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

Glucose is catabolized by two fundamental pathways, glycolysis to create ATP and also the oxidative pentose phosphate path to create reduced nicotinamide adenine dinucleotide phosphate (NADPH). The initial step from the oxidative pentose phosphate path is catalyzed through the enzyme glucose-6-phosphate dehydrogenase (G6PD). Ideas develop metabolite reporter and deuterium tracer assays to watch cellular G6PD activity. With such, we reveal that probably the most broadly reported G6PD antagonist, dehydroepiandosterone, doesn’t robustly hinder G6PD in cells. Then we identify a little molecule (G6PDi-1) more effectively inhibits G6PD. Across a variety of cultured cells, G6PDi-1 depletes NADPH most strongly in lymphocytes. In T cells although not macrophages, G6PDi-1 markedly decreases inflammatory cytokine production. In neutrophils, it suppresses respiratory system burst. Thus, we offer a cell-active small molecule tool for oxidative pentose phosphate path inhibition, and employ it to recognize G6PD like a medicinal target for modulating immune response.