Pentose Phosphates Cycle (With Diagram) | Carbohydrates

In this article we will discuss about the pentose phosphates cycle, explained with the help of suitable diagrams.

This series of reactions enables the cells to metabolize glucose-6-℗ without using the glycolytic pathways; it is therefore also called “hexosemonophosphate shunt”, or “phosphogluconate pathway” (after the name of one of the inter­mediates of the cycle), or “Dickens-Horecker pathway” (in view of the con­tribution of these two authors to the study of this cycle).

This pathway distinguishes itself from glycolysis by two main characteristics: the oxidation does not require any ATP, and it is mainly an aerobic process because there is no specific mechanism (other than the electron transport chain) permitting the reoxidation of the coenzymes reduced during the oxidation reactions; however some reactions (especially during the biosynthesis of fatty acids or cholesterol, see figs. 5-19 and 5-22) use NADPH and therefore generate NADP⁺.

It may be said that the advantage of this pathway is fourfold:

1. It provides pentose phosphates which are indispensable for the synthesis of nucleotides found in various coenzymes and in nucleic acids;

2. It permits the formation of NADPH required for various reactions particularly for the synthesis of fatty acids and steroids;

3. It can perform the oxidation of glucose into CO₂, with formation of ATP in appreciable quantity, if transhydrogenation (from NADPH to NAD⁺) can take place and provided the NADPH is not used to carry out reactions requir­ing this reduced coenzyme;

4. In photosynthetic organisms, it permits the synthesis of carbohydrates (and therefore of other organic compounds) from CO₂.

Oxidation of Glucose-6-℗ into Ribulose-5-℗:

The reactions permitting this transformation are represented in figure 4-39.

Glucose-6-℗-dehydrogenase, a NADP⁺ enzyme (discovered by Warburg) catalyzes the oxidation of glucose-6-℗ to 6-℗-gluconic acid. It appears that there is intermediate formation of 6-phosphoglucono-δ-lactone, which hydrolyzes itself either spontaneously or by the effect of a lactonase.

Then, a second oxidation takes place under the effect of 6-℗-gluconate dehydrogenase, also a NADP⁺ enzyme, with possible formation of an intermediate (3-keto-6-℗-gluconic acid) which is decarboxylated to D-ribulose-5-℗.

For each carbon atom leaving in the form of CO₂ there are therefore two oxidations both accompanied by a formation of NADPH, the electrons of which can be transferred to NAD⁺, and from there to the electron transport chain; 3 ATP will be formed per pair of electrons, i.e. 6 ATP.

Since the cycle starts from glucose-6-℗, 1 ATP (required for the phosphorylation of glucose) must be deducted in order to draw the balance starting from glucose; the oxidation to ribulose-5-℗ is then represented by the departure of a CO₂ and a net gain of 5 ATP.

Besides this energetic advantage of NADPH, it should be stressed that this reduced coenzyme is necessary for some important reactions, particularly for the biosynthesis of fatty acids (see fig. 5-19), the synthesis of sterols (fig. 5-22), the reduction of dihydrofolic acid to tetrahydrofolic acid, the hydroxylation of a wide variety of compounds (for example, the hydroxylation of tyrosine and various sterols), the carboxylation of pyruvic acid to malic acid (fig. 4-34), etc.

The two oxidations of the cycle of pentose-phosphates which generate NADPH, therefore provide the reduced coenzyme indispensable to other important reactions of cellular metabolism.

Isomerization of Ribulose-5-℗:

As may be observed in figure 4-40, ribulose-5-℗ which is a ketopentose, can, on the one hand, be converted into an aldose, the ribose-5-℗, bypliosphoribose isomerase (whose action is similar to that of phosphohexose isomerase ob­served in glycolysis) thus providing the pentose required for the formation of nucleotides needed to synthesize nucleotide coenzymes and nucleic acids.

On the other hand, ribulose-5-℗ can also be converted into an epimer ketose (the change in configuration is relative to carbon 3), xylulose-5-℗, by phos- phoketopentose epimerase.

These two reactions are important because they represent the junction point between the first part of the cycle (oxidation of glucose-6-℗ to ribulose-5-℗) and the second part (reversible interconversion of pentose-℗ into hexose-℗ by transaldolization and transketolization).

Interconversions of Pentose-℗ and Hexose-℗ by Transaldolization and Transketolization:

Transaldolization is a transfer of a group of 3 carbon atoms (dihydroxyacetone) from a donor which is a ketose phosphate (fructose-6-℗, sedoheptulose-7-℗) to an acceptor which is an aldose phosphate (glyceral- dehyde-3-℗, erythrose-4-℗).

