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A small molecule G6PD inhibitor reveals immune dependence on pentose phosphate pathway.
Nature Chemical Biology ( IF 14.8 ) Pub Date : 2020-05-11 , 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 1, 3
Affiliation  

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.

中文翻译:

一种小分子G6PD抑制剂显示出对磷酸戊糖途径的免疫依赖性。

葡萄糖通过两个基本途径分解代谢:糖酵解生成ATP,氧化戊糖磷酸生成减少的烟酰胺腺嘌呤二核苷酸磷酸(NADPH)。氧化戊糖磷酸途径的第一步是由葡萄糖6-磷酸脱氢酶(G6PD)催化。在这里,我们开发代谢物报告基因和氘示踪剂检测方法来监测细胞G6PD活性。使用这些,我们显示出被广泛引用的G6PD拮抗剂,脱氢表雄酮,不能强有力地抑制细胞中的G6PD。然后,我们确定了一个更有效地抑制G6PD的小分子(G6PDi-1)。在一系列培养的细胞中,G6PDi-1在淋巴细胞中最强烈地消耗NADPH。在T细胞而非巨噬细胞中,G6PDi-1明显降低了炎症细胞因子的产生。在中性粒细胞中,它抑制呼吸爆发。从而,
更新日期:2020-05-11
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