Gut microbial beta-glucuronidases are one of the key players in reactivating drug metabolites in the gut lumen. This reactivation can sometimes lead to dose-limiting side effects, such as severe diarrhea and intestinal bleeding. Thus, understanding the structures and functions of these beta-glucuronidases is critical for developing adjuvant therapies to alleviate the gut microbial beta-glucuronidase-induced gastrointestinal toxicities. However, the structural and functional diversities of gut microbial beta-glucuronidase enzyme class are still poorly characterized. In this thesis, we describe three independent studies to understand these diversities. First, we studied the biochemical aspects of Streptococcus Agalactiae beta-glucuronidase and Bacteroides dorei beta-glucuronidase and of structural aspects Bacteroides dorei beta-glucuronidase inhibition. Next, we used loop swap mutants in an attempt to understand the function diversity caused by the extended active site loops. Last, we performed biochemical assays on a previously poorly characterized class of beta-glucuronidase. Our works are a part of a collective effort to explore the gut microbial beta-glucuronidase as an enzyme family. In the future, we can use our knowledge gained from these studies to further our knowledge on the interactions between the gut microbiota and drug metabolites and select beta-glucuronidases as targets for inhibitor design.Bachelor of Scienc
