Given the vast numbers of genes encoded by the human intestinal microbiome, it is not surprising that bacteria play an essential role in the metabolism of xenobiotic and endobiotic compounds that reach the GI tract.  Indeed, just for the glycoside hydrolase family of enzymes, gut microbes encode hundreds of thousands of distinct orthologs, while the human genome harbors less than one hundred.  A specific set of gut microbial glycoside hydrolases will be presented and their roles in xenobiotic and endobiotic processing will be discussed.  The enzymes of interest are the beta-glucuronidases from the human gut microbiome that function as natural counterparts to the human Phase II metabolizing glucuronosyltransferases that append glucuronic acid sugars to endogenous and exogenous compounds. Numerous foods also contain glucuronic acid, which differs from glucose only in the presence of a 6-carboxylic acid. We show that the gut microbiome encodes several hundred distinct beta-glucuronidases (GUS) proteins that can be categorized into eight functional clades based on substrate preferences and more than two dozen crystal and cryo-EM structures.  Finally, activity-based probe-enabled proteomics from human fecal samples reveals that specific GUS enzymes can be identified and their levels quantified even from this most complex milieu of proteins, and connecting therapeutic outcomes to components of the gut microbiome.  Taken together, the data presented support the conclusion that microbial enzymes partner with human factors to perform specific molecular transformations that impact human physiology and disease.

Human gut microbial enzymes in xenobiotic and endobiotic processing

ACS Fall 2021

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