Potential cytotoxic effect of hydroxypyruvate produced from D-serine by astroglial D-amino acid oxidase.
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.
Chung
Seong Pil
SP
Division of Enzyme Pathophysiology, The Institute for Enzyme Research (KOSOKEN), The University of Tokushima, 3-18-15 Kuramoto, Tokushima, Japan.
Sogabe
Kimiko
K
Park
Hwan Ki
HK
Song
Ying
Y
Ono
Koji
K
Abou El-Magd
Rabab M
RM
Shishido
Yuji
Y
Yorita
Kazuko
K
Sakai
Takashi
T
Fukui
Kiyoshi
K
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001253:Astrocytes / Q000378:metabolism*; D055162:Biocatalysis; D001921:Brain / Q000201:enzymology* / Q000503:physiopathology; D002470:Cell Survival; D002478:Cells, Cultured; D003605:D-Amino-Acid Oxidase / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D057075:Enzyme Assays; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D051379:Mice; D011773:Pyruvates / Q000378:metabolism; D051381:Rats; D012694:Serine / Q000378:metabolism / Q000494:pharmacology; D013552:Swine; D014162:Transfection
D011773:Pyruvates; D012694:Serine; C012375:hydroxypyruvic acid; D003605:D-Amino-Acid Oxidase