biostudies-literatureChurchill GCIntraBioWellcome Trust15812https://www.ebi.ac.uk/biostudies/studies/S-EPMC8338929biostudies-literatureUnknown11(1)Small changes to molecules can have profound effects on their pharmacological activity as exemplified by the addition of the two-carbon acetyl group to make drugs more effective by enhancing their pharmacokinetic or pharmacodynamic properties. N-acetyl-D,L-leucine is approved in France for vertigo and its L-enantiomer is being developed as a drug for rare and common neurological disorders. However, the precise mechanistic details of how acetylation converts leucine into a drug are unknown. Here we show that acetylation of leucine switches its uptake into cells from the L-type amino acid transporter (LAT1) used by leucine to organic anion transporters (OAT1 and OAT3) and the monocarboxylate transporter type 1 (MCT1). Both the kinetics of MCT1 (lower affinity compared to LAT1) and the ubiquiScientific reportsAcetylation turns leucine into a drug by membrane transporter switching.PMC8338929202834/Z/16/ZBremova-Ertl TStrupp MChurchill GCFactor CFactor MGalione APatterson MCPlatt FMfalseAcetylation turns leucine into a drug by membrane transporter switching.Small changes to molecules can have profound effects on their pharmacological activity as exemplified by the addition of the two-carbon acetyl group to make drugs more effective by enhancing their pharmacokinetic or pharmacodynamic properties. N-acetyl-D,L-leucine is approved in France for vertigo and its L-enantiomer is being developed as a drug for rare and common neurological disorders. However, the precise mechanistic details of how acetylation converts leucine into a drug are unknown. Here we show that acetylation of leucine switches its uptake into cells from the L-type amino acid transporter (LAT1) used by leucine to organic anion transporters (OAT1 and OAT3) and the monocarboxylate transporter type 1 (MCT1). Both the kinetics of MCT1 (lower affinity compared to LAT1) and the ubiqui2021-01-01T00:00:00Z2021 Aug2026-05-08T06:29:09.382Z2022-02-11T14:20:14.338ZS-EPMC83389293434918010.1038/s41598-021-95255-5