Presented by: Marissa Bivins
Mycophenolate mofetil (MMF) is an immunosuppressant used chronically by organ transplant and autoimmune patients. Unfortunately, MMF causes dose-limiting, gastrointestinal side effects, including ulcers, weight loss, vomiting, and diarrhea. The active form of MMF, mycophenolic acid (MPA), is inactivated to mycophenolate-glucuronide (MPA-G) via human drug metabolism and sent to the gut for elimination. Bacteria residing within the gut express β-glucuronidase enzymes (GUSs) that convert drug-glucuronides into their active forms and have been subjected to targeted inhibition. Reactivation of MPA-G within the gut is predicted to cause this drug’s intestinal toxicity and drive difficulties in dosing due to enterohepatic recirculation. Here, we show that complex enzyme slurries from MMF-treated patient fecal samples have variable MPA-G processing activities that are not inhibited by previously validated GUS inhibitors. To identify the GUS enzymes that process MPA-G, we kinetically evaluated a panel of GUSs in vitro and discovered two highly efficient isoforms from Bacteroides uniformis and Roseburia hominis. Structural analyses pinpointed specific motifs that enable MPA-G reactivation by these enzymes. Defining the structural basis of efficient MPA-G processing by microbial GUS proteins will facilitate the development of novel inhibitors to prevent MMF-induced gut toxicity.
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