Graduate School of Pharmaceutical Sciences, International University of Health and Welfare, 2600-1 Kitakanemaru, Ohtawara, Tochigi 324-8501, Japan.
Chem Biodivers. 2010 Jun;7(6):1450-8. doi: 10.1002/cbdv.200900303.
D-amino acid oxidase (DAO) catalyzes oxidative deamination of D-amino acids. Since D-amino acids are considered to be rare in eukaryotes, physiological function of this enzyme has been enigmatic for a long time. Mutant mice lacking DAO were found, and their strain was established. The urine of the mutant mice contained large amounts of D-amino acids. D-Amino acids were also present in their organs and blood. The origin of these D-amino acids was pursued. The results indicate that one of the physiological functions of DAO is the metabolism of D-amino acids of internal and external origin. A large amount of D-serine is shown to exist in the brain of mammals. It binds to the coagonist-binding site of N-methyl-D-aspartate (NMDA) subtype of glutamate receptors and enhances the neurotransmission. DAO metabolizes this D-serine and, therefore, modulates neurotransmission. Mutant mice displayed phenotypes resulting from the enhanced NMDA receptor function. Recent studies have shown that DAO is associated with schizophrenia. Mutant mice were resistant to the drugs which act on NMDA receptors and elicit schizophrenia-like symptoms. Recently, mutant rats lacking DAO have also been found. They were free from D-serine-induced nephrotoxicity, indicating involvement of DAO in this toxicity. The mutant mice and rats lacking DAO would be useful for the elucidation of the physiological functions of DAO and the etiology of neuronal diseases associated with DAO.
D-氨基酸氧化酶（DAO）催化 D-氨基酸的氧化脱氨。由于 D-氨基酸被认为在真核生物中很少见，因此该酶的生理功能长期以来一直是个谜。缺乏 DAO 的突变小鼠被发现，并建立了它们的品系。突变小鼠的尿液中含有大量的 D-氨基酸。它们的器官和血液中也存在 D-氨基酸。这些 D-氨基酸的来源被追踪。结果表明，DAO 的生理功能之一是代谢内外源 D-氨基酸。大量的 D-丝氨酸被证明存在于哺乳动物的大脑中。它与 N-甲基-D-天冬氨酸（NMDA）型谷氨酸受体的共激动剂结合位点结合，增强神经传递。DAO 代谢这种 D-丝氨酸，从而调节神经传递。突变小鼠表现出增强的 NMDA 受体功能引起的表型。最近的研究表明，DAO 与精神分裂症有关。突变小鼠对作用于 NMDA 受体并引起类精神分裂症症状的药物有抗性。最近，还发现缺乏 DAO 的突变大鼠。它们没有受到 D-丝氨酸引起的肾毒性的影响，表明 DAO 参与了这种毒性。缺乏 DAO 的突变小鼠和大鼠将有助于阐明 DAO 的生理功能以及与 DAO 相关的神经元疾病的病因。
