D-Serine, an emerging biomarker of kidney diseases, is a hidden substrate of sodium-coupled monocarboxylate transporters

Wiriyasermkul, P.; Moriyama, S.; Tanaka, Y.; Kongpracha, P.; Nakamae, N.; Suzuki, M.; Kimura, T.; Mita, M.; Sasabe, J.; Nagamori, S.

doi:10.1101/2020.08.10.244822

bioRxiv · 10.1101/2020.08.10.244822

D-Serine, an emerging biomarker of kidney diseases, is a hidden substrate of sodium-coupled monocarboxylate transporters

Wiriyasermkul, P.·Moriyama, S.·Tanaka, Y.·Kongpracha, P.·Nakamae, N.·Suzuki, M.·Kimura, T.·Mita, M.·Sasabe, J.·Nagamori, S.

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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 noncanonical 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.

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Wiriyasermkul, P., Moriyama, S., Tanaka, Y., Kongpracha, P., Nakamae, N., Suzuki, M., Kimura, T., Mita, M., Sasabe, J., Nagamori, S.. 2020-08-10. D-Serine, an emerging biomarker of kidney diseases, is a hidden substrate of sodium-coupled monocarboxylate transporters. https://doi.org/10.1101/2020.08.10.244822

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