Abstract
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.
Highlights
LAT1 (SLC7A5) is a sodium and pH-independent transmembrane transporter that forms a heterodimeric complex with the glycoprotein 4F2hc (CD98, SLC3A2) to import large and neutral amino acids in exchange for intracellular amino acids [1,2]
LAT1 is a member of Heterodimeric Amino acid Transporters (HATs) that are composed of a light chain (SLC7) that mediates the transport of amino acids, and a heavy chain (SLC3) that catalyzes plasma membrane localization and stabilization of the light chains
Experimental and ligand-based studies have demonstrated that unsubstituted α-carboxyl and α-amino groups and a neutral hydrophobic side chain are indispensable features for LAT1 recognition
Summary
LAT1 (SLC7A5) is a sodium and pH-independent transmembrane transporter that forms a heterodimeric complex with the glycoprotein 4F2hc (CD98, SLC3A2) to import large and neutral amino acids (e.g., leucine, phenylalanine) in exchange for intracellular amino acids (e.g., glutamine) [1,2]. The functional significance of LAT1 in the growth of tumors has been demonstrated through genetic manipulation, whereby knockdown of LAT1 with RNA interference (RNAi) [21,22,23,24,25] and its genetic disruption by zinc fingers nucleases-mediated gene knockout [26] in cancer cells exhibited reduced leucine uptake and cell proliferation. With the crystallization of arginine/agmatine antiporter (AdiC), numerous homology models of LAT1 have been reported and are proving invaluable in the study of the transporter structure and mechanism of amino acid transport. These models have guided the elucidation of the substrate binding site, inter- and intra-molecular interactions, substrate translocation mechanism, and conformational states of the protein. This article highlights the structure, function, transport mechanism, and in silico studies of LAT1
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