Reevaluating the Substrate Specificity of the L-Type Amino Acid Transporter (LAT1).

Chien, Huan-Chieh; Colas, Claire; Finke, Karissa; Springer, Seth; Stoner, Laura; Zur, Arik A; Venteicher, Brooklynn; Campbell, Jerome; Hall, Colton; Flint, Andrew; Augustyn, Evan; Hernandez, Christopher; Heeren, Nathan; Hansen, Logan; Anthony, Abby; Bauer, Justine; Fotiadis, Dimitrios José; Schlessinger, Avner; Giacomini, Kathleen M and Thomas, Allen A (2018). Reevaluating the Substrate Specificity of the L-Type Amino Acid Transporter (LAT1). Journal of medicinal chemistry, 61(16), pp. 7358-7373. American Chemical Society 10.1021/acs.jmedchem.8b01007

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Other Institutions > NCCR TransCure
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

UniBE Contributor:

Fotiadis, Dimitrios José

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

0022-2623

Publisher:

American Chemical Society

Language:

English

Submitter:

Barbara Järmann-Bangerter

Date Deposited:

27 Feb 2019 10:47

Last Modified:

27 Feb 2019 10:47

Publisher DOI:

10.1021/acs.jmedchem.8b01007

PubMed ID:

30048132

BORIS DOI:

10.7892/boris.124486

URI:

https://boris.unibe.ch/id/eprint/124486

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