Textbook - BIOLOGICAL CHEMISTRY - Gubsky Yu.I. - 2000

Section III. METABOLISM OF MAJOR CLASSES OF BIOMOLECULES

CHAPTER 12. CARBOHYDRATE METABOLISM. II. ALTERNATIVE PATHWAYS OF MONOSACCHARIDE METABOLISM. REGULATION OF GLUCOSE METABOLISM

12.1. PENTOSE PHOSPHATE PATHWAY OF GLUCOSE METABOLISM

The Glycolytic Pathway of glucose oxidation generates NADH and ATP as Energy Sources for endergonic processes in biological systems. At the same time, an alternative mechanism of glucose METABOLISM exists — the pentose phosphate (phosphogluconate) pathway, the operation of which produces another type of metabolic energy, namely reduced NADP⁺ (NADPH), which is subsequently utilized in various reductive Biosynthesis reactions, particularly lipid synthesis. In addition to generating NADPH, the Pentose Phosphate Pathway serves as a supplier of pentoses required for the synthesis of many essential Biomolecules.

Class="center">General characteristics of The pentose phosphate Pathway

The reactions and Enzymes of the pentose phosphate pathway (PPP) of glucose oxidation are localized in The Cell Cytosol.

The overall equation of the process is as follows:

As follows from the reaction equation, As a result of PPP reactions, one (out of six) molecule of glucose-6-phosphate is completely oxidized with the release of carbon dioxide and the accumulation of reduction equivalents (twelve hydrogen atoms) in the form of NADPH.

The overall process consists of two stages:

Stage I — the oxidative stage, during which an activated glucose molecule (six molecules of glucose-6-phosphate) undergoes dehydrogenation and decarboxylation to form a phosphorylated pentose — ribulose-5-phosphate (six molecules); unlike Glycolysis, the hydrogen acceptor in the dehydrogenation reactions is NADP⁺:

Stage II — the stage of isomerization reactions, during which ribulose-5-phosphate (six molecules) is reconverted into glucose-6-phosphate (five molecules):

Specific to this stage are the enzymes transketolase and transaldolase, which catalyze intermolecular transfer reactions of two- and three-carbon carbonyl radicals:

Radical transported by transketolase (a Thiamine diphosphate-dependent enzyme).

Radical transported by transaldolase.

Due to the action of transketolase and transaldolase, numerous intermediate metabolites of the PPP are formed, specifically: phosphorylated carbohydrate derivatives — C₅ (ribulose-5-phosphate isomers — ribose-5-phosphate, xylulose-5-phosphate), C₃ (triose phosphates), C₇ (sedoheptulose-7-phosphate), C₄ (erythrose-4-phosphate), C₆ (fructose-6-phosphate).

Pentose Phosphate Cycle of Glucose Oxidation

As a result of the operation of the two Stages of the pentose phosphate pathway of glucose metabolism, hexoses are sequentially converted into pentoses and vice versa (pentoses into hexoses), which allows these transformations to be represented as a metabolic cycle — the pentose phosphate cycle (PPC) of glucose oxidation (Fig. 12.1).

Fig. 12.1. Scheme of the pentose phosphate cycle of glucose oxidation (G-6-P — glucose-6-phosphate; Fr-6-P — fructose-6-phosphate; Ru-5-P — ribulose-5-phosphate; PYR — Pyruvate).

As can be seen from the diagram above, the Reactions of the pentose phosphate pathway (PPP) bypass the glycolytic pathway of glucose conversion to pyruvate. Therefore, one of the alternative names for this metabolic pathway is the "glucose oxidation hexose monophosphate shunt."

Considering that the pentose phosphate pathway (PPP) involves the cyclic interconversion of six- and five-carbon molecules—namely, converting hexoses (C₆) into pentoses (C₅) with the release of six C₁ molecules (CO₂)—the following 5 x (2 C₃) formalized model of the cycle can be proposed:

ENZYMATIC REACTIONS OF the pentose phosphate pathway

Stage I. The oxidative phase consists of the sequential dehydrogenation of two PPP metabolites—the starting substrate glucose-6-phosphate and the intermediate 6-phosphogluconate—catalyzed by NADP-dependent dehydrogenases.

I.1. Oxidation of glucose-6-phosphate (six molecules) to 6-phosphoglucono-δ-lactone (catalyzed by NADP-dependent glucose-6-phosphate dehydrogenase), followed by the Hydrolysis of the lactone to 6-phosphogluconate (catalyzed by lactonase):

I.2. Oxidative Decarboxylation of 6-phosphogluconate to the ketopentose D-ribulose-5-phosphate (catalyzed by NADP-dependent 6-phosphogluconate dehydrogenase):

With The formation of ribulose-5-phosphate (which can easily be converted into its isomer ribose-5-phosphate)—that is, upon completion of the oxidative phase—the functioning of the pentose phosphate pathway may come to an end. This metabolic situation occurs in the Liver, Adrenal Glands, Gonads, and lactating Mammary Glands—Tissues characterized by prevailing anabolic processes with a balanced demand for NADPH (required for the synthesis of Fatty acids and Steroids) and ribose-5-phosphate (required for the synthesis of NUCLEOTIDES and Nucleic Acids) (Fig. 12.2).

Fig. 12.2. Schematic representation of the pentose phosphate pathway in tissue Cells with balanced demands for NADPH and pentose phosphates.

