| Autor: |
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 |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
|
| Zdroj: |
Acta Pharmaceutica Sinica B, Vol 12, Iss 11, Pp 4180-4192 (2022) |
| Druh dokumentu: |
article |
| ISSN: |
2211-3835 |
| DOI: |
10.1016/j.apsb.2022.05.012 |
| Popis: |
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 Kd = 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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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