Like glycolysis, the enzymes of the pentose phosphate path way are cytosolic. Unlike glycolysis, oxidation is achieved by dehydrogenation using NADP⁺, not NAD⁺, as the hydrogen acceptor. The sequence of reactions of the pathway may be divided into two phases: an irreversible oxidative phase and a reversible nonoxidative phase. In the first phase, glucose-6-phosphate undergoes dehydrogenation and decarboxylation to yield a pentose, ribulose-5-phosphate. In the second phase, ribulose-5-phosphate is converted back to glucose-6-phosphate by a series of reactions involving mainly two enzymes: transketolase and transaldolase (see Figure 1).

Fig1. Flowchart of pentose phosphate pathway and its connections with the pathway of glycolysis. The full pathway, as indicated, consists of three interconnected cycles in which glucose-6-phosphate is both substrate and end product. The reactions above the broken line are nonreversible, whereas all reactions under that line are freely reversible apart from that catalyzed by fructose 1,6-bisphosphatase.

The Oxidative Phase Generates NADPH

Dehydrogenation of glucose-6-phosphate to 6-phosphogluconate occurs via the formation of 6-phosphogluconolactone, catalyzed by glucose-6-phosphate dehydrogenase, an NADP dependent enzyme (Figures 1 and2). The hydrolysis of 6-phosphogluconolactone is accomplished by the enzyme gluconolactone hydrolase. A second oxidative step is catalyzed by 6-phosphogluconate dehydrogenase, which also requires NADP⁺ as hydrogen acceptor. Decarboxylation forms the ketopentose ribulose-5-phosphate.

Fig2. The pentose phosphate pathway.(P, —PO₃^2–; PRPP, 5-phosphoribosyl 1-pyrophosphate.)

In the endoplasmic reticulum, an isoenzyme of glucose 6-phosphate dehydrogenase, hexose-6-phosphate dehydrogenase, provides NADPH for hydroxylation (mixed function oxidase) reactions, and also for 11-β-hydroxysteroid dehydrogenase-1. This enzyme catalyzes the reduction of (inactive) cortisone to (active) cortisol in liver, the nervous system, and adipose tissue. It is the major source of intracellular cortisol in these tissues and may be important in obesity and the metabolic syndrome.

The Nonoxidative Phase Generates Ribose Precursors

Ribulose-5-phosphate is the substrate for two enzymes. Ribulose 5-phosphate 3-epimerase alters the configuration about carbon 3, forming the epimer xylulose 5-phosphate, also a ketopentose. Ribose-5-phosphate ketoisomerase converts ribulose-5 phosphate to the corresponding aldopentose, ribose-5-phosphate, which is used for nucleotide and nucleic acid synthesis. Trans ketolase transfers the two-carbon unit comprising carbons 1 and 2 of a ketose onto the aldehyde carbon of an aldose sugar. It therefore affects the conversion of a ketose sugar into an aldose with two carbons less and an aldose sugar into a ketose with two carbons more. The reaction requires Mg²⁺ and thiamin diphosphate (vitamin B1) as coenzyme. Measurement of erythrocyte transketolase and its activation by thiamin diphosphate provides an index of vitamin B1 nutritional status . The two-carbon moiety is transferred as glycolaldehyde bound to thiamin diphosphate. Thus, transketolase catalyzes the transfer of the two-carbon unit from xylulose 5-phosphate to ribose-5 phosphate, producing the seven-carbon ketose sedoheptulose 7-phosphate and the aldose glyceraldehyde-3-phosphate. These two products then undergo transaldolation. Transaldolase catalyzes the transfer of a three-carbon dihydroxyacetone moiety (carbons 1–3) from the ketose sedoheptulose-7-phosphate onto the aldose glyceraldehyde-3-phosphate to form the ketose fructose-6-phosphate and the four-carbon aldose erythrose 4-phosphate. Transaldolase has no cofactor, and the reaction proceeds via the intermediate formation of a Schiff base of dihydroxyacetone to the ε-amino group of a lysine residue in the enzyme. In a further reaction catalyzed bytransketolase, xylulose 5-phosphate serves as a donor of glycolaldehyde. In this case, erythrose-4-phosphate is the acceptor, and the products of the reaction are fructose-6-phosphate and glyceraldehyde-3-phosphate.

