Bacterial β-glucuronidase (GUS)

Bacterial β-glucuronidases (GUS) are a diverse family of enzymes produced by the human gut microbiota, primarily within the Firmicutes and Bacteroidetes phyla, that catalyze the hydrolysis of β-glucuronide conjugates (Roberts et al., 2013, mBio). These enzymes play a pivotal role in the enterohepatic circulation by deconjugating metabolites excreted by the liver into the bile, thereby allowing the reabsorption of the aglycone into the bloodstream. While this process is essential for recycling endogenous compounds like estrogens and bilirubin, it also reactivates pharmacologically active or toxic metabolites of drugs, such as the potent topoisomerase inhibitor SN-38 from its inactive glucuronide SN-38G (Wallace et al., 2010, Science). This reactivation in the intestinal lumen is the primary cause of severe, dose-limiting diarrhea associated with irinotecan chemotherapy and contributes to NSAID-induced intestinal damage (Saitta et al., 2014, Aliment Pharmacol Ther). Consequently, bacterial GUS enzymes are targeted by selective small-molecule inhibitors designed to prevent drug-induced toxicity without compromising systemic drug efficacy or inhibiting the human ortholog, lysosomal β-glucuronidase (Ervin et al., 2020, Nature Communications).

Other names

Microbiome β-glucuronidaseBeta-D-glucuronoside glucuronosohydrolasebgusGUS

Selective inhibition of bacterial β-glucuronidase enzymes to prevent the reactivation of glucuronidated drug metabolites in the gastrointestinal tract.