Also known as the pentose phosphate shunt, Pentose Phosphate Pathway (PPP) is one of the metabolic pathways (the others being glycolysis and Krebs cycle) that specifically serves to produce NADPH (Reduced nicotinamide adenine dinucleotide phosphate is a reduced form of NADP+) and ribose 5-triphosphate (R5P).
Products of the Pentose Phosphate Pathway are essential for normal cell functioning and proliferation thus making PPP one of the most important metabolic processes in various organisms.
* Ribose 5 phosphate is required for the synthesis of nucleic acid while NADPH is essential for the synthesis of various organic molecules (non-essential amino acids, sterols, and fatty acids etc). As well, NADPH is involved in the conversion of oxidized glutathione to glutathione, a process that contributes to cellular antioxidant defenses.
* In most organisms, the Pentose Phosphate Pathway occurs in the cytosol (this is where most enzymes involved in the processes are located). In plants, however, some of the steps of the pathway occur in the plastids.
For the majority of organisms, metabolic pathways have been shown to occur in the cytosol (cytoplasmic matrix/cytoplasm) where the majority of associated enzymes are located. In some organisms (plants, parasites, protozoa, etc), however, some of the steps in the pathway occur in some of the organelles like glycosomes, the endoplasmic reticulum, and plastids.
Generally, the Pentose Phosphate Pathway may be viewed as a pathway that branches off from glycolysis. During glycolysis, glucose, a 6-carbon molecule, is converted into glucose-6-phosphate by the addition of a phosphate group.
This occurs through a process known as phosphorylation. Here, hexokinase (or glucokinase in some cases) is involved in the addition of the phosphate group onto the sixth carbon of glucose.
The production of glucose-6-phosphate is commonly regarded as the most important step/phase of metabolism given that it is the convergence point for all metabolic pathways including glycogen synthesis, glycolysis, and Pentose Phosphate Pathway. For all these processes to occur, then this step has to occur.
Following the production of glucose-6-phosphate, the manner in which the Pentose Phosphate Pathway proceeds is largely dependent on the needs of the cell. For this reason, before looking at the pathway in detail, it's important to consider several scenarios (with regards to cellular needs) and their impact on the pathway.
Cell requires both ribose 5-phosphate and NADPH - In a scenario where the cell requires both ribose-5-phosphate and NADPH, then glucose-6-phosphate enters the oxidative phase in order to produce these products. For cells with a high demand for the two molecules, studies have shown that only the oxidative phase occurs. Here, then, the non-oxidative phase of the pathway may not take place.
In this reaction, a single molecule of glucose-6-phosphate (in the presence of a water molecule and NADP+) produces two (2) molecules of NADPH and a single molecule of ribulose 5-phosphate. Other products of these reactions include hydrogen ions and carbon dioxide.
Some of the enzymes involved in the oxidative phase include glucose 6-phosphate dehydrogenase (responsible for the production of NADPH), lactonase (involved in the production of 6-phosphogluconate), and 6-phosphogluconate dehydrogenase which is involved in the production of ribulose 5-phosphate and an additional molecule of NADPH.
A cell requires ribose-5-phosphate - In a case where the cell requires higher amounts of ribose 5-phosphate than NADPH, (e.g. cells that are about to undergo cell division and thus have to replicate the nucleic acid), the glucose 6-phosphate enters the glycolytic pathway to produce fructose 6-phosphate and glyceraldehyde 3-phosphate (GAP).
The two molecules are then involved in the production of ribose 5-phosphate through the reverse non-oxidative phase. The oxidative phase is also prevented from taking place and therefore NADPH is not produced. Unlike the previous scenario, ATP energy is required here to generate 6 ribose 5-phosphate molecules. In addition, ADP and two (2) ions of hydrogen are produced.
* In this phase, ATP is required to transform fructose 6-phosphate (which was produced from glucose 6-phosphate in the glycolytic process) into fructose 1,6 bisphosphate. It's fructose 1,6 bisphosphate that is then converted to glyceraldehyde 3-phosphate (GAP involved in the production of ribose 5-phosphate) and dihydroxyacetone phosphate.
Cell requires high amounts of NADPH - The third scenario is where the cell demands higher amounts of NADPH than ribose 5-phosphate. A good example of such cells are fat cells (involved in fatty acids biosynthesis). Here, glucose 6-phosphate first enters the oxidative phase to produce ribose 5-phosphate. This is then followed by the non-oxidative phase which results in the production of fructose 6-phosphate and glyceraldehyde 3-phosphate.
