Discovery and inhibition of an interspecies gut bacterial pathway for Levodopa metabolism

Vayu Maini Rekdal; Elizabeth N Bess; Jordan E Bisanz; Peter J Turnbaugh; Emily P Balskus

doi:10.1126/science.aau6323

Discovery and inhibition of an interspecies gut bacterial pathway for Levodopa metabolism

Science. 2019 Jun 14;364(6445):eaau6323. doi: 10.1126/science.aau6323.

Authors

Vayu Maini Rekdal¹, Elizabeth N Bess^{2

3

4}, Jordan E Bisanz², Peter J Turnbaugh^{5

6}, Emily P Balskus⁷

Affiliations

¹ Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA.
² Department of Microbiology and Immunology, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA.
³ Department of Chemistry, University of California, Irvine, 1102 Natural Sciences 2, Irvine, CA 92617, USA.
⁴ Department of Molecular Biology and Biochemistry, University of California, Irvine, 1102 Natural Sciences 2, Irvine, CA 92617, USA.
⁵ Department of Microbiology and Immunology, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA. [email protected] [email protected].
⁶ Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
⁷ Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA. [email protected] [email protected].

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Actinobacteria / drug effects
Actinobacteria / enzymology*
Actinobacteria / genetics
Animals
Antiparkinson Agents / administration & dosage
Antiparkinson Agents / metabolism*
Bacterial Proteins / antagonists & inhibitors
Bacterial Proteins / genetics
Bacterial Proteins / metabolism*
Decarboxylation / drug effects
Dopamine / metabolism
Enterococcus faecalis / drug effects
Enterococcus faecalis / enzymology*
Enterococcus faecalis / genetics
Gastrointestinal Microbiome* / genetics
Genome, Bacterial
HeLa Cells
Humans
Levodopa / administration & dosage
Levodopa / metabolism*
Male
Metabolic Networks and Pathways / drug effects
Mice, Inbred BALB C
Tyrosine / administration & dosage
Tyrosine / analogs & derivatives*
Tyrosine / chemistry
Tyrosine / pharmacology
Tyrosine Decarboxylase / antagonists & inhibitors
Tyrosine Decarboxylase / genetics
Tyrosine Decarboxylase / metabolism*

Substances

Antiparkinson Agents
Bacterial Proteins
3-fluoro-alpha-fluoromethyltyrosine
Tyrosine
Levodopa
Tyrosine Decarboxylase
Dopamine

Abstract

Publication types

MeSH terms

Substances

Grants and funding