@article{5618234829b7433fa792bc02d75d46cf,
title = "Discovery and inhibition of an interspecies gut bacterial pathway for Levodopa metabolism",
abstract = "The human gut microbiota metabolizes the Parkinson{\textquoteright}s disease medication Levodopa (L-dopa), potentially reducing drug availability and causing side effects. However, the organisms, genes, and enzymes responsible for this activity in patients and their susceptibility to inhibition by host-targeted drugs are unknown. Here, we describe an interspecies pathway for gut bacterial L-dopa metabolism. Conversion of L-dopa to dopamine by a pyridoxal phosphate-dependent tyrosine decarboxylase from Enterococcus faecalis is followed by transformation of dopamine to m-tyramine by a molybdenum-dependent dehydroxylase from Eggerthella lenta. These enzymes predict drug metabolism in complex human gut microbiotas. Although a drug that targets host aromatic amino acid decarboxylase does not prevent gut microbial L-dopa decarboxylation, we identified a compound that inhibits this activity in Parkinson{\textquoteright}s patient microbiotas and increases L-dopa bioavailability in mice.",
author = "Rekdal, {Vayu Maini} and Bess, {Elizabeth N.} and Bisanz, {Jordan E.} and Turnbaugh, {Peter J.} and Balskus, {Emily P.}",
note = "Funding Information: We acknowledge the Broad Institute Microbial Omics Core (MOC) for assistance with RNA and 16S rRNA gene sequencing analysis and experimental design, the Harvard Bauer Core Proteomics facility for assistance with proteomics, M. Wilson (Harvard University) for helpful discussions and input, M. Gilmore and E. Selleck (Massachusetts Eye and Ear, Harvard Medical School, and Broad Institute) for supplying the E. faecalis tyrDC mutant and helpful discussions, F. Lebreton (Massachusetts Eye and Ear and Harvard Medical School) for supplying E. faecalis and E. faecium strains, R. Nayak [University of California, San Francisco (UCSF)] and M. Krueger (UCSF) for help with sample collection from healthy control subjects, and the Biocollective for collection and provision of stool samples from Parkinson{\textquoteright}s patients. We thank Merck for the gift of AFMT. This work was supported by the Packard Fellowship for Science and Engineering (2013-39267) (E.P.B), the Howard Hughes Medical Institute (HHMI)–Gates Faculty Scholars Program (OPP1158186) (E.P.B), the National Institutes of Health (R01HL122593) (P.J.T.), the Searle Scholars Program (SSP-2016-1352) (P.J.T), the UCSF-Stanford Arthritis Center of Excellence (supported in part by the Arthritis Foundation) (P.J.T), and the Rheumatology Research Foundation (P.J.T.). V.M.R. is the recipient of a National Science Foundation Graduate Research Fellowship, a Gilliam Fellowship from HHMI, and the Ardis and Robert James Graduate Research Fellowship from Harvard University and acknowledges support from a National Institutes of Health Training Grant (5T32GM007598-38). E.N.B. is a Howard Hughes Medical Institute fellow of the Life Sciences Research Foundation. J.E.B. has fellowship support from the Natural Sciences and Engineering Research Council of Canada. P.J.T. 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). Publisher Copyright: 2017 {\textcopyright} The Authors, some rights reserved",
year = "2019",
month = jun,
day = "14",
doi = "10.1126/science.aau6323",
language = "English (US)",
volume = "364",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6445",
}
