A small molecule G6PD inhibitor reveals immune dependence on pentose phosphate pathway.

TitleA small molecule G6PD inhibitor reveals immune dependence on pentose phosphate pathway.
Publication TypeJournal Article
Year of Publication2020
AuthorsGhergurovich, JM, García-Cañaveras, JC, Wang, J, Schmidt, E, Zhang, Z, TeSlaa, T, Patel, H, Chen, L, Britt, EC, Piqueras-Nebot, M, Gomez-Cabrera, MCarmen, Lahoz, A, Fan, J, Beier, UH, Kim, H, Rabinowitz, JD
JournalNat Chem Biol
Volume16
Issue7
Pagination731-739
Date Published2020 07
ISSN1552-4469
KeywordsAnimals, Cell Line, Dehydroepiandrosterone, Dose-Response Relationship, Drug, Enzyme Assays, Enzyme Inhibitors, Glucose, Glucosephosphate Dehydrogenase, Glycolysis, HCT116 Cells, Hep G2 Cells, Humans, Immunity, Innate, Lymphocyte Activation, Lymphocytes, Macrophage Activation, Macrophages, NADP, Neutrophils, 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>

DOI10.1038/s41589-020-0533-x
Alternate JournalNat Chem Biol
PubMed ID32393898
PubMed Central IDPMC7311271
Grant ListDP1 DK113643 / DK / NIDDK NIH HHS / United States
R01 CA163591 / CA / NCI NIH HHS / United States