P219L substitution in human D-amino acid oxidase impacts the ligand binding and catalytic efficiency

• 資料種別: 博士論文
• タイトル: P219L substitution in human D-amino acid oxidase impacts the ligand binding and catalytic efficiency
• 著者・編者: Rachadech, Wanitcha; Kato, Yusuke; El-Magd, Rabab M. Abou; Shishido, Yuji; Kim, Soo Hyeon; Sogabe, Hirofumi; Maita, Nobuo; Yorita, Kazuko; Fukui, Kiyoshi
• 著者標目: Rachadech, Wanitcha; Kato, Yusuke; El-Magd, Rabab M. Abou; Shishido, Yuji; Kim, Soo Hyeon; Sogabe, Hirofumi; Maita, Nobuo; Yorita, Kazuko; Fukui, Kiyoshi
• 出版事項: Oxford University Press
• 出版年月日等: 2020-07-30
• 出版年（W3CDTF）: 2020-07-30
• 並列タイトル等: ヒトD-アミノ酸酸化酵素のP219L置換が与えるリガンド結合と触媒効率に対する影響; P219L DAO alters ligand binding and catalytic efficiency
• タイトル（掲載誌）: The Journal of Biochemistry
• 巻号年月日等（掲載誌）: 168 5
• 掲載巻: 168
• 掲載号: 5
• 掲載ページ: 557-567
• ISSN（掲載誌）: ISSN : 1756-2651; ISSN : 0021-924X
• 授与機関名: 徳島大学
• 授与年月日: 2021-03-23
• 報告番号: 甲第3497号
• 学位: 博士（医学）
• 本文の言語コード: eng
• 件名標目: human D-amino acid oxidase; point-mutation; active site lid; structure–function relationship; X-ray crystallography
• 対象利用者: 一般
• 一般注記: Human D-amino acid oxidase (DAO) is a flavoenzyme that is implicated in neurodegenerative diseases. We investigated the impact of replacement of proline with leucine at position 219 (P219L) in the active site lid of human DAO on the structural and enzymatic properties, because porcine DAO contains leucine at the corresponding position. The turnover numbers (kcat) of P219L were unchanged, but its Km values decreased compared to wild-type, leading to an increase in the catalytic efficiency (kcat/Km). Moreover, benzoate inhibits P219L with lower Ki value (0.7-0.9 μM) compared to wild-type (1.2-2.0 μM). Crystal structure of P219L in complex with flavin adenine dinucleotide (FAD) and benzoate at 2.25 Å resolution displayed conformational changes of the active site and lid. The distances between the H-bond-forming atoms of arginine 283 and benzoate and the relative position between the aromatic rings of tyrosine 224 and benzoate were changed in the P219L complex. Taken together, the P219L substitution leads to an increase in the catalytic efficiency and binding affinity for substrates/inhibitors due to these structural changes. Furthermore, an acetic acid was located near the adenine ring of FAD in the P219L complex. The present study provides new insights into the structure-function relationship of human DAO.
• 記録形式（IMT）: application/pdf
• オンライン閲覧公開範囲: インターネット公開
• 関連情報（DOI）: 10.1093/jb/mvaa083
• 連携機関・データベース: 国立情報学研究所 : 学術機関リポジトリデータベース（IRDB）（機関リポジトリ）; https://irdb.nii.ac.jp
• 提供元機関・データベース: 徳島大学 : 徳島大学機関リポジトリ

目次

http://repo.lib.tokushima-u.ac.jp/files/public/11/116051/202106101555171624/k3497_abstract_review.pdf fulltext

http://repo.lib.tokushima-u.ac.jp/files/public/11/116051/20210628141231301835/k3497_fulltext.pdf fulltext