Thepentose phosphate pathway (also called thephosphogluconate pathway and thehexose monophosphate shunt orHMP shunt) is ametabolic pathway parallel toglycolysis.[1] It generatesNADPH andpentoses (five-carbonsugars) as well asribose 5-phosphate, a precursor for the synthesis ofnucleotides.[1] While the pentose phosphate pathway does involve oxidation ofglucose, its primary role isanabolic rather thancatabolic. The pathway is especially important inred blood cells (erythrocytes). The reactions of the pathway were elucidated in the early 1950s byBernard Horecker and co-workers.[2][3]
There are two distinct phases in the pathway. The first is theoxidative phase, in which NADPH is generated, and the second is the non-oxidativesynthesis of five-carbon sugars. For most organisms, the pentose phosphate pathway takes place in thecytosol; in plants, most steps take place inplastids.[4]
Likeglycolysis, the pentose phosphate pathway appears to have a very ancient evolutionary origin. The reactions of this pathway are mostly enzyme catalyzed in modern cells, however, they also occur non-enzymatically under conditions that replicate those of theArchean ocean, and are catalyzed bymetal ions, particularlyferrous ions (Fe(II)).[5] This suggests that the origins of the pathway could date back to the prebiotic world.
The primary results of the pathway are:
Aromatic amino acids, in turn, are precursors for many biosynthetic pathways, including thelignin in wood.[citation needed]
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. In humans, it is found to be most active in the liver, mammary glands, and adrenal cortex.[citation needed] The PPP is one of the three main ways the body creates molecules withreducing power, accounting for approximately 60% of NADPH production in humans.[citation needed]
One of the uses of NADPH in the cell is to preventoxidative stress. It reducesglutathione viaglutathione reductase, which converts reactive H2O2 into H2O byglutathione peroxidase. If absent, the H2O2 would be converted to hydroxyl free radicals byFenton 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.
Hydrogen peroxide is also generated forphagocytes in a process often referred to as arespiratory burst.[6]
In this phase, two molecules ofNADP+ are reduced toNADPH, utilizing the energy from the conversion ofglucose-6-phosphate intoribulose 5-phosphate.
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 hydroxyl on carbon 1 of glucose 6-phosphate turns into a carbonyl, 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 | Oxidativedecarboxylation. NADP+ is the electron acceptor, generating another molecule ofNADPH, a CO2, andribulose 5-phosphate. |
The overall reaction for this process is:
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[citation needed]. It isallosterically stimulated by NADP+ and strongly inhibited byNADPH.[7] The ratio of NADPH:NADP+ is the primary mode of regulation for the enzyme and is normally about 100:1 in liver cytosol[citation needed]. This makes the cytosol a highly-reducing environment. An NADPH-utilizing pathway forms NADP+, which stimulatesGlucose-6-phosphate dehydrogenase to produce more NADPH. This step is also inhibited byacetyl CoA.[citation needed]
G6PD activity is also post-translationally regulated by cytoplasmic deacetylaseSIRT2. SIRT2-mediated deacetylation and activation of G6PD stimulates oxidative branch of PPP to supply cytosolicNADPH to counteractoxidative damage or supportde novo lipogenesis.[8][9]
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 parasitePlasmodium 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.[10]
Metabolism map | ||
|---|---|---|
 Majormetabolic pathways inmetro-style map. Click any text (name of pathway or metabolites) to link to the corresponding article. Single lines: pathways common to most lifeforms. Double lines: pathways not in humans (occurs in e.g. plants, fungi, prokaryotes).  Orange nodes:carbohydrate metabolism. Violet nodes:photosynthesis. Red nodes:cellular respiration. Pink nodes:cell signaling. Blue nodes:amino acid metabolism. Grey nodes:vitamin andcofactor metabolism. Brown nodes:nucleotide andprotein metabolism. Green nodes:lipid metabolism. | ||
