Pentose phosphate pathway

Pentose phosphate pathway

Overview
The pentose phosphate pathway (also called the phosphogluconate pathway and the hexose monophosphate shunt) is a process that generates NADPH and pentose
Pentose
A pentose is a monosaccharide with five carbon atoms. Pentoses are organized into two groups. Aldopentoses have an aldehyde functional group at position 1...

s (5-carbon
Carbon
Carbon is the chemical element with symbol C and atomic number 6. As a member of group 14 on the periodic table, it is nonmetallic and tetravalent—making four electrons available to form covalent chemical bonds...

 sugar
Sugar
Sugar is a class of edible crystalline carbohydrates, mainly sucrose, lactose, and fructose, characterized by a sweet flavor.Sucrose in its refined form primarily comes from sugar cane and sugar beet...

s). 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
Glycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...

.
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Encyclopedia
The pentose phosphate pathway (also called the phosphogluconate pathway and the hexose monophosphate shunt) is a process that generates NADPH and pentose
Pentose
A pentose is a monosaccharide with five carbon atoms. Pentoses are organized into two groups. Aldopentoses have an aldehyde functional group at position 1...

s (5-carbon
Carbon
Carbon is the chemical element with symbol C and atomic number 6. As a member of group 14 on the periodic table, it is nonmetallic and tetravalent—making four electrons available to form covalent chemical bonds...

 sugar
Sugar
Sugar is a class of edible crystalline carbohydrates, mainly sucrose, lactose, and fructose, characterized by a sweet flavor.Sucrose in its refined form primarily comes from sugar cane and sugar beet...

s). 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
Glycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...

. While it does involve oxidation of glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...

, its primary role is anabolic rather than catabolic. For most organisms, it takes place in the cytosol
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....

; in plants, most steps take place in plastid
Plastid
Plastids are major organelles found in the cells of plants and algae. Plastids are the site of manufacture and storage of important chemical compounds used by the cell...

s.

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
    Fatty acid synthesis
    Fatty acid synthesis is the creation of fatty acids from acetyl-CoA and malonyl-CoA precursors through action of enzymes called fatty acid synthases...

    )
  • 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
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...

. It reduces glutathione
Glutathione
Glutathione is a tripeptide that contains an unusual peptide linkage between the amine group of cysteine and the carboxyl group of the glutamate side-chain...

 via glutathione reductase
Glutathione reductase
Glutathione reductase, also known as GSR or GR, is an enzyme that reduces glutathione disulfide to the sulfhydryl form GSH, which is an important cellular antioxidant....

, which converts reactive H2O2 into H2O by glutathione peroxidase
Glutathione peroxidase
Glutathione peroxidase is the general name of an enzyme family with peroxidase activity whose main biological role is to protect the organism from oxidative damage...

. If absent, the H2O2 would be converted to hydroxyl free radicals by Fenton chemistry
Fenton's reagent
Fenton's reagent is a solution of hydrogen peroxide and an iron catalyst that is used to oxidize contaminants or waste waters. Fenton's reagent can be used to destroy organic compounds such as trichloroethylene and tetrachloroethylene ....

, 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
Hydrogen peroxide
Hydrogen peroxide is the simplest peroxide and an oxidizer. Hydrogen peroxide is a clear liquid, slightly more viscous than water. In dilute solution, it appears colorless. With its oxidizing properties, hydrogen peroxide is often used as a bleach or cleaning agent...

 is also generated for phagocytes in a process often referred to as a respiratory burst
Respiratory burst
Respiratory burst is the rapid release of reactive oxygen species from different types of cells....

.

Oxidative phase


In this phase, two molecules of NADP+ are reduced to NADPH, utilizing the energy from the conversion of glucose-6-phosphate
Glucose-6-phosphate
Glucose 6-phosphate is glucose sugar phosphorylated on carbon 6. This compound is very common in cells as the vast majority of glucose entering a cell will become phosphorylated in this way....

 into ribulose 5-phosphate
Ribulose 5-phosphate
Ribulose 5-phosphate is one of the end-products of the pentose phosphate pathway. It is also an intermediate in the Calvin cycle.It is formed by phosphogluconate dehydrogenase, and it can be acted upon by phosphopentose isomerase and phosphopentose epimerase....

.

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
Dehydrogenation
Dehydrogenation is a chemical reaction that involves the elimination of hydrogen . It is the reverse process of hydrogenation. Dehydrogenation reactions may be either large scale industrial processes or smaller scale laboratory procedures....

