Division of Enzyme Pathophysiology

Main Research AreasResearch ProjectsMemberPublications

 

Main Research Areas

  • Enzyme Pathophysiology on D-Amino Acid Biosystem, especially in the neural network system operated and mediated by excitatory amino acid receptor.
  • Molecular biological studies on the pathophysiology of the regulatory system mediated by novel apoptosis-associated molecule, Nucling.

 

Research Projects

Our Division focuses on the pathophysiological roles of D-amino acid oxidase (DAO) and Nucling as the new regulatory factors in the physiological systems regulating neuronal, cardiovascular and immunological functions, in order to solve the problems such as schizophrenia, stroke and cancers, for the development of the novel therapeutic strategies to overcome these diseases.

Existence of D-amino acids in mammalian system has not been accepted for a long time, but recently it was found that D-amino acids exist in the mammalian brain and D-serine works as neuromodulator of the excitatory amino acid receptor. DAO oxidizes these D-amino acids including D-serine, which is the neuromodulator of NMDA receptor. We also identified the new regulator for apoptosis, Nucling, that is induced during the differentiation of the cardiac muscle.

Our goals of the research are to understand the pathophysiology and to reveal the regulatory mechanisms of central nervous, cardiovascular and immune systems through the proteomic and genomic studies with the use of new molecular biological and enzymological methodologies.

Expression and function of D-amino acid oxidase in central nervous system. (Fig.1)
◆Expression and function of D-amino acid oxidase in central nervous system. (Fig.1)

 

D-amino acid is identified as new regulatory factor in central nervous system. Our research is focused on the research of the new neurotransmission regulatory system through the functional analyses of D-amino acids, and also the expression analyses of their metabolic enzyme, D-amino acid oxidase (DAO). We propose the potential roles of DAO in the pathogenesis of Schizophrenia by inducing hypofunction of NMDA receptor through the metabolism of D-serine, co-agonist of NMDA receptor.

Structure proteomics of D-amino acid oxidase (Fig. 2)
◆Structure proteomics of D-amino acid oxidase (Fig. 2)

 

Two genes, encoding D-amino acid oxidase (DAO) and its activator (DAOA), are reported to be the disease susceptibility genes for Schizophrenia. The structural biological research of this metabolic system of D-amino acids in the central nervous system is important for the solution of the pathogenesis and symptoms of this disease. We also aim to develop new therapeutic strategies for the treatment of Schizophrenia through the studies on the structure of these molecules.

Regulation of development and differentiation by Nucling, a novel stress-induced regulator of apoptosis and NF-κB signaling. (Fig. 3)
◆ Regulation of development and differentiation by Nucling, a novel stress-induced regulator of apoptosis and NF-κB signaling. (Fig. 3)

 

The gene encoding Nucling is induced in the process of the cell differentiation of cardiac muscle, and plays an important role in the regulatory system of cell death, apoptosis. We aim to solve its pathophysiological roles. Nucling protein induces cell death by the up-regulation of apoptotic pathway through Apaf-1/caspase 9 system, activates NF-kB and regulates the expression of galectin-3.

 

Member

Professor Kiyoshi FUKUI, M.D., Ph. D.Professor
Kiyoshi FUKUI, M.D., Ph. D.
TEL : 088-633-7429
E-mail : kiyo@ier.tokushima-u.ac.jp
Associate Professor Takashi SAKAI, M.D., Ph. D.Associate Professor
Takashi SAKAI, M.D., Ph. D.
TEL : 088-633-7430
E-mail : sakai@ier.tokushima-u.ac.jp
Assistant Professor Kazuko YORITA, Ph. D.Assistant Professor
Kazuko YORITA, Ph. D.
TEL : 088-633-7430
E-mail : yorita@ier.tokushima-u.ac.jp
Research Fellow Yuji SHISHIDO, Ph. D.Research Fellow
Yuji SHISHIDO, Ph. D.
TEL : 088-633-7430
E-mail : shishido@ier.tokushima-u.ac.jp
Visiting Research Fellow Rabab M. Abou El-MagdVisiting Research Fellow
Rabab M. Abou El-Magd
Seong Pil Chung
TEL : 088-633-7430
E-mail : rabab@ier.tokushima-u.ac.jp
Research Fellow Seong Pil CHUNGResearch Fellow
Seong Pil CHUNG
TEL : 088-633-7430
E-mail : mirage12@ier.tokushima-u.ac.jp

