Acetylation turns leucine into a drug by membrane transporter switching

Journal article

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 ubiquitous tissue expression of MCT1 make it well suited for uptake and distribution of N-acetyl-L-leucine. MCT1-mediated uptake of a N-acetyl-L-leucine as a prodrug of leucine bypasses LAT1, the rate-limiting step in activation of leucine-mediated signalling and metabolic process inside cells such as mTOR. Converting an amino acid into an anion through acetylation reveals a way for the rational design of drugs to target anion transporters.

Authors: Churchill, GC; Strupp, M; Factor, C; Bremova-Ertl, T; Factor, M

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Scientific Reports
• Volume: 11
• Issue: 1
• Pages: 15812-15812
• Article number: 15812
• Publication date: 2021-08-04
• DOI: 10.1038/s41598-021-95255-5
• EISSN: 2045-2322
• ISSN: 2045-2322
• Language: English
• Keywords: Pharmacology; Leucine; Prodrug; Gene; Biology; Biochemistry; Transporter; Organic anion transporter 1; Amino acid transporter; Amino acid; Acetylation; Chemistry