. 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
6-Phosphogluconate
6-Phosphogluconic acid is an intermediate in the pentose phosphate pathway and the Entner–Doudoroff pathway.It is formed by 6-phosphogluconolactonase, and acted upon by phosphogluconate dehydrogenase to produce ribulose 5-phosphate. It may also be acted upon by 6-phosphogluconate dehydratase to...

 + H+
6-phosphogluconolactonase
6-phosphogluconolactonase
6-Phosphogluconolactonase is an enzyme in the pentose phosphate pathway. It converts 6-phosphogluconolactone to 6-phosphogluconate....

 
Hydrolysis
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...


>-
| 6-phosphogluconate
6-Phosphogluconate
6-Phosphogluconic acid is an intermediate in the pentose phosphate pathway and the Entner–Doudoroff pathway.It is formed by 6-phosphogluconolactonase, and acted upon by phosphogluconate dehydrogenase to produce ribulose 5-phosphate. It may also be acted upon by 6-phosphogluconate dehydratase to...

 + NADP+
ribulose 5-phosphate
Ribulose 5-phosphate
Ribulose 5-phosphate is one of the end-products of the pentose phosphate pathway. It is also an intermediate in the Calvin cycle.It is formed by phosphogluconate dehydrogenase, and it can be acted upon by phosphopentose isomerase and phosphopentose epimerase....

 + NADPH + CO2
6-phosphogluconate dehydrogenase 


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

Non-oxidative phase



Reactants Products Enzymes
>-
| ribulose 5-phosphate
Ribulose 5-phosphate
Ribulose 5-phosphate is one of the end-products of the pentose phosphate pathway. It is also an intermediate in the Calvin cycle.It is formed by phosphogluconate dehydrogenase, and it can be acted upon by phosphopentose isomerase and phosphopentose epimerase....

 
ribose 5-phosphate
Ribose 5-phosphate
Ribose 5-phosphate is both a product and an intermediate of the pentose phosphate pathway. The last step of the oxidative reactions in the pentose phosphate pathway is the production of ribulose-5-phosphate. Depending on the body's state, ribulose-5-phosphate can reversibly isomerize to...

 
>-
| ribulose 5-phosphate
Ribulose 5-phosphate
Ribulose 5-phosphate is one of the end-products of the pentose phosphate pathway. It is also an intermediate in the Calvin cycle.It is formed by phosphogluconate dehydrogenase, and it can be acted upon by phosphopentose isomerase and phosphopentose epimerase....

 
xylulose 5-phosphate
Xylulose 5-phosphate
D-Xylulose 5-phosphate is an intermediate in the Pentose Phosphate Pathway. It is a ketose sugar formed from ribulose-5-phosphate...

 
>-
| xylulose 5-phosphate
Xylulose 5-phosphate
D-Xylulose 5-phosphate is an intermediate in the Pentose Phosphate Pathway. It is a ketose sugar formed from ribulose-5-phosphate...

 + ribose 5-phosphate
Ribose 5-phosphate
Ribose 5-phosphate is both a product and an intermediate of the pentose phosphate pathway. The last step of the oxidative reactions in the pentose phosphate pathway is the production of ribulose-5-phosphate. Depending on the body's state, ribulose-5-phosphate can reversibly isomerize to...

 
glyceraldehyde 3-phosphate
Glyceraldehyde 3-phosphate
Glyceraldehyde 3-phosphate, also known as triose phosphate or 3-phosphoglyceraldehyde and abbreviated as G3P, GADP, GAP, TP, GALP or PGAL, is a chemical compound that occurs as an intermediate in several central metabolic pathways of all organisms...

 + sedoheptulose 7-phosphate
Sedoheptulose 7-phosphate
Sedoheptulose 7-phosphate is an intermediate in the pentose phosphate pathway.It is formed by transketolase and acted upon by transaldolase....

 
transketolase
Transketolase
Transketolase, an enzyme of both the pentose phosphate pathway in animals and the Calvin cycle of photosynthesis, catalyzes two important reactions, which operate in opposite directions in these two pathways...


>-
| sedoheptulose 7-phosphate
Sedoheptulose 7-phosphate
Sedoheptulose 7-phosphate is an intermediate in the pentose phosphate pathway.It is formed by transketolase and acted upon by transaldolase....

