1. A multi-hierarchical approach reveals d-serine as a hidden substrate of sodium-coupled monocarboxylate transporters
- Author
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Pattama Wiriyasermkul, Satomi Moriyama, Masataka Suzuki, Pornparn Kongpracha, Nodoka Nakamae, Saki Takeshita, Yoko Tanaka, Akina Matsuda, Masaki Miyasaka, Kenji Hamase, Tomonori Kimura, Masashi Mita, Jumpei Sasabe, and Shushi Nagamori
- Subjects
transporter ,amino acid ,kidney diseases ,micronutrient ,biomarker ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
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.
- Published
- 2024
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