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

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.

The Human SLC1A5 (ASCT2) Amino Acid Transporter: From Function to Structure and Role in Cell Biology

“…However, besides cancer, ASCT2 expression/function is altered also in other pathological conditions such as IUGR (IntraUterine Growth Restriction) (Aiko et al, 2014 ), ALS (Amyotrophic Lateral Sclerosis) (Lee et al, 2017 ), and schizophrenia (Maucler et al, 2013 ). Being a plasma membrane transporter, ASCT2 could also be either a first level drug target or a relevant player in drug disposition, similarly to LAT1 which is an acknowledged transporter of several amino acid-like drugs (del Amo et al, 2008 ; Fotiadis et al, 2013 ; Scalise et al, 2018a ; Singh and Ecker, 2018 ). In spite of such evidence, the scientific community, the scientific community still did not include ASCT2, or any other transporter for amino acids, in the list of the International Transporter Consortium for drug-transporter interactions (Giacomini and Huang, 2013 ).…”

Transcriptional alterations in opioid use disorder reveal an interplay between neuroinflammation and synaptic remodeling

“…In the NAc forestgreen module, we also identified a transcript encoding the RNA-binding protein, YBX3. YBX3 regulates the expression of the large neutral amino acid transporter 1 (LAT1)(90), which is necessary for the uptake of catecholamine precursor, L-DOPA in dopaminergic cells (91). Interestingly, changes in the expression of YBX3 in human midbrain has previously been implicated in opioid dependence (92).…”

Function and Regulation of Acid Resistance Antiporters

“…l-Amino acid transporters (LATs) are pH-independent human APC transporters that form heterodimeric complexes with the glycoprotein 4F2hc. The latter controls intracellular trafficking and membrane topology of LAT in the covalent complex, while LAT functions as an amino acid antiporter, importing large neutral amino acid into the cells for the exchange of intracellular amino acid (Fotiadis et al 2013;Singh and Ecker 2018). LATs are involved in diseases as cystinuria (Feliubadaló et al 1999), lysinuric protein intolerance (Borsani et al 1999;Torrents et al 1999), autism (Tărlungeanu et al 2016), and age-related hearing loss (Espino Guarch et al 2018).…”