In order to oxidize glucose completely to CO₂ via the pentose phosphate pathway, there must be enzymes present in the tissue to convert glyceraldehyde-3-phosphate to glucose 6-phosphate. This involves reversal of glycolysis and the gluconeogenic enzyme fructose 1,6-bisphosphatase. In tissues that lack this enzyme, glyceraldehyde-3-phosphate follows the normal pathway of glycolysis to pyruvate.

The Two Major Pathways for the Catabolism of Glucose Have Little in Common

 Although glucose-6-phosphate is common to both pathways, the pentose phosphate pathway is markedly different from glycolysis. Oxidation utilizes NADP⁺ rather than NAD⁺, and CO₂ , which is not produced in glycolysis, is produced. No ATP is generated in the pentose phosphate pathway, whereas it is a product of glycolysis.

The two pathways are, however, connected. Xylulose 5-phosphate activates the protein phosphatase that dephosphorylates the 6-phosphofructo-2-kinase/fructose 2,6-bisphophatase bifunctional enzyme . This activates the kinase and inactivates the phosphatase, leading to increased formation of fructose 2,6-bisphosphate, increased activity of phosphofructokinase-1, and hence increased glycolytic flux. Xylulose 5-phosphate also activates the protein phosphatase that initiates the nuclear translocation and DNA binding of the carbohydrate response element-binding protein, leading to increased synthesis of fatty acids in response to a high-carbohydrate diet. This couples the demand for NADPH for lipogenesis and activation of the lipogenic enzymatic machinery.

Reducing Equivalents Are Generated in Those Tissues Specializing in Reductive Syntheses

The pentose phosphate pathway is active in liver, adipose tis sue, adrenal cortex, thyroid, erythrocytes, testis, and lactating mammary gland. Its activity is low in nonlactating mammary gland and skeletal muscle. Those tissues in which the pathway is active use NADPH in reductive syntheses, for example, of fatty acids, steroids, amino acids via glutamate dehydrogenase, and reduced glutathione. The synthesis of glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase may also be induced by insulin in the fed state, when lipogenesis increases. NADPH is also used by NADPH oxidase in phagocytes and neutrophils to destroy “respiratory burst” engulfed cells and bacteria using superoxide .

 Ribose Can Be Synthesized in Virtually

All Tissues Little or no ribose circulates in the bloodstream, so tissues have to synthesize the ribose they require for nucleotide and nucleic acid synthesis using the pentose phosphate pathway (see Figure 2). It is not necessary to have a completely functioning pentose phosphate pathway for a tissue to synthesize ribose-5-phosphate. Muscle has only low activity of glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase, but, like most other tissues, it is capable of synthesizing ribose-5-phosphate by reversal of the nonoxidative phase of the pentose phosphate pathway utilizing fructose-6-phosphate.

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مواضيع ذات صلة

Galactose is Needed for the Synthesis of Lactose, Glycolipids, Proteoglycans, & Glycoproteins

Ingestion of Large Quantities of Fructose has Profound Metabolic Consequences

Blood Glucose is Derived From the Diet, Gluconeogenesis, & Glycogenolysis

Glycolysis & gluconeogenesis share the same pathway but in opposite directions, & are reciprocally regulated

Glucose-1-Phosphate & Glycogen

Thermodynamic Barriers Prevent a Simple Reversal of Glycolysis

Gluconeogenesis & the Control of Blood Glucose: Biomedical Importance

Glycogen Metabolism is Regulated by A Balance in Activities Between Glycogen Synthase & Phosphorylase

cAMP Activates Glycogen Phosphorylase

Cyclic AMP Integrates The Regulation of Glycogenolysis & Glycogenesis

Glycogenolysis is not the Reverse of Glycogenesis, it is A Separate Pathway

Glycogenesis Occurs Mainly in Muscle & Liver