6-phosphogluconolactone and ribulose-5-phosphate

The oxidative pentose phosphate pathway (oxiPPP) contributes to cell metabolism through not only the production of metabolic intermediates and reductive NADPH but also inhibition of LKB1-AMPK signaling by ribulose-5-phosphate (Ru-5-P), the product of the third oxiPPP enzyme 6-phosphogluconate dehydrogenase (6PGD). However, we found that knockdown of glucose-6-phosphate dehydrogenase (G6PD), the first oxiPPP enzyme, did not affect AMPK activation despite decreased Ru-5-P and subsequent LKB1 activation, due to enhanced activity of PP2A, the upstream phosphatase of AMPK. In contrast, knockdown of 6PGD or 6-phosphogluconolactonase (PGLS), the second oxiPPP enzyme, reduced PP2A activity. Mechanistically, knockdown of G6PD or PGLS decreased or increased 6-phosphogluconolactone level, respectively, which enhanced the inhibitory phosphorylation of PP2A by Src. Furthermore, γ-6-phosphogluconolactone, an oxiPPP byproduct with unknown function generated through intramolecular rearrangement of δ-6-phosphogluconolactone, the only substrate of PGLS, bound to Src and enhanced PP2A recruitment. Together, oxiPPP regulates AMPK homeostasis by balancing the opposing LKB1 and PP2A.

Topics: A549 Cells; AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Animals; Cell Proliferation; Enzyme Activation; Gluconates; Glucosephosphate Dehydrogenase; HEK293 Cells; HT29 Cells; Humans; K562 Cells; MCF-7 Cells; Mice, Nude; Neoplasms; PC-3 Cells; Pentose Phosphate Pathway; Protein Binding; Protein Phosphatase 2; Protein Serine-Threonine Kinases; Reactive Oxygen Species; Ribulosephosphates; Signal Transduction; src-Family Kinases; Superoxide Dismutase; Tumor Burden