The two products of the non-oxidative phase are then converted to glucose 6-phosphate through a process known as gluconeogenesis. Here, it's worth noting that during the oxidative phase, glucose 6-phosphate uses a water molecule and NADP+ to release two molecules of NADPH, carbon dioxide, and two hydrogen ions. Therefore, NADPH is released during the oxidative phase.
The non-oxidative phase also allows the ribose 5-phosphate that was produced to be transformed back to glucose 6-phosphate (they are recycled) repeating the process. As a result, this process is primarily involved in the production of high amounts of NADPH which is required by the cell.
* While the oxidative phase is sufficient for the production of the required NADPH, the non-oxidative phase allows for recycling of ribose 5-phosphate into glucose 6-phosphate
Cell requires NADPH and ATP - As is the case with the scenario where the cell requires high amounts of NADPH, this scenario involves both the oxidative and non-oxidative phase. However, the end products of the non-oxidative phase do not undergo gluconeogenesis.
During the oxidative phase, glucose 6-phosphate is converted to NADPH and ribose 6-phosphate. This phosphate (ribose 6-phosphate) then enters the non-oxidative phase to produce fructose 6-phosphate and glyceraldehyde 3-phosphate. In turn, the two enter the glycolytic pathway where they are involved in the production of pyruvate and two molecules of ATP.
As mentioned, there are two main phases of the Pentose Phosphate Pathway. The oxidative phase of the pathway has been shown to be particularly active in the majority of eukaryotic cells and serves to convert glucose 6-phosphate into NADPH, ribulose 5-phosphate as well as carbon dioxide.
The non-oxidative phase, on the other hand, has been shown to be ubiquitous where intermediates of glycolysis ( fructose 6-phosphate and glyceraldehyde 3-phosphate) are metabolized to produce ribose 5-phosphate which is required for the synthesis of nucleic acids.
Moreover, the ribose is also involved in the production of sugar phosphates that serve as the precursors of amino acid synthesis. This section will focus on the different steps/stages of both oxidative and non-oxidative phases of the Pentose Phosphate Pathway.
As mentioned, the oxidative phase of the Pentose Phosphate Pathway is to oxidize the glucose molecule (glucose 6-phosphate) and ultimately produce the much-needed NADPH (a reducing agent).
This phase of the pathway consists of several important steps that include:
Step 1 - In this step of the oxidative phase, the enzyme glucose 6-phosphate dehydrogenase, in the presence of NADP+ (a universal electron acceptor), converts glucose 6-phosphate into 6 phosphoglucono delta lactone.
During this reaction, the NADP+ molecule, which is an electron acceptor, accepts two electrons from the glucose 6-phosphate. As a result, a reduced form of NADP+ is formed (NADPH) as well as an extra hydrogen ion. By releasing the two electrons, glucose 6-phosphate is then converted to 6-phosphoglucono-delta-lactone.
Step 2 - The second step of the oxidative phase is aimed at preparing the 6-phosphoglucono-delta-lactone for decarboxylation (removal of the carboxyl group from the molecule). For this to occur, the molecule is first hydrated under the influence of lactonase (a protein involved in hydrolysis reactions).
This reaction transforms the 6-phosphoglucono-delta-lactone into 6 phosphogluconate and a hydrogen ion. In this form, the molecule is ready for decarboxylation.
Step 3 - Then, the 6 phosphogluconate undergoes decarboxylation to form ribulose 5-phosphate (a pentose or 5 carbon molecule). In this reaction, the enzyme 6-phosphogluconate is involved in the decarboxylation of the 6-phosphogluconate molecule.
This reaction not only entails the removal of the carboxyl group on the molecule (6-phosphogluconate) to produce carbon dioxide, but also the release of two electrons that are accepted by NADP+ to form NADPH. Here, the reduction of NADP+ results in the net increase in NADPH.
Step 4 - The last reaction of the oxidative phase, also commonly referred to as an isomerization reaction, results in the formation of an isomer. During this reaction, the enzyme phosphopentose isomerase is responsible for converting the ribulose (ribulose 5-phosphate) into ribose 5-phosphate.
* The rate at which these reactions occur largely depend on the needs of the cell. Being an electron donor required for the reduction of oxidized compounds, NADPH is largely produced for a range of redox reactions including reductive biosynthesis (e.g. in the synthesis of such molecules as steroid hormones, fatty acids, and non-essential amino acids, etc), detoxification, as well as generation of reactive oxygen species etc. Here, the reactions yield NADP+ following the reduction of NADPH.
