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6-Phosphogluconate dehydrogenase, decarboxylating (6PGDH, PGD, PGDH)

6-Phosphogluconate dehydrogenase (6PGDH) is a homodimeric protein with the molecular weight of each subunit being 51 kDa. Its sequence is highly conserved among species. The enzyme belongs to the class of pyridine nucleotide linked oxidative decarboxylases. This class of enzymes generally utilizes one of the pyridine nucleotides NAD+ or NADP+ as a cofactor to catalyze oxidative decarboxylation of a β-hydroxy acid, yielding a ketone and CO2 . 6-Phosphogluconate dehydrogenase catalyzes reversible oxidative decarboxylation of 6 phosphogluconate to ribulose 5-phosphate and CO2 in the presence of NADP+ and the generation of its reduced form NADPH. This reaction is the third step of the pentose phosphate pathways (PPP), which is an alternative to glycolysis. The pentose phosphate pathway is primarily an anabolic pathway that utilizes glucose-6-phosphate to generate five carbon sugars and a NADPH. The PPP is an important source of NADPH for reductive biosynthesis reactions within cells such as fatty acid or steroid biosynthesis and also, a source of ribose-5-phosphate required for the synthesis of the nucleotides and nucleic acids. The first three reactions of the PPP are referred to as the oxidative and yield NADPH. The non-oxidative reactions of PPP are primarily designed to generate ribose-5-phosphate or to convert excess five-carbon sugars into intermediates of the glycolytic pathway. Although the PPP operates in all cells, high levels of PPP enzymes are found in cells of liver, adipose tissue, adrenal cortex, testis and lactating mammary gland, and the highest levels were detected in neutrophils and macrophages. Pentose phosphate pathways are considered important in tumor proliferation processes because of their role in supplying tumor cells with NADPH and carbons for intracellular anabolic processes. Flux measurements showed that PPP can be elevated by almost 8-fold in breast cancer cells compared to normal mammary epithelial cells. Recent study indicates that knockdown of 6-phosphogluconate dehydrogenase inhibits growth of lung cancer cells by senescence induction. This inhibition is not due to a defect in the oxidative PPP per se. Presumably, some of the glucose metabolites accumulated in 6PGD knockdown may be growth inhibitory and, therefore, 6PGDH inhibition may provide a novel strategy to treat glycolytic tumors such as lung cancer. Mutations within the gene encoding for this enzyme result in 6-phosphogluconate dehydrogenase deficiency, a rare autosomal hereditary disease affecting the red blood cells.

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