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oxidative phase

Image: “oxidativer Teil des Pentosephosphatweges” by Yikrazuul. License: Public Domain


Definition

The pentose phosphate pathway may be referred to as the pentose phosphate cycle, phosphogluconate pathway, hexose monophosphate cycle, or Warburg-Dickens-Horecker shunt. They all mean the same thing: the provision of NADPH and pentoses that can be used in other biochemical pathways.

NADPH is mainly found in tissues in which biosynthetic processes are important, which means that in those tissues, the pentose phosphate pathway is required to generate NADPH by reducing glucose. Examples are hepatocytes and adipocytes, which synthesize fatty acids, or the ovaries, testes and adrenal cortex, which synthesize steroids.

In addition to the synthesis of fatty acids, NADPH is also required for the biosynthesis of cholesterol, neurotransmitters, and nucleotides via phosphoribosyl-pyrophosphate (PRPP). Furthermore, NADPH-dependent reductases are involved in tissue detoxification and are further used in the reduction of glutathione in erythrocytes. The pentose phosphate pathway can be divided into 2 distinct phases: a first oxidative and a second non-oxidative (reductive) phase. Both processes occur exclusively in the cytoplasm.

Oxidative Phase

In the first oxidative phase of the pentose phosphate pathway, glucose is oxidized to generate 2 molecules of NADPH. This step is essentially irreversible and the committing step, as the reactions are strongly exergonic.

oxidative phase

Image: ‘Oxidative Phase’ by Yikrazuul. License: Public Domain

First Reaction

The initial metabolite of the pentose phosphate pathway is glucose-6-phosphate, 2 NADP+, and H2O. The oxidative phase starts with dehydrogenation at the C1 atom of glucose-6-phosphate, a reaction catalyzed by glucose-6-phosphate dehydrogenase (G6PD). The reaction product is 6-phosphogluconolactone. Conversely, NADP+ is reduced to NADPH during this process.

Second Reaction

6-phosphogluconolactone is hydrolyzed to 6-phosphogluconate by a specific enzyme called lactonase.

Third Reaction

The oxidative decarboxylation of 6-phosphogluconate by gluconate-6-phosphate dehydrogenase yields 3-keto-6-phosphogluconate, which is converted to ribulose-5-phosphate, a substrate for non-oxidative reactions, and NADPH.

Non-Oxidative Phase

This second, non-oxidative phase is reversible and reductive. It yields pentoses used in the synthesis of nucleotides and catalyzes the interconversion of 3, 4, 5, 6, and 7-carbon sugars. This, in turn, may result in intermediates, which, for example, may enter glycolysis.

non-oxidative phase

Image: ‘The non-oxidative steps of the pentose phosphate pathway’  by Yikrazuul. License: (CC BY-SA 3.0)

First Reaction

Ribulose-5-phosphate generated in the oxidative phase is partly converted to xylulose-5-phosphate, catalyzed by ribulose-5-phosphate epimerase, and partly isomerized by the enzyme phosphopentose isomerase (ribose-5-phosphate isomerase) to ribose-5-phosphate.

Second Reaction

The 2 resulting C5 carbohydrates are now required for the next step: xylulose-5-phosphate serves as a C2 donor. The enzyme transketolase transfers 2 carbon fragments to the pentose ribose-5-phosphate, which yields glyceraldehyde-3-phosphate and sedoheptulose-7-phosphate.

Third Reaction

The 2 products of the previous step continue to transfer carbon fragments: The enzyme transaldolase transfers 3 carbon atoms of sedoheptulose-7-phosphate to glyceraldehyde-3-phosphate; thus, 2 new carbohydrates are generated: erythrose-4-phosphate and fructose-6-phosphate.

Fourth Reaction

This step is also catalyzed by a transketolase; together with erythrose-4-phosphate, generated in the third reaction, another xylulose-5-phosphate is used to generate another fructose-6-phosphate and an additional glyceraldehyde-3-phosphate.

Ultimately, this means that 3 molecules of ribose-5-phosphate can generate 2 molecules of fructose-6-phosphate and 1 molecule of glyceraldehyde-3-phosphate, which may be fed into the glycolytic pathway. Furthermore, fructose-6-phosphate can be converted back into glucose-6-phosphate and enter into a new pentose phosphate pathway.

Regulation Mechanisms of the Pentose Phosphate Pathway

The demand and availability of different reaction products, intermediates, and substrates (starting reactants) of the pathway determine which part of the pentose phosphate pathway is operative and how fast the part is. The most important regulatory factor is intracellular NADP+ concentration.

In a cell with low NADP+ levels, the dehydrogenation of glucose-6-phosphate is inhibited, which means that hardly any NADPH is produced. Only when NADPH is required for reductive biosynthesis reactions, is the first phase of the pentose phosphate pathway active. It is assumed that insulin upregulates the transcription rate of glyceraldehyde-3-phosphate dehydrogenase, which amplifies the first step of the pentose phosphate pathway.

While the concentration of NADP+ mainly has an effect on the first phase of the pentose phosphate pathway, the concentrations of different substrates tend to influence the second phase.

Energy Balance of the Pentose Phosphate Pathway

As the pentose phosphate pathway and the glycolytic pathway are directly connected and defined by a coordinated interplay or exchange of various molecules between them, the output of the pentose phosphate pathway is determined by the needs of the cell. Four different metabolic situations are described as follows:

If the cell, for example, requires many nucleotides for DNA synthesis, it has to generate a large amount of ribose-5-phosphate. For this, the cell can reverse the reactions described above and, using ATP, can generate 3 molecules of ribose-5-phosphate from 2 fructose-6-phosphate molecules and 1 molecule of glyceraldehyde-3-phosphate.

If the cell requires both ribose-5-phosphate and NADPH, the oxidative phase of the pentose phosphate pathway is triggered, forming 2 molecules of NADPH and 1 molecule of ribose-5-phosphate from 1 molecule of glucose-6-phosphate.

If the cell needs a large amount of NADPH for reductive biosynthesis, it will use the reaction products of the second phase of the pentose phosphate pathway, glyceraldehyde-3-phosphate and fructose-6-phosphate, converting them back to glucose-6-phosphate and feeding them into the pentose phosphate pathway. This way, 1 molecule of glucose-6-phosphate can convert 12 NADP+ to NADPH.

If the cell needs both NADPH and ATP, products of the pentose phosphate pathway, namely fructose-6-phosphate and glyceraldehyde-3-phosphate, will enter the glycolytic pathway (rather than reverting to glucose-6-phosphate). Thud, 3 molecules of glucose-6-phosphate can be converted into 5 pyruvate molecules, 6 NADPH, and 8 ATP.

Pathophysiology

As mentioned above, NADPH generated in the pentose phosphate pathway plays a key role in antioxidant defenses (cellular detoxification) as it reduces oxidized glutathione. Glutathione is a tripeptide that reduces reactive oxygen species and thus, combats the so-called oxidative stress that causes many diseases.

If the pentose phosphate pathway is not functioning properly, e.g. in case of a G6PD deficiency, an insufficient amount of NADPH is generated. As the pentose phosphate pathway is the only source of reduced glutathione in erythrocytes, this leads to cell decay; thus, individuals with G6PD deficiency are at risk of hemolytic anemia. The associated clinical presentation is called Favism.

However, G6PD deficiency confers natural protection against malaria as the pathogenic parasites require reduced glutathione for their growth. This selective advantage explains why this genetic deficiency is widespread in sub-Saharan Africa and the Mediterranean region.

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