Acetylation turns leucine into a drug by membrane transporter switching.
Acetylation
Biological Transport
HEK293 Cells
Humans
Kinetics
Large Neutral Amino Acid-Transporter 1
/ metabolism
Leucine
/ analogs & derivatives
Monocarboxylic Acid Transporters
/ metabolism
Organic Anion Transport Protein 1
/ metabolism
Organic Anion Transporters, Sodium-Independent
/ metabolism
Prodrugs
/ chemistry
Signal Transduction
Symporters
/ metabolism
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
04 08 2021
04 08 2021
Historique:
received:
12
05
2021
accepted:
23
07
2021
entrez:
5
8
2021
pubmed:
6
8
2021
medline:
9
11
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34349180
doi: 10.1038/s41598-021-95255-5
pii: 10.1038/s41598-021-95255-5
pmc: PMC8338929
doi:
Substances chimiques
Large Neutral Amino Acid-Transporter 1
0
Monocarboxylic Acid Transporters
0
Organic Anion Transport Protein 1
0
Organic Anion Transporters, Sodium-Independent
0
Prodrugs
0
SLC22A6 protein, human
0
Symporters
0
monocarboxylate transport protein 1
0
organic anion transport protein 3
0
Leucine
GMW67QNF9C
acetylleucine
K76S41V71X
Banques de données
ClinicalTrials.gov
['NCT03759639', 'NCT03759665', 'NCT03759678']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
15812Subventions
Organisme : Wellcome Trust
ID : 202834/Z/16/Z
Pays : United Kingdom
Informations de copyright
© 2021. The Author(s).
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