Deorphaning a solute carrier 22 family member, SLC22A15, through functional genomic studies

The human solute carrier 22A (SLC22A) family consists of 23 members, representing one of the largest families in the human SLC superfamily. Despite their pharmacological and physiological importance in the absorption and disposition of a range of solutes, eight SLC22A family members remain classifie...

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Bibliographic Details
Published in:The FASEB journal 2020-12, Vol.34 (12), p.15734-15752
Main Authors: Yee, Sook Wah, Buitrago, Dina, Stecula, Adrian, Ngo, Huy X., Chien, Huan‐Chieh, Zou, Ling, Koleske, Megan L., Giacomini, Kathleen M.
Format: Article
Language:English
Subjects:
Biological Transport - drug effects
Biological Transport - genetics
carnitine
Carnitine - pharmacology
carnosine
Carnosine - pharmacology
Cell Line
ergothioneine
Ergothioneine - pharmacology
Gabapentin - pharmacology
Genomics - methods
HEK293 Cells
Humans
Ligands
metabolomic
Organic Cation Transport Proteins - genetics
Phylogeny
Transfection - methods
transporter
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Summary:The human solute carrier 22A (SLC22A) family consists of 23 members, representing one of the largest families in the human SLC superfamily. Despite their pharmacological and physiological importance in the absorption and disposition of a range of solutes, eight SLC22A family members remain classified as orphans. In this study, we used a multifaceted approach to identify ligands of orphan SLC22A15. Ligands of SLC22A15 were proposed based on phylogenetic analysis and comparative modeling. The putative ligands were then confirmed by metabolomic screening and uptake assays in SLC22A15 transfected HEK293 cells. Metabolomic studies and transporter assays revealed that SLC22A15 prefers zwitterionic compounds over cations and anions. We identified eight zwitterions, including ergothioneine, carnitine, carnosine, gabapentin, as well as four cations, including MPP+, thiamine, and cimetidine, as substrates of SLC22A15. Carnosine was a specific substrate of SLC22A15 among the transporters in the SLC22A family. SLC22A15 transport of several substrates was sodium‐dependent and exhibited a higher Km for ergothioneine, carnitine, and carnosine compared to previously identified transporters for these ligands. This is the first study to characterize the function of SLC22A15. Our studies demonstrate that SLC22A15 may play an important role in determining the systemic and tissue levels of ergothioneine, carnosine, and other zwitterions.
ISSN:0892-6638
1530-6860
DOI:10.1096/fj.202001497R