2.A.3.8.6
L-type neutral amino acid transporter, LAT2 (Na⁺-independent with broad specificity for all L-isomers of neutral amino acids; preferred substrate: Phe, His, Trp, Ile, Val, Leu, Gln, Cys, Ser; catalyzes obligatory exchange with μM affinities on the outside and mM affinities on the inside [1000x difference]). Both LAT2 and LAT1 (2.A.3.8.1) catalyze uptake of S-nitro-L-cysteine (Li and Whorton, 2005). Also transports thyroid hormones (Kinne et al., 2011). Lat1 transports 26 biologically active ultrashort peptides (USPs) into cells as is also true of LAT2 and PEPT1 (Khavinson et al. 2023). The sizes and structures of ligand-binding sites of the amino acid transporters LAT1, LAT2, and of the peptide transporter PEPT1 are sufficient for the transport of the 26 biologically active di-, tri-, and tetra-peptides. Comparative analyses of the binding of all possible di- and tri-peptides (8400 compounds) at the binding sites of the LAT and PEPT family transporters was considered (Khavinson et al. 2023). The 26 biologically active USPs systematically showed higher binding scores to LAT1, LAT2, and PEPT1, as compared with di- and tri-peptides. Most of the 26 studied USPs were found to bind to the LAT1, LAT2, and PEPT1 transporters more efficiently than the previously known substrates or inhibitors of these transporters. Peptides ED, DS, DR, EDR, EDG, AEDR, AEDL, KEDP, and KEDG, and peptoids DS7 and KE17 with negatively charged Asp^- or Glu^- amino acid residues at the N-terminus and neutral or positively charged residues at the C-terminus of the peptide were found to be the most effective ligands of the transporters under investigation. It can be assumed that the antitumor effect of the KE, EW, EDG, and AEDG peptides could be associated with their ability to inhibit the LAT1, LAT2, and PEPT1 amino acid transporters (Khavinson et al. 2023).