Kynurenic Acid Synthesis from D-Kynurenine in the Cerebellum: A Distinct Role of D-Amino Acid Oxidase
The enzymatic formation of kynurenic acid (KYNA), a neuromodulator metabolite of the kynurenine pathway (KP) of tryptophan metabolism, in the mammalian brain is widely attributed to kynurenine aminotransferase II (KATII). However, an alternative biosynthetic route, involving the conversion of D-kynu...
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2025-07-01
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| author | Verónica Pérez de la Cruz Korrapati V. Sathyasaikumar Xiao-Dan Wang Tonali Blanco Ayala Sarah Beggiato Dinora F. González Esquivel Benjamin Pineda Robert Schwarcz |
| author_facet | Verónica Pérez de la Cruz Korrapati V. Sathyasaikumar Xiao-Dan Wang Tonali Blanco Ayala Sarah Beggiato Dinora F. González Esquivel Benjamin Pineda Robert Schwarcz |
| author_sort | Verónica Pérez de la Cruz |
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| description | The enzymatic formation of kynurenic acid (KYNA), a neuromodulator metabolite of the kynurenine pathway (KP) of tryptophan metabolism, in the mammalian brain is widely attributed to kynurenine aminotransferase II (KATII). However, an alternative biosynthetic route, involving the conversion of D-kynurenine (D-KYN) to KYNA by D-amino acid oxidase (D-AAO), may play a role as well. In the present study, we first confirmed that purified D-AAO efficiently converted D-KYN—but not L-KYN—to KYNA. We then examined KYNA formation from D-KYN (100 µM) in vitro, using tissue homogenates from several human brain regions. KYNA was generated in all areas, with D-AAO-specific production being most effective by far in the cerebellum. Next tested in homogenates from rat cerebellum, KYNA neosynthesis was significantly reduced by D-AAO inhibition, whereas KATII inhibition had no effect. Finally, KYNA production was assessed by in vivo microdialysis in rat cerebellum. Local D-KYN perfusion, alone and in combination with inhibitors of D-AAO (kojic acid) or aminotransferases (AOAA), caused a substantive increase in extracellular KYNA levels. This effect was attenuated dose-dependently by micromolar concentrations of kojic acid, whereas co-perfusion of AOAA (1 mM) was ineffective. Together, our findings indicate that D-AAO should be considered a major contributor to KYNA production in the cerebellum, highlighting region-specific qualitative differences in cerebral KYNA metabolism. |
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| language | English |
| publishDate | 2025-07-01 |
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| spelling | doaj-art-172fad1720f94e879ad01733ec82ea802025-08-20T03:28:28ZengMDPI AGCells2073-44092025-07-011413103010.3390/cells14131030Kynurenic Acid Synthesis from D-Kynurenine in the Cerebellum: A Distinct Role of D-Amino Acid OxidaseVerónica Pérez de la Cruz0Korrapati V. Sathyasaikumar1Xiao-Dan Wang2Tonali Blanco Ayala3Sarah Beggiato4Dinora F. González Esquivel5Benjamin Pineda6Robert Schwarcz7Neurobiochemistry and Behavior Laboratory, National Institute of Neurology and Neurosurgery “Manuel Velasco Suárez”, Mexico City 14269, MexicoMaryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21228, USAMaryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21228, USANeurobiochemistry and Behavior Laboratory, National Institute of Neurology and Neurosurgery “Manuel Velasco Suárez”, Mexico City 14269, MexicoDepartment of Life Sciences and Biotechnology, University of Ferrara, Via Borsari 46, 44121 Ferrara, ItalyNeurobiochemistry and Behavior Laboratory, National Institute of Neurology and Neurosurgery “Manuel Velasco Suárez”, Mexico City 14269, MexicoNeuroimmunology Department, National Institute of Neurology and Neurosurgery “Manuel Velasco Suárez”, Mexico City 14269, MexicoMaryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21228, USAThe enzymatic formation of kynurenic acid (KYNA), a neuromodulator metabolite of the kynurenine pathway (KP) of tryptophan metabolism, in the mammalian brain is widely attributed to kynurenine aminotransferase II (KATII). However, an alternative biosynthetic route, involving the conversion of D-kynurenine (D-KYN) to KYNA by D-amino acid oxidase (D-AAO), may play a role as well. In the present study, we first confirmed that purified D-AAO efficiently converted D-KYN—but not L-KYN—to KYNA. We then examined KYNA formation from D-KYN (100 µM) in vitro, using tissue homogenates from several human brain regions. KYNA was generated in all areas, with D-AAO-specific production being most effective by far in the cerebellum. Next tested in homogenates from rat cerebellum, KYNA neosynthesis was significantly reduced by D-AAO inhibition, whereas KATII inhibition had no effect. Finally, KYNA production was assessed by in vivo microdialysis in rat cerebellum. Local D-KYN perfusion, alone and in combination with inhibitors of D-AAO (kojic acid) or aminotransferases (AOAA), caused a substantive increase in extracellular KYNA levels. This effect was attenuated dose-dependently by micromolar concentrations of kojic acid, whereas co-perfusion of AOAA (1 mM) was ineffective. Together, our findings indicate that D-AAO should be considered a major contributor to KYNA production in the cerebellum, highlighting region-specific qualitative differences in cerebral KYNA metabolism.https://www.mdpi.com/2073-4409/14/13/1030D-amino acid oxidasekynurenic acidcerebellumD-kynurenine |
| spellingShingle | Verónica Pérez de la Cruz Korrapati V. Sathyasaikumar Xiao-Dan Wang Tonali Blanco Ayala Sarah Beggiato Dinora F. González Esquivel Benjamin Pineda Robert Schwarcz Kynurenic Acid Synthesis from D-Kynurenine in the Cerebellum: A Distinct Role of D-Amino Acid Oxidase Cells D-amino acid oxidase kynurenic acid cerebellum D-kynurenine |
| title | Kynurenic Acid Synthesis from D-Kynurenine in the Cerebellum: A Distinct Role of D-Amino Acid Oxidase |
| title_full | Kynurenic Acid Synthesis from D-Kynurenine in the Cerebellum: A Distinct Role of D-Amino Acid Oxidase |
| title_fullStr | Kynurenic Acid Synthesis from D-Kynurenine in the Cerebellum: A Distinct Role of D-Amino Acid Oxidase |
| title_full_unstemmed | Kynurenic Acid Synthesis from D-Kynurenine in the Cerebellum: A Distinct Role of D-Amino Acid Oxidase |
| title_short | Kynurenic Acid Synthesis from D-Kynurenine in the Cerebellum: A Distinct Role of D-Amino Acid Oxidase |
| title_sort | kynurenic acid synthesis from d kynurenine in the cerebellum a distinct role of d amino acid oxidase |
| topic | D-amino acid oxidase kynurenic acid cerebellum D-kynurenine |
| url | https://www.mdpi.com/2073-4409/14/13/1030 |
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