Journal
CHEMICAL COMMUNICATIONS
Volume 59, Issue 8, Pages 1022-1025Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/d2cc05440j
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This study identified phosphatidyl-ethanolamine binding protein1 (PEBP1) as a cellular target of ethyl gallate (EG), a natural small molecule for ulcerative colitis (UC) treatment. EG inhibited the phosphorylation of PEBP1 and enhanced PEBP1-Raf-1 interaction to block the NF-kappa B inflammatory pathway in macrophages. It was also found that PEBP1 serves as an essential anti-inflammation mechanism in UC therapy.
Ulcerative colitis (UC) is an inflammatory disease of the colon with an unmet need for therapeutic targets. Ethyl gallate (EG) is a natural small molecule for UC treatment, but its cellular target is unknown. By labelling EG with a diazirine photocrosslinker and a click chemistry handle, we identified phosphatidyl-ethanolamine binding protein1 (PEBP1) as a direct cellular target of EG by forming hydrogen bonds with Asp70 and Tyr120. In particular, hydrogen/deuterium exchange mass spectrometry indicated that EG induced the sequence (residues 141-153) embedding to inhibit S153 phosphorylation of PEBP1. Additionally, the EG-mediated sequence (residues 108-122) exposure significantly enhanced PEBP1-Raf-1 interaction to block the downstream NF-kappa B inflammatory pathway in macrophages. Moreover, PEBP1 siRNA substantially reversed the EG-dependent down-regulation of the phosphorylation of IKK beta, I kappa B alpha and NF-kappa B, demonstrating that the NF-kappa B signal functioned as an essential anti-inflammation mechanism of PEBP1. Collectively, we revealed PEBP1 as a previously undescribed cellular target in macrophages for UC therapy and identified a new allosteric site for PEBP1 biology study using EG as a chemical probe.
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