6-Phosphogluconate dehydrogenase

6-Phosphogluconate dehydrogenase (6PGD) is an enzyme that plays a crucial role in the pentose phosphate pathway (PPP), a metabolic pathway parallel to glycolysis. It catalyzes the oxidative decarboxylation of 6-phosphogluconate to ribulose 5-phosphate, carbon dioxide (CO2), and nicotinamide adenine dinucleotide phosphate (NADPH). This reaction is significant for cellular processes as it contributes to the production of NADPH, which is essential for biosynthesis of fatty acids and nucleotides, and for maintaining the reducing environment of the cell.

Function

The primary function of 6PGD is to facilitate the production of NADPH and ribulose 5-phosphate within the PPP. NADPH generated by this pathway is critical for reductive biosynthetic reactions within the cell, particularly in lipid synthesis and the maintenance of reduced glutathione levels, which protect the cell against oxidative damage. Ribulose 5-phosphate, on the other hand, can be utilized in the synthesis of nucleotides and nucleic acids, or it can be converted to xylulose 5-phosphate and enter the non-oxidative phase of the PPP, leading to the production of intermediates for glycolysis and gluconeogenesis.

Structure

6PGD is a dimer in most organisms, with each monomer consisting of approximately 470 amino acids. The enzyme binds to its substrate, 6-phosphogluconate, and a molecule of NADP+ at each active site. The structure of 6PGD includes a Rossmann fold for NADP+ binding and a mixed alpha/beta domain for substrate binding, which is typical for enzymes that catalyze oxidation-reduction reactions.

Clinical Significance

Alterations in 6PGD activity have been implicated in various diseases. Overexpression of 6PGD has been observed in several types of cancer, where it contributes to the altered metabolism of cancer cells, known as the Warburg effect. Inhibiting 6PGD activity has been proposed as a potential therapeutic strategy for targeting cancer cell metabolism. Additionally, mutations in the gene encoding 6PGD can lead to 6-phosphogluconate dehydrogenase deficiency, a rare metabolic disorder that can cause non-spherocytic hemolytic anemia.

Inhibitors

Several inhibitors of 6PGD have been identified, which could serve as potential therapeutic agents. These include physiologic inhibitors like ATP and NADPH, and synthetic inhibitors that have been developed to specifically target the enzyme's activity in cancer cells. Research into developing more effective and selective 6PGD inhibitors continues, with the aim of exploiting the enzyme's role in disease for therapeutic benefit.

See Also

• Pentose phosphate pathway
• Glucose-6-phosphate dehydrogenase
• Cancer metabolism
• Oxidative stress