Structural Insights into Endobiotic Reactivation by Human Gut Microbiome-Encoded Sulfatases

Phase
II drug metabolism inactivates xenobiotics and endobiotics
through the addition of either a glucuronic acid or sulfate moiety
prior to excretion, often via the gastrointestinal tract. While the
human gut microbial β-glucuronidase enzymes that reactivate
glucuronide conjugates in the intestines are becoming well characterized
and even controlled by targeted inhibitors, the sulfatases encoded
by the human gut microbiome have not been comprehensively examined.
Gut microbial sulfatases are poised to reactivate xenobiotics and
endobiotics, which are then capable of undergoing enterohepatic recirculation
or exerting local effects on the gut epithelium. Here, using protein
structure-guided methods, we identify 728 distinct microbiome-encoded
sulfatase proteins from the 4.8 million unique proteins present in
the Human Microbiome Project Stool Sample database and 1766 gut microbial
sulfatases from the 9.9 million sequences in the Integrated Gene Catalogue.
We purify a representative set of these sulfatases, elucidate crystal
structures, and pinpoint unique structural motifs essential to endobiotic
sulfate processing. Gut microbial sulfatases differentially process
sulfated forms of the neurotransmitters serotonin and dopamine, and
the hormones melatonin, estrone, dehydroepiandrosterone, and thyroxine
in a manner dependent both on variabilities in active site architecture
and on markedly distinct oligomeric states. Taken together, these
data provide initial insights into the structural and functional diversity
of gut microbial sulfatases, providing a path toward defining the
roles these enzymes play in health and disease.