The L-type amino acid transporter 1 (LAT1, SLC7A5), transports specific amino acids across the blood-brain barrier (BBB) and other tissues including thymus, testis, placenta, spleen, and skeletal muscle. It is also upregulated in cancer cells to support their increased metabolism. The origin of the name “L-type” was due to its preference for transporting leucine instead of alanine. However, in recent years, the “L” in LAT1 has been accepted as meaning “large” in reference to its amino acid substrates: Phe, Leu, His, Trp, Tyr, Met and Val. Coincidentally, the “L” could also be interpreted as meaning selectivity for L isomers, since it is known that LAT1 is stereoselective for some, but not all, of its substrates. For example, the D isomers of most amino acids, with the exception of Leu, Phe and Met, were previously reported to have poor affinity. As we have been researching LAT1 for the purposes of using it in targeted drug delivery, we were curious as to whether this discrepancy in selectivity may be explained by different binding modes depending on the amino acid. Based on our computational models of the binding site, we hypothesized that the size and polarity of the side chains may be preventing some of the D amino acids from being transported. We have tested both D and L isomers of endogenous LAT1 substrates using <i>cis</i>-inhibition and <i>trans</i>-stimulation assays in HEK cells containing inducible levels of LAT1 expression. Surprisingly, based on our assays, we have found that with the exception of Val, LAT1 does transport both L and D isomers. Besides uncovering a potential unknown function for LAT1, the ability to use D amino acids to form LAT1-targeted prodrugs may allow for improvement in pharmacokinetics relative to L isomers.

LAT1 membrane transporter selectivity for L and D amino acids

255th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.