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Chiral resolution of plasma amino acids reveals enantiomer-selective associations with organ functions


Plasma amino acids reflect the dynamics of amino acids in organs and their levels have clinical significance. Amino acids as clinical indicators have been evaluated as a mixture of d- and l-amino acids because d-enantiomers are believed to be physiologically nonexistent. However, it has become clear that some d-amino acids are synthesized by endogenous enzymes and symbiotic bacteria. Here, using a two-dimensional HPLC system, we measured enantiomers of all proteinogenic amino acids in plasma and urine and analyzed for correlation with other biochemical parameters in humans who underwent health checkups at our institutional hospital. Four d-amino acids (d-asparagine, d-alanine, d-serine, and d-proline) were detected in the plasma, amounting to less than 1% of the quantities of l-amino acids, but in the urine at several tens of percent, showing that d-amino acids have much higher fractional excretion than their L-counterparts. Detected plasma d-amino acids and d-/l-amino acid ratios were well correlated with renal parameters, such as blood urea nitrogen, creatinine, and cystatin C. On the other hand, a set of plasma l-amino acids were associated with body mass index and correlated with metabolic parameters such as liver enzymes, lipids, blood glucose, and uric acid. Thus, chiral resolution of plasma amino acids revealed totally different associations of the enantiomers with organ functions, and warrants further investigation for clinical and laboratory usefulness.

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We are grateful to Sadakazu Aiso, Yasushi Iwao, and Masato Yasui for essential support. We thank Hiroshi Imoto, Tatsuhiko Ikeda, Eiichi Negishi, Shoto Ishigo, and Maiko Nakane for technical support on chiral amino acid analysis; Kanako Makino for organization of clinical data; Steven D. Aird for editing the manuscript; and clinical staff members in the Center of Preventive Medicine in Keio University Hospital for sample collection.


This research was funded by Shiseido. Co. Ltd., Keio University Grant-in-Aid for Encouragement of Young Medical Scientists (MS), and Keio Gijuku Fukuzawa Memorial Fund for the Advancement of Education and Research (JS).

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Conceptualization: MS and RSH; methodology: MM, and KH; validation: RSH, and MM; formal analysis: MS and JS; investigation: MS, RSH, and JS; resources: MM; data curation, MS and RSH; manuscript writing, MS and JS; visualization: MS; supervision: JS; project administration: JS; funding acquisition: MS and JS.

Corresponding author

Correspondence to Jumpei Sasabe.

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Financial interests

The authors have no relevant financial interests to disclose.

Non-financial interests

MM is founder and CEO of KAGAMI INC., a startup company working on chiral amino acids analysis and research for medical application.

Ethics approval

This study was approved by the institutional Ethics Committee and conducted in accordance with the Helsinki Declaration and institutional guidelines for clinical studies at Keio University Hospital (Approval number: 20150165). We obtained consent from 93 of 104 individuals, who had received a colonoscopy or a comprehensive health examination in the Center of Preventive Medicine at Keio University Hospital from March to May, 2016.

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Handling editor: J. M. Phang.

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Suzuki, M., Shimizu-Hirota, R., Mita, M. et al. Chiral resolution of plasma amino acids reveals enantiomer-selective associations with organ functions. Amino Acids 54, 421–432 (2022).

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  • Enantiomers
  • d-amino acids
  • Renal function
  • Clinical laboratory test