BIOCHEMISTRY - L. Stryer - 1984

VOLUME 2

PART II GENERATION AND STORAGE OF METABOLIC ENERGY

CHAPTER 15. THE PENTOSE PHOSPHATE PATHWAY AND GLUCONEOGENESIS

Summary

The Pentose Phosphate Pathway generates NADPH and ribose 5-phosphate in the Cytosol; NADPH is utilized in reductive biosyntheses, whereas ribose 5-phosphate is used in the synthesis of RNA, DNA, and nucleotide Coenzymes. The pentose phosphate pathway begins with the dehydrogenation of glucose 6-phosphate to form a lactone, which is hydrolyzed to yield 6-phosphogluconate, followed by oxidative decarboxylation to form ribulose 5-phosphate. The electron acceptor in both oxidative reactions is NADP⁺. The final step is the isomerization of ribulose 5-phosphate (a ketose) to ribose 5-phosphate (an aldose). When the cellular demand for NADPH exceeds that for ribose 5-phosphate, another mechanism comes into play. Under these conditions, ribose 5-phosphate is converted into glyceraldehyde 3-phosphate and fructose 6-phosphate through the action of transketolase and transaldolase. Transketolase contains TPP as a prosthetic group. These Enzymes establish a reversible link between the pentose phosphate pathway and Glycolysis. The intermediates in these interconversions include xylulose 5-phosphate, sedoheptulose 7-phosphate, and erythrose 4-phosphate. In this manner, 12 molecules of NADPH can be generated for every molecule of glucose 6-phosphate that is completely oxidized to CO₂. When the demand for ribose 5-phosphate synthesis significantly outweighs The Need for NADPH, only the non-oxidative branch of the pathway is active. Under such conditions, fructose 6-phosphate and glyceraldehyde 3-phosphate (formed via The Glycolytic Pathway) are converted into ribose 5-phosphate without the generation of NADPH. Ribose 5-phosphate formed via the oxidative branch can also be converted into Pyruvate via fructose 6-phosphate and glyceraldehyde 3-phosphate. This process generates ATP and NADPH, while five out of the six carbon atoms of glucose 6-phosphate appear in pyruvate. The interplay between the glycolytic and Pentose Phosphate Pathways ensures the continuous adaptation of the concentrations of NADPH, ATP, and building blocks—such as ribose 5-phosphate and pyruvate—to meet the metabolic needs of The Cell.

Gluconeogenesis is the Synthesis of glucose from non-carbohydrate precursors such as lactate, Amino Acids, and glycerol. Several of the conversion steps from pyruvate—the primary entry point—are shared by both gluconeogenesis and glycolysis. However, gluconeogenesis requires four bypass reactions to circumvent the irreversibility of the corresponding glycolytic steps. Pyruvate is carboxylated in the Mitochondria to oxaloacetate, which is subsequently decarboxylated and phosphorylated to phosphoenolpyruvate in the cytosol. These reactions, catalyzed by pyruvate carboxylase and phosphoenolpyruvate carboxykinase, consume two high-energy phosphate bonds. Pyruvate carboxylase contains biotin as a prosthetic group. The other two pathway-specific reactions of gluconeogenesis are the hydrolytic steps of fructose 1,6-bisphosphate and glucose 6-phosphate, which are catalyzed by specific Phosphatases. Gluconeogenesis and glycolysis are reciprocally regulated, such that when The activity of one pathway is relatively depressed, the activity of the other is enhanced.