Escherichia coli beta-glucuronidase (EcGUS)

Escherichia coli beta-glucuronidase (EcGUS) is a member of the glycosyl hydrolase 2 family that plays a critical role in the metabolic processing of glucuronidated compounds within the mammalian gut. While the human liver conjugates various drugs and endogenous toxins with glucuronic acid to facilitate their excretion, EcGUS and related bacterial enzymes in the microbiome can reverse this process by hydrolyzing the glucuronide bond. This deconjugation reactivates the compounds into their aglycone forms, which can lead to significant local toxicity or reabsorption into the systemic circulation. In clinical oncology, EcGUS is a primary target for mitigating the severe gastrointestinal side effects associated with the chemotherapeutic agent irinotecan. Irinotecan's active metabolite, SN-38, is detoxified in the liver to SN-38-glucuronide (SN-38G) and excreted into the bile; however, EcGUS in the intestines converts SN-38G back into toxic SN-38, causing severe diarrhea and mucosal injury. Selective inhibitors of EcGUS are being developed to prevent this reactivation without harming the beneficial gut bacteria or inhibiting the essential human ortholog of the enzyme. (Sources: UniProt P06708; PubMed: 21051632, 24127551; PMC3040117).

Other names

Beta-D-glucuronoside glucuronosohydrolaseGUSuidABacterial beta-glucuronidase

Inhibition of the bacterial enzyme prevents the reactivation of glucuronidated drug metabolites (such as SN-38G) into their toxic aglycone forms (such as SN-38) within the intestinal lumen, thereby reducing local mucosal damage.