The pentose phosphate pathway, also known as the hexose monophosphate diversion, is a fundamental metabolic pathway whose end product is riboses, necessary for nucleotide and nucleic acid synthesis pathways, such as DNA, RNA, ATP, NADH, FAD and coenzyme A.
It also produces NADPH (nicotinamide adenine dinucleotide phosphate), used in various enzymatic reactions. This pathway is very dynamic and capable of adapting its products depending on the momentary needs of the cells.
ATP (adenosine triphosphate) is considered the "energy currency" of the cell, because its hydrolysis can be coupled to a wide range of biochemical reactions.
In the same way, NADPH is an essential second energy currency for the reductive synthesis of fatty acids, cholesterol synthesis, neurotransmitter synthesis, photosynthesis and detoxification reactions, among others.
Although NADPH and NADH are similar in structure, they cannot be used interchangeably in biochemical reactions. NADPH participates in the utilization of free energy in the oxidation of certain metabolites for reductive biosynthesis.
In contrast, NADH is involved in the utilization of free energy from oxidation of metabolites to synthesize ATP.
History and location
The indications of the existence of this path began in 1930 thanks to the researcher Otto Warburg, who is credited with the discovery of NADP +.
Certain observations allowed the discovery of the pathway, particularly the continuation of respiration in the presence of glycolysis inhibitors, such as the fluoride ion.
Then, in 1950, scientists Frank Dickens, Bernard Horecker, Fritz Lipmann and Efraim Racker described the pentose phosphate pathway.
The tissues involved in the synthesis of cholesterol and fatty acids, such as the mammary glands, adipose tissue, and kidneys, have high concentrations of pentose phosphate enzymes.
The liver is also an important tissue for this pathway: approximately 30% of glucose oxidation in this tissue occurs thanks to the enzymes of the pentose phosphate pathway.
Features
The pentose phosphate pathway is responsible for maintaining carbon homeostasis in the cell. Likewise, the pathway synthesizes the precursors of nucleotides and molecules involved in the synthesis of amino acids (the building blocks of peptides and proteins).
It is the main source of reducing power for enzymatic reactions. In addition, it provides the necessary molecules for anabolic reactions and for defense processes against oxidative stress. The last phase of the pathway is critical in redox processes under stress situations.
Phases
The pentose phosphate pathway consists of two phases in the cell cytosol: an oxidative one, which generates NADPH with the oxidation of glucose-6-phosphate to ribose-5-phosphate; and a non-oxidative one, which involves the interconversion of three, four, five, six and seven carbon sugars.
This route presents reactions shared with the Calvin cycle and with the Entner – Doudoroff pathway, which is an alternative to glycolysis.
Oxidative phase
The oxidative phase begins with the dehydrogenation of the glucose-6-phosphate molecule at carbon 1. This reaction is catalyzed by the enzyme glucose-6-phosphate dehydrogenase, which has a high specificity for NADP +.
The product of this reaction is 6-phosphonoglucon-δ-lactone. This product is then hydrolyzed by the enzyme lactonase to give 6-phosphogluconate. The latter compound is taken up by the enzyme 6-phosphogluconate dehydrogenase and becomes ribulose 5-phosphate.
The enzyme phosphopentose isomerase catalyzes the final step of the oxidative phase, which involves the synthesis of ribose 5-phosphate by the isomerization of ribulose 5-phosphate.
This series of reactions produces two molecules of NADPH and one molecule of ribose 5-phosphate for every molecule of glucose 6-phosphate that enters this enzymatic pathway.
In some cells, the requirements for NADPH are greater than those for ribose 5-phosphate. Therefore, the enzymes transketolase and transaldolase take ribose 5-phosphate and convert it into glyceraldehyde 3-phosphate and fructose 6-phosphate, giving way to the non-oxidative phase. These last two compounds can enter the glycolytic pathway.
Non-oxidative phase
The phase begins with an epimerization reaction catalyzed by the enzyme pentose-5-phosphate epimerase. Ribulose-5-phosphate is taken up by this enzyme and converted to xylulose-5-phosphate.
The product is taken up by the enzyme transketolase that acts together with the coenzyme thiamine pyrophosphate (TTP), which catalyzes the passage of xylulose-5-phosphate to ribose-5-phosphate. With the transfer of ketose to aldose, glyceraldehyde-3-phosphate and sedoheptulose-7-phosphate are produced.
The enzyme transaldolase then transfers the C3 from the sedoheptulose-7-phosphate molecule to glyceraldehyde-3-phosphate, producing a four-carbon sugar (erythrose-4-phosphate) and a six-carbon sugar (fructose-6 -phosphate). These products are capable of feeding the glycolytic pathway.
The transketosal enzyme acts again to transfer a C2 from xylulose-5-phosphate to erythrose-4-phosphate, resulting in fructose-6-phosphate and glyceraldehyde-3-phosphate. As in the previous step, these products can enter glycolysis.
This second phase connects the pathways that generate NADPH with those responsible for synthesizing ATP and NADH. Furthermore, the products fructose-6-phosphate and glyceraldehyde-3-phosphate can enter gluconeogenesis.
Related diseases
Different pathologies are related to the pentose phosphate pathway, between these neuromuscular diseases and different types of cancer.
Most clinical studies focus on quantifying the activity of glucose-6-phosphate dehydrogenase, because it is the main enzyme responsible for regulating the pathway.
In the blood cells belonging to individuals susceptible to anemia, they present a low enzymatic activity of glucose-6-phosphate dehydrogenase. In contrast, cell lines related to carcinomas in the larynx exhibit high enzyme activity.
NADPH is involved in the production of glutathione, a key peptide molecule in protection against reactive oxygen species, involved in oxidative stress.
Different types of cancer lead to the activation of the pentose pathway and it is associated with processes of metastasis, angiogenesis and responses to chemotherapy and radiotherapy treatments.
On the other hand, chronic granulomatous disease develops when there is a deficiency in the production of NADPH.
References
- Berg, JM, Tymoczko, JL, Stryer, L (2002). Biochemistry. WH Freeman
- Konagaya, M., Konagaya, Y., Horikawa, H., & Iida, M. (1990). Pentose phosphate pathway in neuromuscular diseases – evaluation of muscular glucose 6 – phosphate dehydrogenase activity and RNA content. Rinsho shinkeigak. Clinical neurology, 30 (10), 1078-1083.
- Kowalik, MA, Columbano, A., & Perra, A. (2017). Emerging role of the pentose phosphate pathway in hepatocellular carcinoma. Frontiers in oncology, 7, 87.
- Patra, KC, & Hay, N. (2014). The pentose phosphate pathway and cancer. Trends in biochemical sciences, 39 (8), 347–354.
- Stincone, A., Prigione, A., Cramer, T., Wamelink, M., Campbell, K., Cheung, E.,… & Keller, MA (2015). The return of metabolism: biochemistry and physiology of the pentose phosphate pathway. Biological Reviews, 90 (3), 927–963.
- Voet, D., & Voet, JG (2013). Biochemistry. Artmed Editor.