 

Publications

  1. Ono K, Shishido Y, Park HK, Kawazoe T, Iwana S, Chung SP, Abou El-Magd RM, Yorita K, Okano M, Watanabe T, Sano N, Bando Y, Arima K, Sakai T, Fukui K. Potential pathophysiological role of D-amino acid oxidase in schizophrenia: immunohistochemical and in situ hybridization study of the expression in human and rat brain. J. Neural Transm. 116: 1335-1347, 2009
  2. Sakai T, Liu L, Teng X, Ishimaru N, Mukai-Sakai R, Tran HN, Kim SM, Sano N, Hayashi Y, Kaji R, Fukui K. The Effect of Risperidone on D-Amino Acid Oxidase Activity as a Hypothesis for a Novel Mechanism of Action in the Treatment of Schizophrenia. Int. J. Cancer 126, 1079-1094 (2010)
  3. Abou El-Magd RM, Park HK, Kawazoe T, Iwana S, Ono K, Chung SP, Miyano M, Yorita K, Sakai T, Fukui K. The Effect of Risperidone on D-Amino Acid Oxidase Activity as a Hypothesis for a Novel Mechanism of Action in the Treatment of Schizophrenia. J. Psychopharmacol. (in press)
  4. Iwana S, Kawazoe T, Park HK, Tsuchiya K, Ono K, Yorita K, Sakai T, Kusumi T, Fukui K. Chlorpromazine oligomer is a potentially active substance that inhibits human D-amino acid oxidase, product of a susceptibility gene for schizophrenia. J. Enzym. Inhib. Med. Chem. 23: 901-911, 2008
  5. Kawazoe T, Tsuge H, Pilone MS, Fukui K. Crystal structure of human D-amino acid oxidase:context-dependent variability of the backbone conformation of the VAAGL hydrophobic stretch located at the si-face of the flavin ring. Protein Sci. 15: 2708 - 2717, 2006
  6. Park HK, Shishido Y, Ichise-Shishido S, Kawazoe T, Ono K, Iwana S, Tomita Y, Yorita K, Sakai T, Fukui K. Potential Role for Astroglial D-Amino Acid Oxidase in Extracelluar D-Serine Metabolism and Cytotoxicity. J. Biochem. 139: 295-304, 2006
  7. Teng X, Sakai T, Liu L, Sakai R, Kaji R, Fukui K. Attenuation of MPTP-induced neurotoxicity and locomotor dysfunction in Nucling-deficient mice via suppression of the apoptosome pathway. J. Neurochemistry 97: 1126-1135, 2006
  8. Sakai T, Liu L, et al. Nucling Recruits Apaf-1/Pro-caspase-9 Complex for the Induction of Stress-Induced Apoptosis. J. Biol. Chem. 279: 41131-41140, 2004
  9. Liu L, Sakai T, Sano N, Fukui, K. Nucling mediates apoptosis by inhibiting expression of galectin-3 through interference with NF-κB signaling. Biochem. J. 380: 31-41, 2004
  10. Raibekas AA, Fukui K, Massy V. Design and properties of human D-amino acid oxidase with covalently attached flavin. Proc. Natl. Acad. Sci. USA 97: 3089-3093, 2000
  11. Yorita K, Matsuoka T, Misaki H, Massey V. Interaction of Two Arginine Residues in Lactate Oxidase with the Enzyme Flavin; Conversion of FMN to 8-formyl-FMN. Proc. Natl. Acad. Sci. USA 97: 13039-13044, 2000
  12. Fukui K, and Miyake Y. Molecular cloning and chromosomal localization of a human gene encoding D-amino acid oxidase. J. Biol. Chem. 267:18631-18638,1992