Generally, the oxidative phase of the pentose phosphate pathway can be represented as follows:
By the end of the oxidation phase, a single molecule of glucose 6-phosphate produces two molecules of NADPH and a single molecule of ribose 5-phosphate (a pentose sugar). As mentioned, NADPH and ribose sugar have different functions.
Whereas NADPH is used for a range of processes including biosynthesis of various macromolecules and detoxification among others, the ribose sugar, on the other hand, is used to generate various nucleotide-based molecules (DNA, RNA, FAD, and CoA, etc).
Generally, cells of the body may require more NADPH than ribose 5-phosphate given that there are many more cell processes that require this molecule. For this reason, some of the ribose 5-phosphate molecules are recycled to produce glucose 6-phosphate which can then re-enter the oxidative phase in order to produce more NADPH. These reactions (involved in recycling ribose 5-phosphate) occur in the non-oxidative phase.
As is the case with the oxidative phase, the non-oxidative phase can be divided into 4 main stages/steps that include:
Step 1 - During the first stage of the non-oxidative phase, there are two main reactions that ultimately result in the production of xylulose 5-phosphate. During the first reaction, phosphopentose isomerase is involved in the conversion of ribose 5-phosphate into ribulose 5-phosphate.
This is the converted into Xylulose 5-phosphate during the second reaction by phosphopentose epimerase. Given that this step starts with two molecules of ribose 5-phosphate, the end products are two molecules of Xylulose 5-phosphate.
Step 2 - During the second stage of the non-oxidative phase, a single molecule of Xylulose 5-phosphate (from the first step) combines with a single molecule of ribose 5-phosphate in the presence of the enzyme transketolase to form Sedoheptulose 7-phosphate and Glyceraldehyde 3-phosphate. This reaction is dependent on a co-factor known as thiamine pyrophosphate.
In the presence of this co-factor, the enzyme (transketolase) removes a two carbon group located on the Xylulose 5-phosphate and adds it onto the ribose 5-phosphate. This results in the production of a seven carbon molecule (Sedoheptulose 7-phosphate) and a three carbon molecule (Glyceraldehyde 3-phosphate).
Step 3 - During the third step, the two molecules produced during the second step are used to produce erythrose 4-phosphate and fructose 6-phosphate. Here, an enzyme known as transaldolase is involved in the transfer of a three carbon group from the Sedoheptulose 7-phosphate onto the Glyceraldehyde 3-phosphate.
In the process, the Sedoheptulose 7-phosphate is transformed into the erythrose 4-phosphate while the Glyceraldehyde 3-phosphate is converted to fructose 6-phosphate.
Step 4 - The fourth step of the non-oxidative phase is the final step. In this step, the erythrose 4-phosphate is combined with one molecule of Xylulose 5-phosphate (from step 1) to form fructose 6-phosphate and glyceraldehyde 3-phosphate.
This reaction is catalyzed by the enzyme transketolase and involves the transfer of the two carbon groups on xylulose 5-phosphate onto the erythrose 4-phosphate. As a result, the erythrose 4-phosphate is converted to fructose 6-phosphate while xylulose 5-phosphate is transformed into glyceraldehyde 3-phosphate (GAP).
* Therefore, in general, the non-oxidative phase as a whole serves to convert the ribose 5-phosphate from the oxidative phase into fructose 6-phosphate and glyceraldehyde 3-phosphate which are glycolytic intermediates involved in the production of Glucose 6-phosphate.
As previously mentioned, the main function of this phase (non-oxidative) is to recycle ribose 5-phosphate into glucose 6-phosphate. Therefore, where there is a high demand for NADPH, this phase plays an important role in recycling the ribose to produce intermediates that are in turn used to form glucose 6-phosphate. The glucose then enters the oxidative phase to produce two molecules of NADPH and a single ribose 5-phosphate as the cycle continues.
The non-oxidative phase can be represented as follows:
Differences between cytosol and cytoplasm
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Anna Stincone et al. (2015). The return of metabolism: biochemistry and physiology of the pentose phosphate pathway.
James D. Mauseth. (1991). Botany: An Introduction to Plant Biology.
Mary K Campbell and Shawn O. Farrell. (1991). Biochemistry.
Marta Anna Kowalik, Amedeo Columbano and Andrea Perra. (2017). Emerging Role of the Pentose Phosphate Pathway in Hepatocellular Carcinoma.
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