<span class="small-caps">A</span> multi-hierarchical approach reveals <span class="small-caps">d</span>-serine as a hidden substrate of sodium-coupled monocarboxylate transporters
Center for SI Medical Research, The Jikei University School of Medicine, Tokyo, Japan; Department of Laboratory Medicine, The Jikei University School of Medicine, Tokyo, Japan; Department of Collaborative Research for Biomolecular Dynamics, Nara Medical University, Nara, Japan
Satomi Moriyama
Department of Collaborative Research for Biomolecular Dynamics, Nara Medical University, Nara, Japan
Masataka Suzuki
Department of Pharmacology, Keio University School of Medicine, Tokyo, Japan
Pornparn Kongpracha
Center for SI Medical Research, The Jikei University School of Medicine, Tokyo, Japan; Department of Laboratory Medicine, The Jikei University School of Medicine, Tokyo, Japan
Nodoka Nakamae
Department of Collaborative Research for Biomolecular Dynamics, Nara Medical University, Nara, Japan
Saki Takeshita
Department of Collaborative Research for Biomolecular Dynamics, Nara Medical University, Nara, Japan
Yoko Tanaka
Department of Collaborative Research for Biomolecular Dynamics, Nara Medical University, Nara, Japan
Akina Matsuda
Department of Pharmacology, Keio University School of Medicine, Tokyo, Japan
Masaki Miyasaka
Center for SI Medical Research, The Jikei University School of Medicine, Tokyo, Japan; Department of Laboratory Medicine, The Jikei University School of Medicine, Tokyo, Japan
Kenji Hamase
Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
Tomonori Kimura
KAGAMI Project, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan; Reverse Translational Research Project, Center for Rare Disease Research, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
Masashi Mita
KAGAMI Inc, Osaka, Japan
Jumpei Sasabe
Department of Pharmacology, Keio University School of Medicine, Tokyo, Japan
Center for SI Medical Research, The Jikei University School of Medicine, Tokyo, Japan; Department of Laboratory Medicine, The Jikei University School of Medicine, Tokyo, Japan; Department of Collaborative Research for Biomolecular Dynamics, Nara Medical University, Nara, Japan
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.
