP⁺ + H₂O → ribulose 5-phosphate + 2 NADPH + 2 H⁺ + CO₂

Non-oxidative phase

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The pentose phosphate pathway's Nonoxidative phase

Reactants	Products	Enzymes
ribulose 5-phosphate	→ ribose 5-phosphate	phosphopentose isomerase
ribose 5-phosphate	→ xylulose 5-phosphate	phosphopentose epimerase
xylulose 5-phosphate + ribose 5-phosphate	→ glyceraldehyde 3-phosphate + sedoheptulose 7-phosphate	transketolase
sedoheptulose 7-phosphate + glyceraldehyde 3-phosphate	→ erythrose 4-phosphate + fructose 6-phosphate	transaldolase
xylulose 5-phosphate + erythrose 4-phosphate	→ glyceraldehyde 3-phosphate + fructose 6-phosphate	transketolase

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.

See also

• G6PDH deficiency - A hereditary disease that disrupts the pentose phosphate pathway
• NADPH
• RNA
• thiamine deficiency

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.

External links

• The chemical logic behind the pentose phosphate pathway
• Pentose+Phosphate+Pathway at the US National Library of Medicine Medical Subject Headings (MeSH)
• http://www.bioon.com/book/biology/mwking/pentose-phosphate-pathway.html