Reevaluating the Substrate Specificity of the L-Type Amino Acid Transporter (LAT1).
- Chien HC Department of Bioengineering and Therapeutic Sciences , University of California, San Francisco , San Francisco , California 94158 , United States.
- Colas C Department of Pharmacological Sciences , Icahn School of Medicine at Mount Sinai , New York , New York 10029 , United States.
- Finke K Department of Chemistry , University of Nebraska at Kearney , Kearney , Nebraska 68849 , United States.
- Springer S Department of Chemistry , University of Nebraska at Kearney , Kearney , Nebraska 68849 , United States.
- Stoner L Department of Chemistry , University of Nebraska at Kearney , Kearney , Nebraska 68849 , United States.
- Zur AA Department of Bioengineering and Therapeutic Sciences , University of California, San Francisco , San Francisco , California 94158 , United States.
- Venteicher B Department of Chemistry , University of Nebraska at Kearney , Kearney , Nebraska 68849 , United States.
- Campbell J Department of Chemistry , University of Nebraska at Kearney , Kearney , Nebraska 68849 , United States.
- Hall C Department of Chemistry , University of Nebraska at Kearney , Kearney , Nebraska 68849 , United States.
- Flint A Department of Chemistry , University of Nebraska at Kearney , Kearney , Nebraska 68849 , United States.
- Augustyn E Department of Chemistry , University of Nebraska at Kearney , Kearney , Nebraska 68849 , United States.
- Hernandez C Department of Chemistry , University of Nebraska at Kearney , Kearney , Nebraska 68849 , United States.
- Heeren N Department of Chemistry , University of Nebraska at Kearney , Kearney , Nebraska 68849 , United States.
- Hansen L Department of Chemistry , University of Nebraska at Kearney , Kearney , Nebraska 68849 , United States.
- Anthony A Department of Chemistry , University of Nebraska at Kearney , Kearney , Nebraska 68849 , United States.
- Bauer J Department of Chemistry , University of Nebraska at Kearney , Kearney , Nebraska 68849 , United States.
- Fotiadis D Institute of Biochemistry and Molecular Medicine, and Swiss National Centre of Competence in Research (NCCR) TransCure , University of Bern , 3012 Bern , Switzerland.
- Schlessinger A Department of Pharmacological Sciences , Icahn School of Medicine at Mount Sinai , New York , New York 10029 , United States.
- Giacomini KM Department of Bioengineering and Therapeutic Sciences , University of California, San Francisco , San Francisco , California 94158 , United States.
- Thomas AA Department of Chemistry , University of Nebraska at Kearney , Kearney , Nebraska 68849 , United States.
- 2018-07-27
Published in:
- Journal of medicinal chemistry. - 2018
Amino Acid Transport Systems
Antiporters
Escherichia coli Proteins
HEK293 Cells
Humans
Large Neutral Amino Acid-Transporter 1
Ligands
Molecular Docking Simulation
Phenylalanine
Stereoisomerism
Structural Homology, Protein
Structure-Activity Relationship
Substrate Specificity
English
The L-type amino acid transporter 1 (LAT1, SLC7A5) transports essential amino acids across the blood-brain barrier (BBB) and into cancer cells. To utilize LAT1 for drug delivery, potent amino acid promoieties are desired, as prodrugs must compete with millimolar concentrations of endogenous amino acids. To better understand ligand-transporter interactions that could improve potency, we developed structural LAT1 models to guide the design of substituted analogues of phenylalanine and histidine. Furthermore, we evaluated the structure-activity relationship (SAR) for both enantiomers of naturally occurring LAT1 substrates. Analogues were tested in cis-inhibition and trans-stimulation cell assays to determine potency and uptake rate. Surprisingly, LAT1 can transport amino acid-like substrates with wide-ranging polarities including those containing ionizable substituents. Additionally, the rate of LAT1 transport was generally nonstereoselective even though enantiomers likely exhibit different binding modes. Our findings have broad implications to the development of new treatments for brain disorders and cancer.
- Language
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- English
- Open access status
- green
- Identifiers
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- DOI 10.1021/acs.jmedchem.8b01007
- PMID 30048132
- Persistent URL
- https://sonar.ch/global/documents/193036
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