This transfer takes place thanks to the formation of an intermediate combination (enzyme-substrate) between the εNH₂ group of a molecule of lysine of the enzyme and the C = O of the dihydroxyacetone group. The principle of transaldolization together with an example, are repre­sented in figure 4-41.

Transketolization consists of a transfer of a group of 2 carbon atoms (ketol or glycolaldehyde) from a donor which is a ketose phosphate (xylulose-5-℗, fructose-6-℗, sedoheptulose-7-℗) to an acceptor which is an aldose phosphate (glyceraldehyde-3-℗, erythrose-4-℗, ribose-5-℗).

Transketolase has the coenzyme thiamine pyrophosphate, on which is fixed the glycoaldehyde group, thus forming an intermediate combination similar to the one described in our study of oxidative decarboxylation of pyruvic acid (see fig. 4-36). The principle of transketolization, together with two examples, are represented in figure 4-42.

The cycle of pentose-phosphates proceeds by a set of reactions including two transketolizations, a transaldolization (these three reactions are represented in detail in figures 4-41 and 4-42) and an aldolization followed by the action of fructose-1, 6-bisphosphatase (two reactions which we studied in connection with glycolysis).

Energy Balance:

We have seen that in the oxidative part of the cycle, one molecule of glucose-6-℗ yielded one molecule of CO₂. Starting from 6 molecules of glucose-6-℗, one obtains 6 molecules of CO₂ and 6 molecules of ribulose-5-℗ in this oxidative phase.

In the interconversion phase, 6 ribulose-5-℗ are con­verted into 5 glucose-6-℗. It may therefore be said that in one turn of the cycle, one molecule of glucose out of six has been completely oxidized (even if, in reality, the 6CO₂ do not originate from a single molecule of glucose-6-® but from the six initial molecules of glucose-6-℗).

In fact, the 5 glucose-6-℗ found at the end of one turn of the cycle, are not 5 of the initial 6 molecules, because there has been a considerable redistribution of carbon atoms during the trans­aldolization and transketolization reactions.

But on the basis of the set of reactions, the balance of one turn of the cycle may be written as follows:

6 glucose-6-℗ + 12 NADP⁺ → 5 glucose-6-℗ + 6CO₂ + P_i + 12 NADPH + 12 H⁺

or simplifying,

1 glucose-6-℗ + 12 NADP⁺ → 6 CO₂ + P_i + 12 (NADPH + H⁺)

It is observed that the pentose-phosphates cycle yields, for each molecule of glucose oxidized, 12 molecules of NADPH which can be either used in reac­tions requiring the reduced form of this coenzyme, or enter (if transhydrogenation from NADPH to NAD⁺ takes place) in the electron transport chain and then enable the formation of 3 x 12 = 36 molecules of ATP.

To refer this energy balance to glucose, one must deduct 1 ATP required for the phos­phorylation of glucose to glucose-6-℗, which gives a gain of 35 ATP (a figure that can be compared with the gain of 38 ATP during the complete oxidation of glucose by the glycolytic pathway followed by Krebs cycle, and the gain of 2 ATP only during anaerobic glycolysis).

Reversibility of Inter-Conversions:

The transaldolization and transketolization reactions are reversible; so also, the reaction catalyzed by aldolase; as for the reaction catalyzed by fructose-1, 6-bisphosphatase, we have seen that it is carried out in the reverse direction thanks to phosphofructokinase. One can therefore pass from hexoses to pen­toses, either by the oxidative pathway, or by interconversions (i.e. in the opposite direction).

The cells use both these possibilities to form ribose-5-℗ which is necessary for the synthesis of nucleic acids; it must be noted that the oxidative pathway requires NADP⁺, and it is only if NADPH can be reoxidized that the cells can continue to utilize this pathway for the synthesis of ribose-5-℗.

But the NADP⁺/NADPH ratio in cytosol of the rat liver cell is about 0.01 (while the NADP7NADH ratio is about 700) and the reactions permitting the reoxidation of NADPH into NADP⁺ are limited (see for example the biosynthesis of fatty acids in fig. 5-19, and that of cholesterol in fig. 5-22).

The cells make greater use of the pathway of interconversions than the oxidative pathway, on the one hand because the former is more economic than the latter (by the pathway of interconversions, 5 hexoses are sufficient to form 6 pentoses whereas 6 hexoses are required by the oxidative pathway, and on the other hand, because the NADP⁺ required for the oxidative pathway is present in limiting quantities in the cells.