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...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Grant C. Churchill, Michael Strupp, Cailley Factor, Tatiana Bremova-Ertl, Mallory Factor, Marc C. Patterson, Frances M. Platt, Antony Galione
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8ec79fdb99cd4403ad6f39300b2c4f15
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:8ec79fdb99cd4403ad6f39300b2c4f15
record_format	dspace
spelling	oai:doaj.org-article:8ec79fdb99cd4403ad6f39300b2c4f152021-12-02T16:35:32ZAcetylation turns leucine into a drug by membrane transporter switching10.1038/s41598-021-95255-52045-2322https://doaj.org/article/8ec79fdb99cd4403ad6f39300b2c4f152021-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-95255-5https://doaj.org/toc/2045-2322Abstract 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.Grant C. ChurchillMichael StruppCailley FactorTatiana Bremova-ErtlMallory FactorMarc C. PattersonFrances M. PlattAntony GalioneNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Grant C. Churchill Michael Strupp Cailley Factor Tatiana Bremova-Ertl Mallory Factor Marc C. Patterson Frances M. Platt Antony Galione Acetylation turns leucine into a drug by membrane transporter switching
description	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.
format	article
author	Grant C. Churchill Michael Strupp Cailley Factor Tatiana Bremova-Ertl Mallory Factor Marc C. Patterson Frances M. Platt Antony Galione
author_facet	Grant C. Churchill Michael Strupp Cailley Factor Tatiana Bremova-Ertl Mallory Factor Marc C. Patterson Frances M. Platt Antony Galione
author_sort	Grant C. Churchill
title	Acetylation turns leucine into a drug by membrane transporter switching
title_short	Acetylation turns leucine into a drug by membrane transporter switching
title_full	Acetylation turns leucine into a drug by membrane transporter switching
title_fullStr	Acetylation turns leucine into a drug by membrane transporter switching
title_full_unstemmed	Acetylation turns leucine into a drug by membrane transporter switching
title_sort	acetylation turns leucine into a drug by membrane transporter switching
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/8ec79fdb99cd4403ad6f39300b2c4f15
work_keys_str_mv	AT grantcchurchill acetylationturnsleucineintoadrugbymembranetransporterswitching AT michaelstrupp acetylationturnsleucineintoadrugbymembranetransporterswitching AT cailleyfactor acetylationturnsleucineintoadrugbymembranetransporterswitching AT tatianabremovaertl acetylationturnsleucineintoadrugbymembranetransporterswitching AT malloryfactor acetylationturnsleucineintoadrugbymembranetransporterswitching AT marccpatterson acetylationturnsleucineintoadrugbymembranetransporterswitching AT francesmplatt acetylationturnsleucineintoadrugbymembranetransporterswitching AT antonygalione acetylationturnsleucineintoadrugbymembranetransporterswitching
_version_	1718383704712151040

Acetylation turns leucine into a drug by membrane transporter switching

Ejemplares similares