Gut microbial β-glucuronidases (gmβ-GUS) played crucial roles in regulating a variety of endogenous substances and xenobiotics on the circulating level, thus had been recognized as key modulators of drug toxicity and human diseases. Inhibition or inactivation of gmβ-GUS enzymes has become a promising therapeutic strategy to alleviate drug-induced intestinal toxicity. Herein, the Rhodiola crenulata extract (RCE) was found with potent and broad-spectrum inhibition on multiple gmβ-GUS enzymes. Subsequently, the anti-gmβ-GUS activities of the major constituents in RCE were tested and the results showed that 1,2,3,4,6-penta-O-galloyl-β-d-glucopyranose (PGG) acted as a strong and broad-spectrum inhibitor on multiple gmβ-GUS (including EcGUS, CpGUS, SaGUS, and EeGUS). Inhibition kinetic assays demonstrated that PGG effectively inhibited four gmβ-GUS in a non-competitive manner, with the Ki values ranging from 0.12 μM to 1.29 μM. Docking simulations showed that PGG could tightly bound to the non-catalytic sites of various gmβ-GUS, mainly via hydrogen bonding and aromatic interactions. It was also found that PGG could strongly inhibit the total gmβ-GUS activity in mice feces, with the IC50 value of 1.24 μM. Collectively, our findings revealed that RCE and its constituent PGG could strongly inhibit multiple gmβ-GUS enzymes, suggesting that RCE and PGG could be used for alleviating gmβ-GUS associated enterotoxicity.
Keywords: 1,2,3,4,6-penta-O-galloyl-β-d-glucopyranose (PGG); Broad-spectrum inhibition; Gut microbial β-glucuronidases (gmβ-GUS); Rhodiolae Crenulatae extract (RCE); gmβ-GUS-associated toxicity.
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