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- Title
A multi-hierarchical approach reveals D-serine as a hidden substrate of sodium-coupled monocarboxylate transporters.
- Authors
Wiriyasermkul, Pattama; Satomi Moriyama; Masataka Suzuki; Kongpracha, Pornparn; Nodoka Nakamae; Saki Takeshita; Yoko Tanaka; Akina Matsuda; Masaki Miyasaka; Kenji Hamase; Tomonori Kimura; Masashi Mita; Jumpei Sasabe; Shushi Nagamori
- 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.
- Subjects
MONOCARBOXYLATE transporters; KIDNEY physiology; BODY fluids; MULTIOMICS; BIOCHEMISTRY; BIOMARKERS; SERINE
- Publication
eLife, 2024, p1
- ISSN
2050-084X
- Publication type
Article
- DOI
10.7554/eLife.92615