Discovery of Tetrahydro Tanshinone I as a Naturally Occurring Covalent Pan-Inhibitor Against Gut Microbial Bile Salt Hydrolases

  • J Agric Food Chem. 2024 Oct 23;72(42):23233-23245. doi: 10.1021/acs.jafc.4c03617.
Xue-Zhang  1 ,  Chun-Yu Li  1 ,  Guang-Hao Zhu  1 ,  Li-Lin Song  1 ,  Yi-Wen Zhao  2 ,  Yu-Hui Ma  1 ,  Ping-Tian  2 ,  Wan-Sheng Chen  3 ,  Guang-Bo Ge  1
Affiliations
  • 1. Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 2. The Research Center of Chiral Drugs, Shanghai Frontiers Science Center for TCM Chemical Biology, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 3. The SATCM Key Laboratory for New Resources & Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
PMID: 39378230 DOI: 10.1021/acs.jafc.4c03617
Abstract

Gut microbial bile salt hydrolases (gmBSHs), an important class of bacteria-produced cysteine hydrolases, play a crucial role in bile acid metabolism. Modulating the total gmBSH activity is a feasible way for ameliorating some metabolic diseases including colorectal Cancer, type 2 diabetes, and obesity. This study reported the discovery and characterization of a botanical compound as a covalent pan-inhibitor of gmBSHs. Following the screening of more than 100 botanical compounds, tanshinones were found with strong time-dependent anti-EfBSH effects. After that, a total of 17 naturally occurring tanshinones were collected, and their anti-EfBSH potentials were tested. Among all tested tanshinones, tetrahydro tanshinone I (THTI) exhibited the most potent inhibitory effects against five gmBSHs (EfBSH, LsBSH, BtBSH, CpBSH, and BlBSH), showing the IC50 values ranging from 0.28 ± 0.05 μM to 1.62 ± 0.07 μM. Further investigations showed that THTI could covalently modify the conserved catalytic cysteine (Cys2) of all tested gmBSHs, while this agent could strongly inhibit the total gmBSHs activity in live Microorganisms and murine gut luminal content. Collectively, THTI is identified as a naturally occurring covalent pan-inhibitor of gmBSHs, which offers a promising lead compound to develop more efficacious gmBSHs inhibitors for the management of bile acid metabolism and related metabolic disorders.

Keywords
covalent pan-inhibitor; gut microbial bile salt hydrolases (gmBSHs); tanshinones; tetrahydro tanshinone I (THTI).
Products