<sc>A</sc> multi-hierarchical approach reveals <sc>d</sc>-serine as a hidden substrate of sodium-coupled monocarboxylate transporters.

Transporter research primarily relies on the canonical substrates of well-established transporters. This approach has limitations when studying transporters for the low-abundant micromolecules, such as micronutrients, and may not reveal physiological functions of the transporters. While d-serine, a trace enantiomer of serine in the circulation, was discovered as an emerging biomarker of kidney function, its transport mechanisms in the periphery remain unknown. Here, using a multi-hierarchical approach from body fluids to molecules, combining multi-omics, cell-free synthetic biochemistry, and ex vivo transport analyses, we have identified two types of renal d-serine transport systems. We revealed that the small amino acid transporter ASCT2 serves as a d-serine transporter previously uncharacterized in the kidney and discovered d-serine as a non-canonical substrate of the sodium-coupled monocarboxylate transporters (SMCTs). These two systems are physiologically complementary, but ASCT2 dominates the role in the pathological condition. Our findings not only shed light on renal d-serine transport, but also clarify the importance of non-canonical substrate transport. This study provides a framework for investigating multiple transport systems of various trace micromolecules under physiological conditions and in multifactorial diseases.
Competing Interests: PW, SM, MS, PK, NN, ST, YT, AM, MM, KH, TK, JS No competing interests declared, MM founder and CEO of KAGAMI Inc, a startup company working on chiral amino acids analysis and research for medical applications, SN A patent (WO/2021/132691) has been applied by KAGAMI Inc, Nara Medical University,and NIBIOHN with P.W., S.M., P.K., T.K., M.Mit., and S.N. as inventors based on this research. The authors declare no potential conflicts of interest
(© 2023, Wiriyasermkul et al.)