Bacterial β-glucuronidase (GUS) (GUS)

Bacterial β-glucuronidase (GUS) refers to a diverse family of enzymes produced by commensal gut microbiota, particularly species within the Firmicutes and Bacteroidetes phyla, that catalyze the hydrolysis of β-D-glucuronic acid residues from various substrates (Dashnyam et al., 2022). In human physiology, the liver detoxifies many drugs and endogenous compounds by conjugating them with glucuronic acid for biliary excretion. Once these glucuronides reach the large intestine, bacterial GUS enzymes can cleave the glucuronide bond, regenerating the original active or toxic aglycone. This reactivation is a primary driver of severe gastrointestinal toxicity, most notably the dose-limiting diarrhea associated with the chemotherapy drug irinotecan, caused by the regeneration of the toxic metabolite SN-38 (Wallace et al., 2010). Beyond drug toxicity, GUS activity is implicated in the recycling of estrogens and bile acids, which may influence the risk of hormone-dependent cancers and metabolic disorders (Ervin et al., 2019). Therapeutic strategies focus on developing small-molecule inhibitors that selectively target bacterial GUS isoforms while sparing the essential human ortholog to improve the safety profile of narrow-therapeutic-index drugs (Redinbo, 2014).

Other names

Microbial beta-glucuronidaseBacterial beta-D-glucuronide glucuronosohydrolaseGut microbial GUSbg

Inhibition of the catalytic activity of microbial β-glucuronidase enzymes to prevent the deconjugation of glucuronide metabolites, thereby reducing the local concentration of toxic aglycones in the intestinal lumen (Wallace et al., 2010).