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

• Published in: Science (American Association for the Advancement of Science) 2019-06, Vol.364 (6445)
• Main Authors: Maini Rekdal, Vayu, Bess, Elizabeth N, Bisanz, Jordan E, Turnbaugh, Peter J, Balskus, Emily P
• Format: Article
• Language: English
• Subjects: 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; Summary; Tyrosine - administration & dosage; Tyrosine - analogs & derivatives; Tyrosine - chemistry; Tyrosine - pharmacology; Tyrosine Decarboxylase - antagonists & inhibitors; Tyrosine Decarboxylase - genetics; Tyrosine Decarboxylase - metabolism
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aau6323

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 is followed by transformation of dopamine to -tyramine by a molybdenum-dependent dehydroxylase from 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.