 + glyceraldehyde 3-phosphate
Glyceraldehyde 3-phosphate
Glyceraldehyde 3-phosphate, also known as triose phosphate or 3-phosphoglyceraldehyde and abbreviated as G3P, GADP, GAP, TP, GALP or PGAL, is a chemical compound that occurs as an intermediate in several central metabolic pathways of all organisms...

 
erythrose 4-phosphate
Erythrose 4-phosphate
Erythrose 4-phosphate is an intermediate in the pentose phosphate pathway and the Calvin cycle. In addition, it serves as a precursor in the biosynthesis of the aromatic amino acids tyrosine, phenylalanine, and tryptophan....

 + fructose 6-phosphate
Fructose 6-phosphate
Fructose 6-phosphate is fructose sugar phosphorylated on carbon 6 . The β-D-form of this compound is very common in cells. The vast majority of glucose and fructose entering a cell will become converted to this at some point...

 
transaldolase
Transaldolase
Transaldolase is an enzyme of the non-oxidative phase of the pentose phosphate pathway. In humans, transaldolase is encoded by the TALDO1 gene.The following chemical reaction is catalyzed by transaldolase:...


>-
| xylulose 5-phosphate
Xylulose 5-phosphate
D-Xylulose 5-phosphate is an intermediate in the Pentose Phosphate Pathway. It is a ketose sugar formed from ribulose-5-phosphate...

 + erythrose 4-phosphate
Erythrose 4-phosphate
Erythrose 4-phosphate is an intermediate in the pentose phosphate pathway and the Calvin cycle. In addition, it serves as a precursor in the biosynthesis of the aromatic amino acids tyrosine, phenylalanine, and tryptophan....

 
glyceraldehyde 3-phosphate
Glyceraldehyde 3-phosphate
Glyceraldehyde 3-phosphate, also known as triose phosphate or 3-phosphoglyceraldehyde and abbreviated as G3P, GADP, GAP, TP, GALP or PGAL, is a chemical compound that occurs as an intermediate in several central metabolic pathways of all organisms...

 + fructose 6-phosphate
Fructose 6-phosphate
Fructose 6-phosphate is fructose sugar phosphorylated on carbon 6 . The β-D-form of this compound is very common in cells. The vast majority of glucose and fructose entering a cell will become converted to this at some point...

 
transketolase
Transketolase
Transketolase, an enzyme of both the pentose phosphate pathway in animals and the Calvin cycle of photosynthesis, catalyzes two important reactions, which operate in opposite directions in these two pathways...



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
Glucose-6-phosphate dehydrogenase
Glucose-6-phosphate dehydrogenase is a cytosolic enzyme in the pentose phosphate pathway , a metabolic pathway that supplies reducing energy to cells by maintaining the level of the co-enzyme nicotinamide adenine dinucleotide phosphate...

 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
Glucose-6-phosphate dehydrogenase
Glucose-6-phosphate dehydrogenase is a cytosolic enzyme in the pentose phosphate pathway , a metabolic pathway that supplies reducing energy to cells by maintaining the level of the co-enzyme nicotinamide adenine dinucleotide phosphate...

 to produce more NADPH.

See also

  • G6PDH deficiency
    Glucose-6-phosphate dehydrogenase deficiency
    Glucose-6-phosphate dehydrogenase deficiency is an X-linked recessive hereditary disease characterised by abnormally low levels of glucose-6-phosphate dehydrogenase , a metabolic enzyme involved in the pentose phosphate pathway, especially important in red blood cell metabolism. G6PD deficiency is...

     - A hereditary disease that disrupts the pentose phosphate pathway
  • NADPH
  • RNA
    RNA
    Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....

  • thiamine deficiency

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-Bisphosphoglycerate
2,3-Bisphosphoglyceric acid is a three-carbon isomer of the glycolytic intermediate 1,3-bisphosphoglyceric acid . 2,3-BPG is present in human red blood cells at approximately 5 mmol/L...

 (2,3-BPG) metabolism (refer to discussion of hemoglobin
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...

 for the role of 2,3-BPG). Glycolysis provides ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...

 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
Hemolysis
Hemolysis —from the Greek meaning "blood" and meaning a "loosing", "setting free" or "releasing"—is the rupturing of erythrocytes and the release of their contents into surrounding fluid...

. 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
Plasmodium falciparum
Plasmodium falciparum is a protozoan parasite, one of the species of Plasmodium that cause malaria in humans. It is transmitted by the female Anopheles mosquito. Malaria caused by this species is the most dangerous form of malaria, with the highest rates of complications and mortality...

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.

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