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

Fecha de publicación: 01/07/2020 Fecha Ahead of Print: 11/05/2020

Autores de IIS La Fe

Marta Piqueras Nebot

Autor
Agustín Lahoz Rodríguez

Autor

Participantes ajenos a IIS La Fe

Ghergurovich JM
García-Cañaveras JC
Wang J
Schmidt E
Zhang Z
TeSlaa T
Patel H
Chen L
Britt EC
Gomez-Cabrera MC
Fan J
Beier UH
Kim H
Rabinowitz JD

Grupos

Unidad de Biomarcadores y Medicina de Precisión (UBYMP)

Leader

Agustín Lahoz Rodríguez

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.

Datos de la publicación

ISSN/ISSNe:: 1552-4450, 1552-4469
Tipo:: Article
Páginas:: 731-739
DOI:: 10.1038/s41589-020-0533-x
Factor de Impacto:: 6,412 SCImago ℠
Cuartil:: Q1 SCImago ℠

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Filiaciones

Ghergurovich JM:: Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA

Department of Molecular Biology, Princeton University, Princeton, NJ, USA
García-Cañaveras JC:: Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA

Department of Chemistry, Princeton University, Princeton, NJ, USA
Wang J:: Department of Chemistry, Princeton University, Princeton, NJ, USA
Schmidt E:: Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA

Department of Chemistry, Princeton University, Princeton, NJ, USA
Zhang Z:: Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA

Department of Chemistry, Princeton University, Princeton, NJ, USA
TeSlaa T:: Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA

Department of Chemistry, Princeton University, Princeton, NJ, USA
Patel H:: Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA

Department of Chemistry, Princeton University, Princeton, NJ, USA
Chen L:: Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA

Department of Chemistry, Princeton University, Princeton, NJ, USA
Britt EC:: Morgridge Institute for Research, Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA
Piqueras-Nebot M:: Instituto de Investigación. Biomarkers and Precision Medicine Unit, Instituto de Investigación Sanitaria Fundación Hospital La Fe, Valencia, Spain
Gomez-Cabrera MC:: Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, Valencia, Spain

Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable, Fundación Investigación Hospital Clínico Universitario/INCLIVA, Valencia, Spain
Lahoz A:: Instituto de Investigación. Biomarkers and Precision Medicine Unit, Instituto de Investigación Sanitaria Fundación Hospital La Fe, Valencia, Spain
Fan J:: Morgridge Institute for Research, Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA
Beier UH:: Division of Nephrology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA
Kim H:: Department of Chemistry, Princeton University, Princeton, NJ, USA

Princeton University Small Molecule Screening Center, Princeton University, Princeton, NJ, USA
Rabinowitz JD:: Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA.

Department of Chemistry, Princeton University, Princeton, NJ, USA.