@article{3812,
  keywords = {Animals, Dose-Response Relationship, Drug, Humans, Cell Line, Glucose, Glycolysis, Immunity, Innate, NADP, Pentose Phosphate Pathway, Enzyme Inhibitors, HCT116 Cells, Lymphocyte Activation, Macrophages, Enzyme Assays, Hep G2 Cells, Lymphocytes, Neutrophils, Dehydroepiandrosterone, Glucosephosphate Dehydrogenase, Macrophage Activation},
  author = {Jonathan Ghergurovich and Juan Garc{\'\i}a-Ca{\~n}averas and Joshua Wang and Emily Schmidt and Zhaoyue Zhang and Tara TeSlaa and Harshel Patel and Li Chen and Emily Britt and Marta Piqueras-Nebot and Mari Gomez-Cabrera and Agust{\'\i}n Lahoz and Jing Fan and Ulf Beier and Hahn Kim and Joshua Rabinowitz},
  title = {A small molecule G6PD inhibitor reveals immune dependence on pentose phosphate pathway.},
  abstract = { <p>Glucose is catabolized by two fundamental pathways, glycolysis to make ATP and the oxidative pentose phosphate pathway to make reduced nicotinamide adenine dinucleotide phosphate (NADPH). The first step of the oxidative pentose phosphate pathway is catalyzed by the enzyme glucose-6-phosphate dehydrogenase (G6PD). Here we develop metabolite reporter and deuterium tracer assays to monitor cellular G6PD activity. Using these, we show that the most widely cited G6PD antagonist, dehydroepiandosterone, does not robustly inhibit G6PD in cells. We then identify a small molecule (G6PDi-1) that more effectively inhibits G6PD. Across a range of cultured cells, G6PDi-1 depletes NADPH most strongly in lymphocytes. In T cells but not macrophages, G6PDi-1 markedly decreases inflammatory cytokine production. In neutrophils, it suppresses respiratory burst. Thus, we provide a cell-active small molecule tool for oxidative pentose phosphate pathway inhibition, and use it to identify G6PD as a pharmacological target for modulating immune response.</p> },
  year = {2020},
  journal = {Nat Chem Biol},
  volume = {16},
  pages = {731-739},
  month = {2020 Jul},
  issn = {1552-4469},
  doi = {10.1038/s41589-020-0533-x},
  language = {eng},
}