Acetylation turns leucine into a drug by membrane transporter switching.
Sci Rep
; 11(1): 15812, 2021 08 04.
Article
em En
| MEDLINE
| ID: mdl-34349180
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Pró-Fármacos
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Transportador 1 de Aminoácidos Neutros Grandes
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Transportadores de Ácidos Monocarboxílicos
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Transportadores de Ânions Orgânicos Sódio-Independentes
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Proteína 1 Transportadora de Ânions Orgânicos
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Simportadores
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Leucina
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article