1.A potent PGK1 antagonist reveals PGK1 regulates the production of IL-1β and IL-6.
Liping LIAO ; Wenzhen DANG ; Tingting LIN ; Jinghua YU ; Tonghai LIU ; Wen LI ; Senhao XIAO ; Lei FENG ; Jing HUANG ; Rong FU ; Jiacheng LI ; Liping LIU ; Mingchen WANG ; Hongru TAO ; Hualiang JIANG ; Kaixian CHEN ; Xingxing DIAO ; Bing ZHOU ; Xiaoyan SHEN ; Cheng LUO
Acta Pharmaceutica Sinica B 2022;12(11):4180-4192
Glycolytic metabolism enzymes have been implicated in the immunometabolism field through changes in metabolic status. PGK1 is a catalytic enzyme in the glycolytic pathway. Here, we set up a high-throughput screen platform to identify PGK1 inhibitors. DC-PGKI is an ATP-competitive inhibitor of PGK1 with an affinity of K d = 99.08 nmol/L. DC-PGKI stabilizes PGK1 in vitro and in vivo, and suppresses both glycolytic activity and the kinase function of PGK1. In addition, DC-PGKI unveils that PGK1 regulates production of IL-1β and IL-6 in LPS-stimulated macrophages. Mechanistically, inhibition of PGK1 with DC-PGKI results in NRF2 (nuclear factor-erythroid factor 2-related factor 2, NFE2L2) accumulation, then NRF2 translocates to the nucleus and binds to the proximity region of Il-1β and Il-6 genes, and inhibits LPS-induced expression of these genes. DC-PGKI ameliorates colitis in the dextran sulfate sodium (DSS)-induced colitis mouse model. These data support PGK1 as a regulator of macrophages and suggest potential utility of PGK1 inhibitors in the treatment of inflammatory bowel disease.
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