A sulfotransferase from a gut microbe acts on diverse phenolic sulfate compounds, including acetaminophen sulfate

Sulfonation is one of the two main phase II detoxification pathways in eukaryotes which transforms nonpolar compounds into hydrophilic metabolites. Sulfotransferases catalyze these reactions by transferring a sulfo group from a donor to an acceptor molecule. Human cytosolic sulfotransferases use only 3'-phosphoadenosine 5'-phosphosulfate (PAPS) as a donor to sulfonate a variety of chemicals. Less understood are microbial aryl-sulfate sulfotransferases (ASSTs), which catalyze sulfo transfer reactions, without utilizing PAPS as a donor. Currently, the identity of physiological sulfo donor substrates remains unknown and sulfo acceptor substrates are underexplored. With this study, we aim to understand the potential contribution of a gut microbial enzyme to sulfonation chemistry by uncovering its substrate preferences. Here, we show that a sulfotransferase (Bacteroides vulgatus ASST) from the prevalent gut microbe B. vulgatus (now Phocaeicola vulgatus) is a versatile catalyst that utilizes a wide range of phenolic molecules as substrates that are commonly encountered by the host. With this action, it modulates concentrations of donor phenolic sulfates such as acetaminophen sulfate, dopamine sulfate, p-cresol sulfate, and related compounds in vitro and displays broad acceptor flexibility by sulfonating diverse phenolic compounds, including p-coumaric acid, p-cresol, 4-ethylphenol, tyramine, among others. These findings suggest that gut microbial enzymes like ASSTs may contribute to host detoxification of phenolics, a role previously attributed solely to human sulfotransferases. However, further in vivo studies are necessary to understand the potential contributions of ASSTs to host detoxification processes.