Designations: see Fig. 12.1; R-5-P – ribose-5-phosphate.

Stage II. This stage begins with the isomerization of ribulose-5-phosphate and involves the interconversion of sugar phosphates.

II.1. Isomerization of six molecules of ribulose-5-phosphate by converting it into four molecules of xylulose-5-phosphate (catalyzed by phosphopentopimerase) and two molecules of ribose-5-phosphate (catalyzed by phosphopentose isomerase):

II.2. The first transketolase reaction—the interaction of two molecules of xylulose-5-phosphate with two molecules of ribose-5-phosphate, yielding two molecules each of glyceraldehyde-3-phosphate and sedoheptulose-7-phosphate:

II.3. The transaldolase reaction—the interaction of two molecules of sedoheptulose-7-phosphate with two molecules of glyceraldehyde-3-phosphate, yielding two molecules each of erythrose-4-phosphate and fructose-6-phosphate:

These steps represent the intersection of the PPP with glycolysis: glyceraldehyde-3-phosphate generated in step II.2 can enter the pool of glycolytic metabolites, or the products of reaction II.3 can enter the second transketolase reaction, thereby continuing through the PPP pathway.

II.4. The second transketolase reaction involves the interaction of two molecules of xylulose-5-phosphate (formed in reaction II.1) with two molecules of erythrose-4-phosphate (formed in the preceding reaction II.3), producing two molecules each of glyceraldehyde-3-phosphate and fructose-6-phosphate:

II.5. Two molecules of glyceraldehyde-3-phosphate generated in reaction II.4 can (via isomerization to dihydroxyacetone phosphate) condense into a molecule of fructose-6-phosphate:

II.6. The isomerization of five molecules of fructose-6-phosphate (formed in reactions II.3, II.4, and II.5) into five molecules of glucose-6-phosphate (catalzyed by the enzyme phosphoglucose isomerase) completes the pentose phosphate cycle.

The metabolic pathway map of the pentose phosphate cycle of glucose oxidation is presented in Fig. 12.3.

Fig. 12.3. Scheme of the pentose phosphate cycle reactions.

Abbreviations: G-6-P — glucose-6-phosphate; 6-P-G — 6-phosphogluconate; Ru-5-P — ribulose-5-phosphate; Xu-5-P — xylulose-5-phosphate; R-5-P — ribose-5-phosphate; G-3-P — glyceraldehyde-3-phosphate; DHAP — dihydroxyacetone phosphate; S-7-P — sedoheptulose-7-phosphate; E-4-P — erythrose-4-phosphate; F-6-P — fructose-6-phosphate; F-1,6-bisP — fructose-1,6-bisphosphate.

As a result of the reactions considered, six molecules of glucose-6-phosphate are converted into five molecules of glucose-6-phosphate; in other words, the process takes the form of a metabolic cycle, as noted above.

Physiological Significance of the Pentose Phosphate Pathway

The pentose phosphate pathway of glucose oxidation is of major physiological importance for the functioning of other anabolic (biosynthetic) mechanisms, namely:

1) through the operation of the pentose phosphate pathway of glucose metabolism, approximately half of the NADPH pool in the Organism is generated (with the remainder produced by the action of NADP-dependent isocitrate dehydrogenase and malate dehydrogenase), which is utilized in the reductive syntheses of fatty acids and steroids;

2) the pentose phosphate pathway serves as a supplier of ribose-5-phosphate, which is used for the formation of nucleic acid nucleotides (DNA and RNA), coenzyme biomolecules (NAD, NADP, FAD, ATP, CoA), and Cyclic Nucleotides (3',5'-cAMP and 3',5'-cGMP);

Due to these biochemical Functions, the reactions of the pentose phosphate pathway proceed most actively in tissues with pronounced anabolism—in cells where the syntheses of Lipids, free nucleotides, and nucleic acids are most intensive, such as adipose tissue, liver, mammary gland during Lactation, adrenal cortex, and Testes. In tissues where oxidative metabolism predominates, notably Skeletal Muscle, the reactions of the pentose phosphate pathway occur at a very low level.

Since the cyclic operation of the pentose phosphate pathway primarily results in the generation of NADPH, the PPP exhibits the character of a metabolic cycle (PPC — Fig. 12.1) in adipose tissue adipocytes, where its principal function is precisely the generation of reducing equivalents for lipid synthesis (i.e., the demand for NADPH outweighs the demand for pentose phosphates). In other cells with high anabolic potential (where both lipid and nucleotide synthesis are active)—tissues with balanced demands for NADPH and pentose phosphates—the pentose phosphate pathway either terminates at the oxidative phase (Fig. 12.2) or feeds into the glycolytic pathway of glucose oxidation at the triose phosphate stage;

3) the pentose phosphate pathway functions actively in human erythrocytes. The Biological Significance of the PPC in these cells lies in the generation of NADPH required to counteract the Lipid Peroxidation of Unsaturated fatty acids in erythrocyte membrane Phospholipids, thereby preventing erythrocyte hemolysis.

Hereditary glucose-6-phosphate dehydrogenase deficiency manifests as an increased susceptibility of patients' erythrocytes to hemolysis, especially upon the administration of certain drugs (aspirin, sulfonamides, the antimalarial drug primaquine). Similar disorders in patients with glucose-6-phosphate dehydrogenase deficiency are triggered by the consumption of Vicia faba beans ("favism"), a disease affecting millions of people in African and Asian countries.