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Characterization of a cardiac drug‐inactivating enzyme from the prominent human gut microbe, Eggerthella lenta
Author(s) -
Koppel Nitzan,
Bisanz Jordan,
Turnbaugh Peter,
Balskus Emily P
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.608.3
Subject(s) - gut flora , drug metabolism , enzyme , biology , xenobiotic , metabolism , drug , reductase , biochemistry , gene , human microbiome , microbial metabolism , bacteria , microbiome , pharmacology , genetics
Metabolism of pharmaceuticals by the human gut microbiota has been appreciated for several decades. Currently, over 50 examples are known in which the pharmacological properties, bioactivities, and toxicities of a drug are altered by the gut microbiota. However, only a few of these examples have been linked to specific bacteria or enzymes, and the precise mechanisms of these transformations remain largely unknown. The gut microbiota harbors approximately 150× more genes than the human genome providing additional metabolic capacity to modify drugs beyond host metabolism. In particular, gut microbial chemistry tends to be reductive and hydrolytic, in contrast to oxidative and conjugative host metabolism of xenobiotics. Additionally, the composition of the microbiota can vary substantially among individuals, leading to differences in drug metabolism. A deeper knowledge of microbial drug metabolism at the molecular level is thus crucial for understanding variability in patient response to drugs, and improving efficacy in the clinic. In our work, we biochemically confirmed that Cgr2, a putative cardiac glycoside reductase from the prominent gut microbe Eggerthella lenta , is responsible for reduction and inactivation of the widely used cardiac drug, digoxin. Cgr2 is a divergent homolog of FAD‐dependent fumarate reductases and harbors Fe‐S clusters with non‐canonical binding motifs that could not be predicted computationally. Bioinformatics and network analyses also revealed that Cgr2 is a highly unique enzyme that likely employs a novel mechanism of substrate binding and reduction. Through microbial isolation and sequencing of human‐associated isolates, we determined that the cgr2 gene is found exclusively in a subset of E. lenta strains, and is remarkably conserved at the amino acid sequence level (>95% identity). Digoxin metabolism does not enhance E. lenta growth, and more work is required to understand the physiological implications of this highly conserved gene. We are also actively working to determine the mechanism of substrate reduction through biochemical and structural methods. Support or Funding Information Funded by Harvard University, National Science Foundation, Packard Fellowship for Science and Engineering, George W. Merck Fund.