Identification of Gut Bacterial Enzymes for Keto-Reductive Metabolism of Xenobiotics

Human gastrointestinal microbiota are known for the keto-reductive metabolism of small-molecule pharmaceuticals; however, the responsible enzymes remain poorly understood. Through in vitro biochemical assays, we report the identification of enzymes encoded in the genome of Clostridium bolteae that can reduce the ketone groups of nabumetone, hydrocortisone, and tacrolimus. The homologues to a newly identified enzyme (i.e., DesE) are potentially widely distributed in the gut microbiome. The selected enzymes display different levels of activities against additional chemicals such as two dietary compounds (i.e., raspberry ketone and zingerone), chemotherapeutic drug doxorubicin, and its aglycone metabolite doxorubicinone. Thus, our results expand the repertoire of enzymes that can reduce the ketone groups in small molecules and could serve as the basis for future personalized medicine approaches.