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Acetylation turns leucine into a drug by membrane transporter switching
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Journal Article
Acetylation turns leucine into a drug by membrane transporter switching
2021
Overview
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ Drugs
/ Humanities and Social Sciences
/ Humans
/ Kinetics
/ Large Neutral Amino Acid-Transporter 1 - metabolism
/ Leucine
/ Leucine - analogs & derivatives
/ Monocarboxylic Acid Transporters - metabolism
/ Organic Anion Transport Protein 1 - metabolism
/ Organic Anion Transporters, Sodium-Independent - metabolism
/ Science
/ Vertigo
