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

Science (New York, N.Y.) (2019-06-15)
Vayu Maini Rekdal, Elizabeth N Bess, Jordan E Bisanz, Peter J Turnbaugh, Emily P Balskus
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Sodium hydrosulfite, technical grade
Sigma-Aldrich
L-Dopa-(phenyl-d3), ≥98 atom % D, ≥98% (CP)
Sigma-Aldrich
Benzyl viologen dichloride, 97%
Supelco
Diquat dibromide monohydrate, PESTANAL®, analytical standard
Sigma-Aldrich
Tetraethylammonium borohydride, technical, ≥95% (T)
Sigma-Aldrich
Iodoacetamide, BioUltra
Sigma-Aldrich
Triethylammonium bicarbonate buffer, 1.0 M, pH 8.5±0.1
Supelco
Carbidopa, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
AFMT racemate, ≥98% (HPLC)
Sigma-Aldrich
Sodium molybdate, ≥98%
Sigma-Aldrich
Pyridoxal 5′-phosphate hydrate, ≥98%
Sigma-Aldrich
L-Tyrosine, reagent grade, ≥98% (HPLC)
Sigma-Aldrich
Methyl viologen dichloride hydrate, 98%
Supelco
Dopamine hydrochloride, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
Tris(2-carboxyethyl)phosphine hydrochloride, BioUltra, ≥98% (NMR)