Glucose Is Sometimes Diverted throughthe Pentose Phosphate Pathway

Glucose Is Sometimes Diverted throughthe Pentose Phosphate Pathway

The pentose phosphate pathway is an alternative to glycolysis and differs from it in several important ways. In glycolysis, one of our most important concerns was the production of ATP. In the pentose phosphate pathway, the production of ATP is not the crux of the matter. As the name of the pathway indicates, five-carbon sugars, including ribose, are produced from glucose. Ribose and its derivative deoxyribose play an important role in the structure of nucleic acids. Another important facet of the pentose phosphate pathway is the production of nicotinamide adenine dinucleotide phosphate (NADPH), a compound that differs from nicotinamide adenine dinucleotide (NADH) by having one extra phosphate group esterified to the ribose ring of the adenine nucleotide portion of the molecule (Figure 18.14). A more important difference is the way these two coenzymes function. NADH is produced in the oxidative reactions that give rise to ATP. NADPH is a reducing agent in biosynthesis, which, by its very nature, is a reductive process.

The pentose phosphate pathway begins with a series of oxidation reactions that produce NADPH and five-carbon sugars. The remainder of the path-way involves nonoxidative reshuffling of the carbon skeletons of the sugars involved. The products of these nonoxidative reactions include substances such as fructose-6-phosphate and glyceraldehyde-3-phosphate, which play a role in glycolysis. Some of these reshuffling reactions will reappear when we look at the production of sugars in photosynthesis.

What are the oxidative reactions of the pentose phosphate pathway?

In the first reaction of the pathway, glucose-6-phosphate is oxidized to 6-phosphogluconate (Figure 18.15, top). The enzyme that catalyzes this reaction is glucose-6-phosphate dehydrogenase. Note that NADPH is produced by the reaction.

The next reaction is an oxidative decarboxylation, and NADPH is produced once again. The 6-phosphogluconate molecule loses its carboxyl group, which is released as carbon dioxide, and the five-carbon keto-sugar (ketose) ribulose-5-phosphate is the other product. The enzyme that catalyzes this reaction is 6-phosphogluconate dehydrogenase. In the process, the C-3 hydroxyl group of the6-phosphogluconate is oxidized to form a β-keto acid, which is unstable and readily decarboxylates to form ribulose-5-phosphate.

What are the nonoxidative reactions of the pentose phosphate pathway, and why are they important?

In the remaining steps of the pentose phosphate pathway, several reactions involve transfer of two- and three-carbon units. To keep track of the carbon backbone of the sugars and their aldehyde and ketone functional groups, we shall write the formulas in the open-chain form.

There are two different reactions in which ribulose-5-phosphate isomer-izes. In one of these reactions, catalyzed by phosphopentose-3-epimerase, there is an inversion of configuration around carbon atom 3, producing xylulose-5-phosphate, which is also a ketose (Figure 18.15, bottom). The other isomeriza-tion reaction, catalyzed by phosphopentose isomerase, produces a sugar with an aldehyde group (an aldose) rather than a ketone. In this second reaction, ribulose-5-phosphate isomerizes to ribose-5-phosphate (Figure 18.15, bottom). Ribose-5-phosphate is a necessary building block for the synthesis of nucleic acids and coenzymes such as NADH.

The group-transfer reactions that link the pentose phosphate pathway with glycolysis require the two five-carbon sugars produced by the isomeriza-tion of ribulose-5-phosphate. Two molecules of xylulose-5-phosphate and one molecule of ribose-5-phosphate rearrange to give two molecules of fructose-6-phosphate and one molecule of glyceraldehyde-3-phosphate. In other words, three molecules of pentose (with five carbon atoms each) give two molecules of hexose (with six carbon atoms each) and one molecule of a triose (with three carbon atoms). The total number of carbon atoms (15) does not change, but there is considerable rearrangement as a result of group transfer.

