Glucuronic acid is a novel source of pentosidine, associated with schizophrenia
Kazuya Toriumi,
Kyoka Iino,
Azuna Ozawa,
Mitsuhiro Miyashita,
Syudo Yamasaki,
Kazuhiro Suzuki,
Hikari Sugawa,
Koichi Tabata,
Satoshi Yamaguchi,
Satoshi Usami,
Masanari Itokawa,
Atsushi Nishida,
Ryoji Nagai,
Hidenori Kamiguchi,
Makoto Arai
Affiliations
Kazuya Toriumi
Schizophrenia Research Project, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, 156-8506, Japan
Kyoka Iino
Schizophrenia Research Project, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, 156-8506, Japan
Azuna Ozawa
Schizophrenia Research Project, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, 156-8506, Japan
Mitsuhiro Miyashita
Schizophrenia Research Project, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, 156-8506, Japan; Unit for Mental Health Promotion, Research Center for Social Science & Medicine, Tokyo Metropolitan Institute of Medical Science, Tokyo, 156-8506, Japan; Department of Psychiatry, Tokyo Metropolitan Matsuzawa Hospital, Tokyo, 156-0057, Japan
Syudo Yamasaki
Unit for Mental Health Promotion, Research Center for Social Science & Medicine, Tokyo Metropolitan Institute of Medical Science, Tokyo, 156-8506, Japan
Kazuhiro Suzuki
Schizophrenia Research Project, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, 156-8506, Japan; Department of Community Mental Health, School of Medicine, Shinshu University, Nagano, 390-8621, Japan
Hikari Sugawa
Laboratory of Food and Regulation Biology, Graduate School of Bioscience, Tokai University, Kumamoto, 862-0970, Japan
Koichi Tabata
Schizophrenia Research Project, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, 156-8506, Japan; Department of Psychiatry and Behavioral Sciences, Tokyo Medical and Dental University Graduate School, Tokyo, 113-8510, Japan
Satoshi Yamaguchi
Unit for Mental Health Promotion, Research Center for Social Science & Medicine, Tokyo Metropolitan Institute of Medical Science, Tokyo, 156-8506, Japan
Satoshi Usami
Center for Research and Development on Transition from Secondary to Higher Education, The University of Tokyo, Tokyo, 113-0033, Japan
Masanari Itokawa
Schizophrenia Research Project, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, 156-8506, Japan; Department of Psychiatry, Tokyo Metropolitan Matsuzawa Hospital, Tokyo, 156-0057, Japan
Atsushi Nishida
Unit for Mental Health Promotion, Research Center for Social Science & Medicine, Tokyo Metropolitan Institute of Medical Science, Tokyo, 156-8506, Japan
Ryoji Nagai
Laboratory of Food and Regulation Biology, Graduate School of Bioscience, Tokai University, Kumamoto, 862-0970, Japan
Hidenori Kamiguchi
Takeda Pharmaceutical Company Ltd., Tokyo, 103-8668, Japan
Makoto Arai
Schizophrenia Research Project, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, 156-8506, Japan; Corresponding author.
Pentosidine (PEN) is an advanced glycation end-product (AGEs), where a fluorescent cross-link is formed between lysine and arginine residues in proteins. Accumulation of PEN is associated with aging and various diseases. We previously reported that a subpopulation of patients with schizophrenia showed PEN accumulation in the blood, having severe clinical features. PEN is thought to be produced from glucose, fructose, pentoses, or ascorbate. However, patients with schizophrenia with high PEN levels present no elevation of these precursors of PEN in their blood. Therefore, the molecular mechanisms underlying PEN accumulation and the molecular pathogenesis of schizophrenia associated with PEN accumulation remain unclear. Here, we identified glucuronic acid (GlcA) as a novel precursor of PEN from the plasma of subjects with high PEN levels. We demonstrated that PEN can be generated from GlcA, both in vitro and in vivo. Furthermore, we found that GlcA was associated with the diagnosis of schizophrenia. Among patients with high PEN, the proportion of those who also have high GlcA is 25.6%. We also showed that Aldo-keto reductase (AKR) activity to degrade GlcA was decreased in patients with schizophrenia, and its activity was negatively correlated with GlcA levels in the plasma. This is the first report to show that PEN is generated from GlcA. In the future, this finding will contribute to understanding the molecular pathogenesis of not only schizophrenia but also other diseases with PEN accumulation.
