The Pentose Phosphate Pathway

Although glucose is the most common sugar, many other carbohydrate compounds are important in cell metabolism. The pathways that break down these sugars yield either glucose or other glycolytic intermediates. Additionally, these pathways can operate in the anabolic direction to transform glycolytic intermediates into other compounds.

It's an unfortunate myth that calories consumed as sugar are better than calories consumed as fat. Both can lead to obesity, if enough are consumed. Foods normally touted as low fat, like fruits, vegetables, and grains, are generally not as calorie ‐dense as “high‐fat” foods, like meat and chocolate candy. Pure carbohydrates yield about 5 kcal of energy per gram and fat about 9 kcal per gram, so the 200 kcal as cocoa (stearic acid) in a small candy bar and the 200 kcal as sugar in a can of soda will contribute equally to obesity. So would the 100 kcal in an apple, except that one tends to eat fewer apples at a sitting. (There’s no free lunch—in several senses!) Glucose is converted to pyruvate and then to acetyl‐CoA, which is used for fatty acid synthesis. Fatty acids are reduced relative to the acetyl groups, so reducing equivalents (as NADPH) must be provided to the fatty acid synthetase system. The NADPH comes from the direct oxidation of glucose‐6‐phosphate. Although NAD and NADP differ only by a single phosphate group, their metabolic roles are very different. NAD is kept oxidized so that it is a ready electron acceptor, as in glyceraldehyde‐3‐phosphate dehydrogenase and the TCA cycle. Most of the NADP pool exists in the reduced form, as NADPH. The NADPH is kept ready to donate electrons in biosynthetic reactions.

The pentose phosphate pathway oxidizes glucose to make NADPH and other carbohydrates for biosynthesis (see Figure 1 ). The major route for reduction of NADP to NADPH is the reaction of glucose‐6‐phosphate through two successive reactions. In the first, carbon 1 of glucose is oxidized from an aldol to an ester form (actually, an internal ester, called a lactone) by glucose‐6‐phosphate dehydrogenase. In the second reaction, the same carbon is further oxidized to CO ₂ and released, leaving behind a 5‐carbon sugar, in a reaction catalyzed by 6‐phosphogluconolactone‐dehydrogenase. Both reactions reduce NADP to NADPH. The 5‐carbon residue is ribulose‐5‐phosphate.

These oxidative reactions that remove electrons from glucose are a major source of the reducing power for biosynthesis. Accordingly, these enzymes are very active in adipose (fatty) tissue. The oxidation of glucose‐6‐phosphate to ribulose‐5‐phosphate and CO ₂ is also very active in mammalian red blood cells, where the NADPH produced by the reaction is used to keep the glutathione inside the cell in a reduced state. Reduced glutathione helps prevent the oxidation of the iron in hemoglobin from Fe(II) to Fe(III). Hemoglobin containing Fe(III) is not effective in binding O ₂.

Ribulose-5-phosphate

Ribulose‐5‐phosphate has several fates. On one hand, it can be isomerized (converted without a change in molecular weight) to ribose‐5‐phosphate, which is incorporated into nucleotides and deoxynucleotides:

Cells that are actively growing need an adequate supply of nucleotides to support RNA and DNA synthesis, and this reaction meets that need.

Alternatively, ribulose‐5‐phosphate can be converted into another 5‐carbon sugar by epimerization (change of one stereoisomer into another) into another pentose, xylulose‐5‐phosphate. This reaction is at equilibrium in the cell:

Converting pentoses to sugars

The pentoses are converted into 6‐ and 3‐carbon sugars. This reaction scheme appears complicated, and it is. The way to decipher it is to remember two key concepts:

Either 3‐carbon units (one reaction) or 2‐carbon units (two reactions) are transferred between acceptor and donor molecules. The enzyme responsible for the 3‐carbon transfers is called transaldolase, and the enzyme that is responsible for the transfer of 2‐carbon units is called transketolase.
The number of carbons involved in the reactions add up to either ten (two reactions) or nine (one reaction).

The first reaction has the shorthand notation:

which stands for the reaction of ribulose‐5‐phosphate and xylulose‐5‐phosphate with transketolase (2‐carbon transfer):

As shown in Figure 2, the 7‐carbon sugar, sedoheptulose‐7‐ phosphate, and the 3‐carbon sugar, glyceraldehyde‐3‐phosphate, react again, in a reaction catalyzed by transaldolase (3‐carbon transfer):

Figure 2

The overall conversion, then, is the conversion of two pentoses into a tetrose (4‐carbon) molecule and a hexose. Fructose‐6‐phosphate, the hexose, is a glycolytic intermediate and can enter that pathway at this stage. As shown in Figure 3, the 4‐carbon sugar, erythrose‐4‐phosphate, reacts with a molecule of xylulose‐5‐phosphate, catalyzed by transketolase (2‐carbon transfer):

The overall reaction scheme of the pentose phosphate pathway is:

Figure 3

In the sugar interconversion phase, three molecules of ribulose‐ 5‐phosphate have thus been converted to two molecules of fructose‐ 6‐phosphate and one molecule of glyceraldehyde‐3‐phosphate. These molecules are glycolytic intermediates and can be converted back into glucose, which can, of course, be used for the synthesis of glycogen.

Catabolism of other carbohydrates

The catabolism of other carbohydrates involves their conversion into glycolytic intermediates. Humans encounter a variety of disaccharides (two‐sugar compounds) in their diet. Glycerol is a product of fat (triglyceride) digestion. Lactose (glucosyl‐galactose) is predominant in milk, the primary nutrient for mammalian infants. Mannose (glucosyl‐glucose) and sucrose (glucosyl‐fructose) are ingested from cereals and sugars. The first step in their utilization is their conversion to monosaccharides by specific hydrolytic enzymes known as glucosidases. A deficiency in these enzymes can cause a variety of gastrointestinal complaints as the unhydrolyzed disaccharides are poorly absorbed in the small intestine. If not absorbed, the carbohydrates pass into the small intestine, where they feed the bacteria there. The bacteria metabolize the sugars, causing diarrhea and flatulence. Lactase, the enzyme responsible for lactose hydrolysis, is not synthesized after weaning by most humans. If these individuals consume dairy products, they show symptoms of lactose intolerance. Addition of purified lactase to milk predigests the lactose, often preventing the symptoms.

Before galactose can be metabolized by the glycolytic pathway, it must be converted into glucose‐6‐phosphate. The first step in the process is the phosphorylation of galactose into galactose‐1‐phosphate by galactokinase.

Then galactose‐1‐phosphate is transferred to a UMP nucleotide by reaction with the sugar nucleotide, Uridine diphosphate glucose (UDP‐glucose). This reaction liberates glucose‐1‐phosphate, which is converted into glucose‐6‐phosphate by phosphoglucomutase (see Figure 4). (This enzyme is also important in the breakdown of glycogen.)

Figure 4

UDP‐glucose is initially formed by reaction of glucose‐1‐phosphate with UTP and the release of inorganic pyrophosphate (see Figure 5).

Figure 5

Finally, UDP‐galactose is epimerized to UDP‐glucose by the action of UDP‐galactose epimerase (see Figure 6). This UDP‐glucose can be used in the galactosyltransferase reaction.

Figure 6

This elaborate scheme is probably due to the need to guard against the toxic buildup of galactose‐1‐phosphate. Humans who lack the enzymes required for galactose epimerization because they have a genetic deficiency of the enzyme suffer from mental retardation and cataracts. In microorganisms, expression of galactokinase in the absence of the epimerase and transferase inhibits cell growth.

Biochemistry I