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Insights into the Structure, Function, and Ligand Discovery of the Large Neutral Amino Acid Transporter 1, LAT1

The large neutral amino acid transporter 1 (LAT1, or SLC7A5) is a sodium- and pH-independent transporter, which supplies essential amino acids (e.g., leucine, phenylalanine) to cells. It plays an important role at the Blood–Brain Barrier (BBB) where it facilitates the transport of thyroid hormones,...

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Autores principales: Singh, Natesh, Ecker, Gerhard F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983779/
https://www.ncbi.nlm.nih.gov/pubmed/29695141
http://dx.doi.org/10.3390/ijms19051278
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author Singh, Natesh
Ecker, Gerhard F.
author_facet Singh, Natesh
Ecker, Gerhard F.
author_sort Singh, Natesh
collection PubMed
description The large neutral amino acid transporter 1 (LAT1, or SLC7A5) is a sodium- and pH-independent transporter, which supplies essential amino acids (e.g., leucine, phenylalanine) to cells. It plays an important role at the Blood–Brain Barrier (BBB) where it facilitates the transport of thyroid hormones, pharmaceuticals (e.g., l-DOPA, gabapentin), and metabolites into the brain. Moreover, its expression is highly upregulated in various types of human cancer that are characterized by an intense demand for amino acids for growth and proliferation. Therefore, LAT1 is believed to be an important drug target for cancer treatment. With the crystallization of the arginine/agmatine antiporter (AdiC) from Escherichia Coli, numerous homology models of LAT1 have been built to elucidate the substrate binding site, ligand–transporter interaction, and structure–function relationship. The use of these models in combination with molecular docking and experimental testing has identified novel chemotypes of ligands of LAT1. Here, we highlight the structure, function, transport mechanism, and homology modeling of LAT1. Additionally, results from structure–function studies performed on LAT1 are addressed, which have enhanced our knowledge of the mechanism of substrate binding and translocation. This is followed by a discussion on ligand- and structure-based approaches, with an emphasis on elucidating the molecular basis of LAT1 inhibition. Finally, we provide an exhaustive summary of different LAT1 inhibitors that have been identified so far, including the recently discovered irreversible covalent inhibitors.
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spelling pubmed-59837792018-06-05 Insights into the Structure, Function, and Ligand Discovery of the Large Neutral Amino Acid Transporter 1, LAT1 Singh, Natesh Ecker, Gerhard F. Int J Mol Sci Review The large neutral amino acid transporter 1 (LAT1, or SLC7A5) is a sodium- and pH-independent transporter, which supplies essential amino acids (e.g., leucine, phenylalanine) to cells. It plays an important role at the Blood–Brain Barrier (BBB) where it facilitates the transport of thyroid hormones, pharmaceuticals (e.g., l-DOPA, gabapentin), and metabolites into the brain. Moreover, its expression is highly upregulated in various types of human cancer that are characterized by an intense demand for amino acids for growth and proliferation. Therefore, LAT1 is believed to be an important drug target for cancer treatment. With the crystallization of the arginine/agmatine antiporter (AdiC) from Escherichia Coli, numerous homology models of LAT1 have been built to elucidate the substrate binding site, ligand–transporter interaction, and structure–function relationship. The use of these models in combination with molecular docking and experimental testing has identified novel chemotypes of ligands of LAT1. Here, we highlight the structure, function, transport mechanism, and homology modeling of LAT1. Additionally, results from structure–function studies performed on LAT1 are addressed, which have enhanced our knowledge of the mechanism of substrate binding and translocation. This is followed by a discussion on ligand- and structure-based approaches, with an emphasis on elucidating the molecular basis of LAT1 inhibition. Finally, we provide an exhaustive summary of different LAT1 inhibitors that have been identified so far, including the recently discovered irreversible covalent inhibitors. MDPI 2018-04-24 /pmc/articles/PMC5983779/ /pubmed/29695141 http://dx.doi.org/10.3390/ijms19051278 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Singh, Natesh
Ecker, Gerhard F.
Insights into the Structure, Function, and Ligand Discovery of the Large Neutral Amino Acid Transporter 1, LAT1
title Insights into the Structure, Function, and Ligand Discovery of the Large Neutral Amino Acid Transporter 1, LAT1
title_full Insights into the Structure, Function, and Ligand Discovery of the Large Neutral Amino Acid Transporter 1, LAT1
title_fullStr Insights into the Structure, Function, and Ligand Discovery of the Large Neutral Amino Acid Transporter 1, LAT1
title_full_unstemmed Insights into the Structure, Function, and Ligand Discovery of the Large Neutral Amino Acid Transporter 1, LAT1
title_short Insights into the Structure, Function, and Ligand Discovery of the Large Neutral Amino Acid Transporter 1, LAT1
title_sort insights into the structure, function, and ligand discovery of the large neutral amino acid transporter 1, lat1
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983779/
https://www.ncbi.nlm.nih.gov/pubmed/29695141
http://dx.doi.org/10.3390/ijms19051278
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