Two enzymes, transketolase and transaldolase, are responsible for the reshuf-fling of the carbon atoms of sugars such as ribose-5-phosphate and xylulose-5-phosphate in the remainder of the pathway, which consists of three reactions. Transketolase transfers a two-carbon unit. Transaldolase transfers a three-carbon unit. Transketolase catalyzes the first and third reactions in the rear-rangement process, and transaldolase catalyzes the second reaction. The results of these transfers are summarized in Table 18.2. In the first of these reactions, a two-carbon unit from xylulose-5-phosphate (five carbons) is trans-ferred to ribose-5-phosphate (five carbons) to give sedoheptulose-7-phosphate (seven carbons) and glyceraldehyde-3-phosphate (three carbons), as shown in Figure 18.15, bottom,red numeral 1.

In the reaction catalyzed by transaldolase, a three-carbon unit is trans-ferred from the seven-carbon sedoheptulose-7-phosphate to the three-carbon glyceraldehyde-3-phosphate (Figure 18.15, red numeral 2). The products of the reaction are fructose-6-phosphate (six carbons) and erythrose-4-phos-phate (four carbons).

In the final reaction of this type in the pathway, xylulose-5-phosphate reacts with erythrose-4-phosphate. This reaction is catalyzed by transketolase. The products of the reaction are fructose-6-phosphate and glyceraldehyde-3-phosphate (Figure 18.15, red numeral 3).

In the pentose phosphate pathway, glucose-6-phosphate can be converted to fructose-6-phosphate and glyceraldehyde-3-phosphate by a means other than the glycolytic pathway. For this reason, the pentose phosphate pathway is also called the hexose monophosphate shunt, and this name is used in some texts. A major feature of the pentose phosphate pathway is the production of ribose-5-phosphate and NADPH. The control mechanisms of the pentose phosphate pathway can respond to the varying needs of organisms for either or both of these compounds.

How is the pentose phosphate pathway controlled?

As we have seen, the reactions catalyzed by transketolase and transaldolase are reversible, which allows the pentose phosphate pathway to respond to the needs of an organism. 

The starting material, glucose-6-phosphate, undergoes different reactions depending on whether there is a greater need for ribose-5-phosphate or for NADPH. The operation of the oxidative portion of the pathway depends strongly on the organism’s requirement for NADPH. The need for ribose-5-phosphate can be met in other ways, since ribose-5-phosphate can be obtained from glycolytic intermediates without the oxidative reactions of the pentose phosphate pathway (Figure 18.16).

If the organism needs more NADPH than ribose-5-phosphate, the reaction series goes through the complete pathway just discussed. The oxidative reac-tions at the beginning of the pathway are needed to produce NADPH. The net reaction for the oxidative portion of the pathway is

6 Glucose-6-phosphate + 12NADP⁺ + 6H₂O - > 6 Ribose-5-phosphate + 6CO₂ + 12NADPH + 12H⁺

The following Biochemical Connections box discusses a clinical manifestation of an enzyme malfunction in the pentose phosphate pathway.

If the organism has a greater need for ribose-5-phosphate than for NADPH, fructose-6-phosphate and glyceraldehyde-3-phosphate can give rise to ribose-5-phosphate by the successive operation of the transketolase and transaldolase reactions, bypassing the oxidative portion of the pentose phosphate pathway (follow the red shaded path down to glyceraldehyde-3-phosphate and then go up to ribose-5-phosphate) (Figure 18.16). The reactions catalyzed by transketo-lase and transaldolase are reversible, and this fact plays an important role in the organism’s ability to adjust its metabolism to changes in conditions. We shall now look at the mode of action of these two enzymes.

Transaldolase has many features in common with the enzyme aldolase, which we met in the glycolytic pathway. Both an aldol cleavage and an aldol condensa-tion occur at different stages of the reaction. We already saw the mechanism of aldol cleavage, involving the formation of a Schiff base, when we discussed the aldolase reaction in glycolysis, and we need not discuss this point further.

Transketolase resembles pyruvate decarboxylase, the enzyme that converts pyruvate to acetaldehyde, in that it also requires Mg²⁺ and thia-mine pyrophosphate (TPP). As in the pyruvate decarboxylase reaction, a carb-anion plays a crucial role in the reaction mechanism, which is similar to that of the conversion of pyruvate to acetaldehyde.

Summary

In the pentose phosphate pathway, two important processes take place. One is the formation of five-carbon sugars, particularly ribose, a compo-nent of RNA.

The other is the formation of NADPH, a reducing agent required in many anabolic reactions.