@article{677999893bb149c8a89bed9c1eb8edff,
title = "Discovery and characterization of a prevalent human gut bacterial enzyme sufficient for the inactivation of a family of plant toxins",
abstract = "Although the human gut microbiome plays a prominent role in xenobiotic transformation, most of the genes and enzymes responsible for this metabolism are unknown. Recently, we linked the two-gene {\textquoteleft}cardiac glycoside reductase{\textquoteright} (cgr) operon encoded by the gut Actinobacterium Eggerthella lenta to inactivation of the cardiac medication and plant natural product digoxin. Here, we compared the genomes of 25 E. lenta strains and close relatives, revealing an expanded 8-gene cgr-associated gene cluster present in all digoxin metabolizers and absent in non-metabolizers. Using heterologous expression and in vitro biochemical characterization, we discovered that a single flavin-and [4Fe-4S] cluster-dependent reductase, Cgr2, is sufficient for digoxin inactivation. Unexpectedly, Cgr2 displayed strict specificity for digoxin and other cardenolides. Quantification of cgr2 in gut microbiomes revealed that this gene is widespread and conserved in the human population. Together, these results demonstrate that human-associated gut bacteria maintain specialized enzymes that protect against ingested plant toxins.",
author = "Nitzan Koppel and Bisanz, {Jordan E.} and Pandelia, {Maria Eirini} and Turnbaugh, {Peter J.} and Balskus, {Emily P.}",
note = "Funding Information: We thank the National Institute of Advanced Industrial Science and Technology (Tokyo, Japan) for providing the Rhodococcocus erythropolis L-88 strain and pTipQ expression vectors, Jos{\'e} Miguel Sahuquillo-Arce (Hospital Universitari i Politecnic La Fe, Spain) for providing the Eggerthella lenta Valencia strain, and Emma Allen-Vercoe (University of Guelph, Canada) for isolating and supplying additional strains of Eggerthella lenta. We are indebted to Patrick Bradley, Stephen Nayfach, Katherine Pollard, and Jack Nicoludis for pivotal discussions; and to Lauren Rajakovich for comments on the manuscript. We are also indebted to Stephen Nayfach for supplying metagenomes from the Metaquery2 set for further analysis. This work was supported by the National Institutes of Health (PJT: R01HL122593; MP: GM111978), the Searle Scholars Program (EB:12-SSP-243; PJT:SSP-2016– 1352), a Fellowship for Science and Engineering from the David and Lucille Packard Foundation (EB:2013–39267), the George W. Merck Fellowship (EB:27–14), the Bill and Melinda Gates Foundation (EB:OPP1158186), and the UCSF Department of Microbiology and Immunology (PJT). PJT is a Chan Zuckerberg Biohub investigator and a Nadia{\textquoteright}s Gift Foundation Innovator supported, in part, by the Damon Runyon Cancer Research Foundation (DRR-42–16). PJT is also supported by the UCSF Program for Breakthrough Biomedical Research (partially funded by the Sandler Foundation). JEB is a Natural Sciences and Engineering Research Council of Canada postdoctoral fellow. NK received funding from the National Institutes of Health (GM095450-01), the Smith Family Graduate Science and Engineering Fellowship, and a National Science Foundation Graduate Research Fellowship (DGE1144152). Publisher Copyright: {\textcopyright} Koppel et al.",
year = "2018",
month = may,
day = "15",
doi = "10.7554/eLife.33953",
language = "English (US)",
volume = "7",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",
}