![]() Before the structure of LAT1 was solved by cryo-electron microscopy (Cryo-EM), several different homology models, structure-activity relationships (SAR), protein-ligand models, and pharmacophore models were proposed. ![]() The exact role of CD98 is not fully understood, but it has been proposed that it chaperones the complex’s localization to the cell membrane and affects the LAT1′s transportation activity. LAT1 consists of a light chain ( SLC7A5) and a CD98 heavy chain (4F2hc SLC3A2), which are linked together via a disulfide bond. Nevertheless, LAT1 is a high affinity–low-capacity transporter, i.e., the K m and V max for LAT1 substrates are typically very low (K m of 13–28 µM and V max of 2–6 pmol/10 6 cells/min for human isoform). The transport rate of LAT1 substrates has been postulated to be controlled by the concentration of intracellular substrates, LAT1 having a higher affinity for intracellular amino acids than amino acids in the extracellular space. Curiously, it has been noted that LAT1 is stereospecific, preferring L-forms over the D-forms, and having a higher affinity for its substrate amino acids than the other transporters in the periphery belonging to the same LAT-family. This heterodimeric protein complex is an essential carrier of large, neutral, aromatic, or branched L-amino acids (e.g., L-Leu, L-Phe, L-Tyr, L-Trp, L-His, L-Met, L-Ile, and L-Val) and some amino acid mimicking drugs (e.g., L-dopa, gabapentin, baclofen, and melphalan). L-Type amino acid transporter 1 (LAT1), commonly referred to as the “large neutral amino acid transporter 1”, less commonly referred to as the “L-leucine preferring amino acid transporter 1”, is a pH and sodium-independent antiporter. Hence, it is discussed herein how the selected methodology influences the outcome and created knowledge of LAT1-utilizing compounds. ![]() Moreover, this study also highlights the importance of understanding the intracellular kinetics of LAT1-ligands, and how they can affect the regular function of LAT1 in critical tissues, such as the brain. In the present study, the usefulness of indirect cis-inhibition methods and direct cellular uptake methods and their variations to interpret the interactions of LAT1-ligands were evaluated. Moreover, the functionality of LAT1 can be measured by several different methods, which may vary between the laboratories and make the comparison of the results challenging. However, less is known of LAT1′s life cycle within the cells. The structure of LAT1 is today very well-known and the interactions of ligands at the binding site of LAT1 can be modeled and explained. L-Type amino acid transporter 1 (LAT1), expressed abundantly in the brain and placenta and overexpressed in several cancer cell types, has gained a lot of interest in drug research and development, as it can be utilized for brain-targeted drug delivery, as well as inhibiting the essential amino acid supply to cancer cells.
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