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

Oct 8, 2024Journal of agricultural and food chemistry

Tetrahydro Tanshinone I as a Natural Broad-Acting Inhibitor of Gut Bacteria Enzymes That Break Down Bile Salts

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Abstract

Tetrahydro tanshinone I (THTI) exhibited potent inhibitory effects on five gut microbial bile salt hydrolases (gmBSHs) with IC values ranging from 0.28 ± 0.05 μM to 1.62 ± 0.07 μM.

Modulating total gmBSH activity may help address metabolic diseases like colorectal cancer, type 2 diabetes, and obesity.
Screening of over 100 botanical compounds identified tanshinones as strong inhibitors of gmBSHs.
THTI was found to covalently modify a specific cysteine in all tested gmBSHs.
Inhibitory effects of THTI were observed in live microorganisms and murine gut content.

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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-inhibitor of gmBSHs. Following the screening of more than 100 botanical compounds, tanshinones were found with strong time-dependent anti-BSH effects. After that, a total of 17 naturally occurring tanshinones were collected, and their anti-BSH potentials were tested. Among all tested tanshinones, tetrahydro tanshinone I (THTI) exhibited the most potent inhibitory effects against five gmBSHs (BSH,BSH,BSH,BSH, andBSH), showing the ICvalues 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-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. pan Ef Ef Ef Ls Bt Cp Bl pan50

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

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