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

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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The passage describes a study in which researchers developed assays to monitor the activity of the enzyme glucose-6-phosphate dehydrogenase (G6PD), which is involved in the oxidative pentose phosphate pathway. This pathway is responsible for producing reduced nicotinamide adenine dinucleotide phosphate (NADPH) and plays a critical role in cellular metabolism.

The researchers aimed to investigate the effectiveness of various compounds in inhibiting G6PD activity. They found that dehydroepiandrosterone (DHEA), a compound widely cited as a G6PD antagonist, did not robustly inhibit G6PD in cells. However, they identified a different small molecule called G6PDi-1 that more effectively inhibited G6PD.

Using G6PDi-1, the researchers conducted experiments on different types of cultured cells. They found that G6PDi-1 had the strongest impact on depleting NADPH in lymphocytes, a type of immune cell. In T cells, but not macrophages, G6PDi-1 significantly decreased the production of inflammatory cytokines, which are molecules involved in immune responses. Additionally, G6PDi-1 suppressed the respiratory burst in neutrophils, which is an important immune defense mechanism.

Based on these findings, the researchers propose G6PD as a potential pharmacological target for modulating immune responses. The development of G6PDi-1 as a cell-active small molecule inhibitor of the oxidative pentose phosphate pathway provides a tool for further studying the role of G6PD in cellular metabolism and immune function.

Related Products

Cat.No. Product Name Information
S9617 G6PDi-1 G6PDi-1 is an effective inhibitor of glucose-6-phosphate dehydrogenase (G6PD). G6PDi-1 depletes NADPH and decreases inflammatory cytokine production.

Related Targets

Dehydrogenase NADPH-oxidase