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

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, Shushi Nagamori

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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.

Original languageEnglish
JournaleLife
Volume12
DOIs
Publication statusPublished - 2024 Apr 23

Keywords

  • amino acid
  • biochemistry
  • biomarker
  • chemical biology
  • kidney diseases
  • micronutrient
  • mouse
  • transporter

ASJC Scopus subject areas

  • General Neuroscience
  • General Biochemistry,Genetics and Molecular Biology
  • General Immunology and Microbiology

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