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

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

  • Nat Chem Biol. 2020 Jul;16(7):731-739. doi: 10.1038/s41589-020-0533-x.
Jonathan M Ghergurovich  # 1 2,  Juan C García-Cañaveras  # 1 3,  Joshua Wang 3,  Emily Schmidt 1 3,  Zhaoyue Zhang 1 3,  Tara TeSlaa 1 3,  Harshel Patel 1 3,  Li Chen 1 3,  Emily C Britt 4,  Marta Piqueras-Nebot 5,  Mari Carmen Gomez-Cabrera 6 7,  Agustín Lahoz 5,  Jing Fan 4,  Ulf H Beier 8,  Hahn Kim 3 9,  Joshua D Rabinowitz 10 11
Affiliations

Affiliations

  • 1 Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA.
  • 2 Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
  • 3 Department of Chemistry, Princeton University, Princeton, NJ, USA.
  • 4 Morgridge Institute for Research, Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA.
  • 5 Biomarkers and Precision Medicine Unit, Instituto de Investigación Sanitaria Fundación Hospital La Fe, Valencia, Spain.
  • 6 Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, Valencia, Spain.
  • 7 Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable, Fundación Investigación Hospital Clínico Universitario/INCLIVA, Valencia, Spain.
  • 8 Division of Nephrology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA.
  • 9 Princeton University Small Molecule Screening Center, Princeton University, Princeton, NJ, USA.
  • 10 Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA. joshr@princeton.edu.
  • 11 Department of Chemistry, Princeton University, Princeton, NJ, USA. joshr@princeton.edu.
  • # Contributed equally.
PMID: 32393898 DOI: 10.1038/s41589-020-0533-x
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.

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