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.
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. 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. Erythrocytes, for example, generate a large amount of NADPH through the pentose phosphate pathway to use in the reduction of glutathione.
The entire set of reactions can be summarized as follows:
|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.|
The overall reaction for this process is:
- Glucose 6-phosphate + 2 NADP+ + H2O → ribulose 5-phosphate + 2 NADPH + 2 H+ + CO2
|ribulose 5-phosphate||→ ribose 5-phosphate||Ribulose 5-Phosphate Isomerase|
|ribulose 5-phosphate||→ xylulose 5-phosphate||Ribulose 5-Phosphate 3-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|
Net reaction: 3 ribulose-5-phosphate → 1 ribose-5-phosphate + 2 xylulose-5-phosphate → 2 fructose-6-phosphate + glyceraldehyde-3-phosphate
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. This step is also inhibited by acetyl CoA.
- G6PDH deficiency - A hereditary disease that disrupts the pentose phosphate pathway
- Thiamine deficiency
- Frank Dickens FRS
Erythrocytes and the pentose phosphate pathway
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.
- Kruger NJ, von Schaewen A (June 2003). "The oxidative pentose phosphate pathway: structure and organisation". Curr. Opin. Plant Biol. 6 (3): 236–46. doi:10.1016/S1369-5266(03)00039-6. PMID 12753973.
- Immunology at MCG 1/cytotox
- Cappadoro M, Giribaldi G, O'Brien E, et al. (October 1998). "Early phagocytosis of glucose-6-phosphate dehydrogenase (G6PD)-deficient erythrocytes parasitized by Plasmodium falciparum may explain malaria protection in G6PD deficiency". Blood 92 (7): 2527–34. PMID 9746794.
- The chemical logic behind the pentose phosphate pathway
- Pentose Phosphate Pathway at the US National Library of Medicine Medical Subject Headings (MeSH)
- Pentose phosphate pathway Map - Homo sapiens