1. Academic Validation
  2. Acetylation turns leucine into a drug by membrane transporter switching

Acetylation turns leucine into a drug by membrane transporter switching

  • Sci Rep. 2021 Aug 4;11(1):15812. doi: 10.1038/s41598-021-95255-5.
Grant C Churchill 1 Michael Strupp 2 Cailley Factor 3 Tatiana Bremova-Ertl 4 5 Mallory Factor 3 Marc C Patterson 6 Frances M Platt 3 Antony Galione 3
Affiliations

Affiliations

  • 1 Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, UK. grant.churchill@pharm.ox.ac.uk.
  • 2 Department of Neurology and German Center for Vertigo and Balance Disorders, Hospital of the Ludwig Maximilians University, Munich, Germany.
  • 3 Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, UK.
  • 4 Department of Neurology, University Hospital Inselspital, Bern, BE, Switzerland.
  • 5 Center for Rare Diseases, University Hospital Inselspital Bern, Bern, BE, Switzerland.
  • 6 Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
Abstract

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.

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