Journal
SCIENCE
Volume 364, Issue 6445, Pages 1055-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aau6323
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Funding
- Packard Fellowship for Science and Engineering [2013-39267]
- Howard Hughes Medical Institute (HHMI)-Gates Faculty Scholars Program [OPP1158186]
- National Institutes of Health [R01HL122593]
- Searle Scholars Program [SSP-2016-1352]
- UCSF-Stanford Arthritis Center of Excellence
- Arthritis Foundation
- Rheumatology Research Foundation
- National Science Foundation Graduate Research Fellowship
- Gilliam Fellowship from HHMI
- Ardis and Robert James Graduate Research Fellowship from Harvard University
- National Institutes of Health Training Grant [5T32GM007598-38]
- Natural Sciences and Engineering Research Council of Canada
- Damon Runyon Cancer Research Foundation [DRR-42-16]
- Bill and Melinda Gates Foundation [OPP1158186] Funding Source: Bill and Melinda Gates Foundation
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The human gut microbiota metabolizes the Parkinson'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's patient microbiotas and increases L-dopa bioavailability in mice.
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