Acetylation turns leucine into a drug by membrane transporter switching.

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.

• Authors: Grant C Churchill, Michael Strupp, Cailley Factor, Tatiana Bremova-Ertl, Mallory Factor, Marc C Patterson, Frances M Platt, Antony Galione
• Journal: Scientific reports (Sci Rep) Vol. 11 Issue 1 Pg. 15812 (08 04 2021) ISSN: 2045-2322 [Electronic] England
• PMID: 34349180 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• Large Neutral Amino Acid-Transporter 1
• Monocarboxylic Acid Transporters
• Organic Anion Transport Protein 1
• Organic Anion Transporters, Sodium-Independent
• Prodrugs
• SLC22A6 protein, human
• Symporters
• monocarboxylate transport protein 1
• organic anion transport protein 3
• Leucine
• acetylleucine

Topics

• Acetylation
• Biological Transport
• HEK293 Cells
• Humans
• Kinetics
• Large Neutral Amino Acid-Transporter 1 (metabolism)
• Leucine (analogs & derivatives, chemistry, metabolism)
• Monocarboxylic Acid Transporters (metabolism)
• Organic Anion Transport Protein 1 (metabolism)
• Organic Anion Transporters, Sodium-Independent (metabolism)
• Prodrugs (chemistry, metabolism)
• Signal Transduction
• Symporters (metabolism)