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

Jonathan M. Ghergurovich, Juan C. García-Cañaveras, Joshua Wang, Emily Schmidt, Zhaoyue Zhang, Tara TeSlaa, Harshel Patel, Li Chen, Emily C. Britt, Marta Piqueras-Nebot, Mari Carmen Gomez-Cabrera, Agustín Lahoz, Jing Fan, Ulf H. Beier, Hahn Kim, Joshua D. Rabinowitz

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

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. [Figure not available: see fulltext.].

Original languageEnglish (US)
Pages (from-to)731-739
Number of pages9
JournalNature Chemical Biology
Volume16
Issue number7
DOIs
StatePublished - Jul 1 2020

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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    Ghergurovich, J. M., García-Cañaveras, J. C., Wang, J., Schmidt, E., Zhang, Z., TeSlaa, T., Patel, H., Chen, L., Britt, E. C., Piqueras-Nebot, M., Gomez-Cabrera, M. C., Lahoz, A., Fan, J., Beier, U. H., Kim, H., & Rabinowitz, J. D. (2020). A small molecule G6PD inhibitor reveals immune dependence on pentose phosphate pathway. Nature Chemical Biology, 16(7), 731-739. https://doi.org/10.1038/s41589-020-0533-x