美国基因泰克公司Vishva M. Dixit团队发现，选择性激活PFKL可抑制吞噬细胞的氧化爆发。相关论文于2021年7月27日在线发表于国际学术期刊《细胞》。

研究人员表示，在中性粒细胞中，通过戊糖磷酸盐途径产生的烟酰胺腺嘌呤二核苷酸磷酸盐（NADPH）为NADPH氧化酶NOX2提供燃料，从而产生活性氧，杀死入侵的病原体。然而，过度的NOX2活动会加剧炎症，如急性呼吸窘迫综合征（ARDS）。

通过使用两种无偏倚的化学蛋白质组学策略，研究人员发现，小分子LDC7559或更有力的设计类似物NA-11，通过激活肝脏型磷酸果糖激酶（PFKL）和抑制通过戊糖磷酸盐途径的流量来抑制中性粒细胞中NOX2依赖的氧化爆发。因此，用NA-11处理的中性粒细胞减少了NOX2依赖性的产出，包括中性粒细胞死亡（NETosis）和组织损伤。

PFKL的高分辨率结构证实了NA-11与AMP/ADP异生激活位点的结合，并解释了为什么NA-11未能激动血小板型磷酸果糖激酶-1（PFKP）或肌肉型（PFKM）。因此，NA-11是一种选择性激活PFKL的工具，并且PFKL是在免疫细胞中表达的主要磷酸果糖激酶1亚型。

附：英文原文

Title: Selective activation of PFKL suppresses the phagocytic oxidative burst

Author: Neri Amara, Madison P. Cooper, Maria A. Voronkova, Bradley A. Webb, Eric M. Lynch, Justin M. Kollman, Taylur Ma, Kebing Yu, Zijuan Lai, Dewakar Sangaraju, Nobuhiko Kayagaki, Kim Newton, Matthew Bogyo, Steven T. Staben, Vishva M. Dixit

Issue&Volume: 2021-07-27

Abstract: In neutrophils, nicotinamide adenine dinucleotide phosphate (NADPH) generated via the pentose phosphate pathway fuels NADPH oxidase NOX2 to produce reactive oxygen species for killing invading pathogens. However, excessive NOX2 activity can exacerbate inflammation, as in acute respiratory distress syndrome (ARDS). Here, we use two unbiased chemical proteomic strategies to show that small-molecule LDC7559, or a more potent designed analog NA-11, inhibits the NOX2-dependent oxidative burst in neutrophils by activating the glycolytic enzyme phosphofructokinase-1 liver type (PFKL) and dampening flux through the pentose phosphate pathway. Accordingly, neutrophils treated with NA-11 had reduced NOX2-dependent outputs, including neutrophil cell death (NETosis) and tissue damage. A high-resolution structure of PFKL confirmed binding of NA-11 to the AMP/ADP allosteric activation site and explained why NA-11 failed to agonize phosphofructokinase-1 platelet type (PFKP) or muscle type (PFKM). Thus, NA-11 represents a tool for selective activation of PFKL, the main phosphofructokinase-1 isoform expressed in immune cells.

DOI: 10.1016/j.cell.2021.07.004

Source: https://www.cell.com/cell/fulltext/S0092-8674(21)00830-8