Division of Enzyme Pathophysiology, The Institute for Enzyme Research (KOSOKEN), The University of Tokushima, 3-18-15 Kuramoto, Tokushima, Japan.
J Biochem. 2010 Dec;148(6):743-53. doi: 10.1093/jb/mvq112. Epub 2010 Sep 27.
D-amino acid oxidase (DAO) is a flavoenzyme that exists in the kidney, liver and brain of mammals. This enzyme catalyzes the oxidation of D-amino acids to the corresponding α-keto acid, hydrogen peroxide and ammonia. Recently D-serine, one of the substrates of DAO, has been found in the mammalian brain, and shown to be a co-agonist of the N-methyl-D-aspartate (NMDA) receptor in glutamate neurotransmission. In this study, we investigated the metabolism of extracellular D-serine and the effects of D-serine metabolites to study the pathophysiological role of DAO. Treatment with a high dose of D-serine induced the cell death in dose-dependent manner in DAO-expressing cells. Moreover, overexpression of DAO in astroglial cells induced the enhanced cytotoxicity. The treatment with 1 mM beta-hydroxypyruvate (HPA), uniquely produced from the D-serine metabolism by DAO activity, also induced cell death, comprising apoptosis, in the astroglial cell, but not in the other cells derived from liver and kidney. Taken together, we consider that high dose of extracellular D-serine induced cell death by the production of not only hydrogen peroxide but also HPA as a result of DAO catalytic activity in astroglial cell. Furthermore, this cytotoxicity of HPA is observed uniquely in astroglial cells expressing DAO.
D-氨基酸氧化酶（DAO）是一种存在于哺乳动物肾脏、肝脏和大脑中的黄素酶。该酶催化 D-氨基酸氧化为相应的α-酮酸、过氧化氢和氨。最近，DAO 的一种底物 D-丝氨酸在哺乳动物大脑中被发现，并被证明是谷氨酸能神经传递中 N-甲基-D-天冬氨酸（NMDA）受体的共激动剂。在这项研究中，我们研究了细胞外 D-丝氨酸的代谢以及 D-丝氨酸代谢物的作用，以研究 DAO 的病理生理作用。高剂量 D-丝氨酸处理以剂量依赖的方式诱导表达 DAO 的细胞死亡。此外，在星形胶质细胞中过表达 DAO 会诱导增强的细胞毒性。用 1mMβ-羟丙酮酸（HPA）处理，这是 DAO 活性从 D-丝氨酸代谢中唯一产生的物质，也会诱导星形胶质细胞发生细胞死亡，包括凋亡，但不会在其他源自肝脏和肾脏的细胞中发生。总之，我们认为，细胞外高剂量 D-丝氨酸通过 DAO 催化活性产生的不仅是过氧化氢，还有 HPA，从而诱导星形胶质细胞死亡。此外，这种 HPA 的细胞毒性仅在表达 DAO 的星形胶质细胞中观察到。
