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Inactivation of the glutamine/amino acid transporter ASCT2 by 1,2,3-dithiazoles: proteoliposomes as a tool to gain insights in the molecular mechanism of action and of antitumor activity
- Source :
- Toxicology and applied pharmacology, Toxicol.Appl.Pharmacol.
- Publication Year :
- 2012
- Publisher :
- Elsevier BV, 2012.
-
Abstract
- The ASCT2 transport system catalyses a sodium-dependent antiport of glutamine and other neutral amino acids which is involved in amino acid metabolism. A library of 1,2,3-dithiazoles was designed, synthesized and evaluated as inhibitors of the glutamine/amino acid ASCT2 transporter in the model system of proteoliposomes reconstituted with the rat liver transporter. Fifteen of the tested compounds at concentration of 20μM or below, inhibited more than 50% the glutamine/glutamine antiport catalysed by the reconstituted transporter. These good inhibitors bear a phenyl ring with electron withdrawing substituents. The inhibition was reversed by 1,4-dithioerythritol indicating that the effect was likely owed to the formation of mixed sulfides with the protein's Cys residue(s). A dose-response analysis of the most active compounds gave IC50 values in the range of 3-30μM. Kinetic inhibition studies indicated a non-competitive inhibition, presumably because of a potential covalent interaction of the dithiazoles with cysteine thiol groups that are not located at the substrate binding site. Indeed, computational studies using a homology structural model of ASCT2 transporter, suggested as possible binding targets, Cys-207 or Cys-210, that belong to the CXXC motif of the protein. © 2012 Elsevier Inc. 265 1 93 102 Cited By :23
- Subjects :
- Amino Acid Transport Systems
Glutamine
Antiporter
Toxicology
amino acid transporter
covalent bond
Neoplasms
dose response
rat
cysteine
antineoplastic agent
Cancer
chemistry.chemical_classification
Chemistry
article
amino acid transporter alanine serine cysteine transporter 2
ASCT2
unclassified drug
Amino acid
dithioerythritol
Biochemistry
1,2,3-dithiazoles
computer analysis
Amino Acid Transport System ASC
Stereochemistry
Proteolipids
animal experiment
Transport
Antineoplastic Agents
antineoplastic activity
animal tissue
Minor Histocompatibility Antigens
Structure-Activity Relationship
[(4 chloro 5 h 1,2,3 dithiazol 5 ylidene)amino]arenes
proteoliposome
inhibition kinetics
drug mechanism
Animals
2 (4 chloro 5 h 1,2,3 dithiazol 5 ylidene)arene 1 (2 h) ones
Structure–activity relationship
Computer Simulation
controlled study
Cysteine
Amino acid transporter
Binding site
enzyme substrate complex
Pharmacology
structural homology
nonhuman
Binding Sites
Dose-Response Relationship, Drug
Rattus
molecular library
IC 50
Transporter
Rats
Kinetics
Thiazoles
Liposomes
thiol group
Subjects
Details
- ISSN :
- 0041008X
- Volume :
- 265
- Database :
- OpenAIRE
- Journal :
- Toxicology and Applied Pharmacology
- Accession number :
- edsair.doi.dedup.....6af4eac0b34ebfd668d9bc4765bd7382