Pentose Phosphate Pathway

The pentose phosphate pathway is a metabolic pathway parallel to glycolysis which generates NADPH and pentoses (5-carbon sugars) as well as ribose 5-phosphate.

The pentose phosphate pathway is also called as the phosphogluconate pathway or hexose monophosphate shunt.

While it involves oxidation of glucose, its primary role is anabolic rather than catabolic. 

It is an important pathway that generates precursors for nucleotide synthesis andis especially important in red blood cells (erythrocytes).

Location

Cytoplasm of cells of the liver, adrenal cortex, and lactating mammary glands.  In plants, most steps take place in plastids.

The Pathway

• Substrate: Glucose-6-phosphate.

There are two distinct phases in the pathway. The first is the oxidative phase, in which NADPH is generated, and the second is the non-oxidative synthesis of 5-carbon sugars.

Reactions of the pentose phosphate pathway

1. The Oxidative Reactions

• Glucose-6-phosphate is converted to 6-phosphogluconolactone, and NADP⁺ is reduced to NADPH ⁺ H⁺.
  • Enzyme: glucose-6-phosphate dehydrogenase
•  6-Phosphogluconolactone is hydrolyzed to 6-phosphogluconate.
  • Enzyme: Gluconolactonase
•  6-Phosphogluconate undergoes an oxidation, followed by a decarboxylation. CO2 is released, and a second NADPH ⁺ H⁺ is generated from NADP⁺. The remaining carbons form ribulose-5-phosphate.
  • Enzyme: 6-phosphogluconate dehydrogenase

 2. The Non-oxidative Reactions

• Ribulose-5-phosphate is isomerized to ribose-5-phosphate or epimerized to xylulose-5-phosphate.
• Ribose-5-phosphate and xylulose-5-phosphate undergo reactions, catalyzed by transketolase and transaldolase, that transfer carbon units, ultimately forming fructose 6-phosphate and glyceraldehyde-3-phosphate.
  • Transketolase, which requires thiamine pyrophosphate, transfers two-carbon units.
  • Transaldolase transfers three-carbon units.

Overall reaction of the pentose phosphate pathway

3 Glucose-6-P + 6 NADP⁺→ 3 ribulose-5-P + 3 CO₂ + 6 NADPH

3 Ribulose-5-P → 2 xylulose-5-P + Ribose-5-P

2 Xylulose-5-P + Ribose-5-P → 2 fructose-6-P + Glyceraldehyde-3-P

Result of Pentose Phosphate Pathway

• Oxidative portion: Irreversible.

 Generates two NADPH, which can then be used in fatty acid synthesis and cholesterol synthesis and for maintaining reduced glutathione inside RBCs.

• Nonoxidative portion: Reversible.

Generates intermediate molecules (ribose-5-phosphate; glyceraldehyde-3-phosphate; fructose-6- phosphate) for nucleotide synthesis and glycolysis.

Regulation of Pentose Phosphate Pathway

• Key enzyme in the pentose-phosphate pathway is glucose-6-phosphate dehydrogenase.
• Levels of glucose-6-phosphate dehydrogenase are increased in the liver and adipose tissue when large amounts of carbohydrates are consumed.
• Glucose-6-phosphate dehydrogenase is stimulated by NADP+ and inhibited by NADPH and by palmitoyl-CoA (part of the fatty acid synthesis pathway).

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Purpose of Pentose Phosphate Pathway

• Pentose phosphate pathway functions as an alternative route for glucose oxidation that does not directly consume or produce ATP.
• The pentose phosphate pathway produces NADPH for fatty acid synthesis. Under these conditions, the fructose-6-phosphate and glyceraldehyde-3-phosphate generated in the pathway reenter glycolysis.
• NADPH is also used to reduce glutathione (γ-glutamylcysteinylglycine).
• Glutathione helps to prevent oxidative damage to cells by reducing hydrogen peroxide (H₂O₂).
• Glutathione is also used to transport amino acids across the membranes of certain cells by the γ-glutamyl cycle.
• Generation of ribose-5-phosphate
• When NADPH levels are low, the oxidative reactions of the pathway can be used to generate ribose-5-phosphate for nucleotide biosynthesis.
• When NADPH levels are high, the reversible nonoxidative portion of the pathway can be used to generate ribose-5-phosphate for nucleotide biosynthesis from fructose-6-phosphate and glyceraldehyde-3-phosphate.

References

1. Smith, C. M., Marks, A. D., Lieberman, M. A., Marks, D. B., & Marks, D. B. (2005). Marks’ basic medical biochemistry: A clinical approach. Philadelphia: Lippincott Williams & Wilkins.
2. Rodwell, V. W., Botham, K. M., Kennelly, P. J., Weil, P. A., & Bender, D. A. (2015). Harper’s illustrated biochemistry (30th ed.). New York, N.Y.: McGraw-Hill Education LLC.
3. Lehninger, A. L., Nelson, D. L., & Cox, M. M. (2000). Lehninger principles of biochemistry. New York: Worth Publishers.
4. Madigan, M. T., Martinko, J. M., Bender, K. S., Buckley, D. H., & Stahl, D. A. (2015). Brock biology of microorganisms (Fourteenth edition.). Boston: Pearson.