Elucidation of the inhibitory mechanism of a lysine deacetylase Siruin by endogenous metabolites

• Project/Area Number: 26650011
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Molecular biology
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Ito Akihiro 国立研究開発法人理化学研究所, 吉田化学遺伝学研究室, 専任研究員 (40391859)
• Co-Investigator(Renkei-kenkyūsha): Moto Kenichi 国立研究開発法人理化学研究所, 小林脂質生物学研究室, 専任研究員 (90333335) ; Kudo Norio 国立研究開発法人理化学研究所, 環境資源科学研究センター, 研究員 (80632421)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2015: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: Sirtuin / 代謝物質 / アセチル化 / SIRT2 / サーチュイン

Outline of Final Research Achievements

Sirtuins possess NAD-dependent deacetylase activity and is involved in diverse biological processes including aging. The enzymatic activity of sirtuins is known to be regulated by cellular NAD/NADH ratio. However, endogenous inhibitors for sirtuins have not been identified yet. Here, we identified N-acyldopamines as endogenous SIRT2 inhibitors. We found that a number of N-acyldopamine species including N-palmitoyldopamine inhibit both in vitro and in vivo SIRT2 activity. In addition, X-ray crystallographic analysis of the SIRT2―N-palmitoyldopamine complex revealed the molecular mechanism by which N-acyldopamines inhibit the SIRT2 activity.

Research Products

• [Journal Article] Efficient N-Acyldopamine Synthesis (2016)
  • Author(s): Matsumoto Y, Ito A, Uesugi M, Kittaka A
  • Journal Title: Chem. Pharm. Bull. Volume: in press
  • NAID: 130005160071
  • Peer Reviewed
• [Journal Article] The subcellular localization and activity of cortactin is regulated by acetylation and interaction with Keap1 (2015)
  • Author(s): Ito A, Shimazu T, Maeda S, Shah AA, Tsunoda T, Iemura S, Natsume T, Suzuki T, Motohashi H, Yamamoto M, Yoshida M.
  • Journal Title: Science Signaling. Volume: 8 Issue: 404 Pages: 404-404
  • DOI: 10.1126/scisignal.aad0667
  • Peer Reviewed / Open Access
• [Journal Article] Kinetic and structural basis for acyl-group selectivity and NAD(+) dependence in sirtuin-catalyzed deacylation (2015)
  • Author(s): Feldman, J. L., Dittenhafer-Reed, K. E., Kudo, N., Thelen, J. N., Ito, A., Yoshida, M., and Denu, J. M.
  • Journal Title: Biochemistry Volume: 54 Issue: 19 Pages: 3037-3050
  • DOI: 10.1021/acs.biochem.5b00150
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Novel functions of lipid metabolites as endogenous SIRT2 inhibitors (2016)
  • Author(s): Akihiro Ito,, Norio Kudo, Akiko Nakata, Satoko Maeda, Minoru Yoshida
  • Organizer: The 8th Korea-Japan Chemical Biology Symposium
  • Place of Presentation: Pacific Hotel Okinawa, Naha, Okinawa
  • Year and Date: 2016-01-19
  • Int'l Joint Research
• [Presentation] NAD依存性脱アセチル化酵素SIRT2による細胞運動制御機構とその内因性阻害物質 (2015)
  • Author(s): 伊藤昭博、吉田 稔
  • Organizer: 第2回北陸エピジェネティクス研究会
  • Place of Presentation: 富山大学、富山市、富山県
  • Year and Date: 2015-11-11
  • Invited
• [Presentation] NAD依存的脱アセチル化酵素SIRT2による細胞運動制御機構 (2015)
  • Author(s): 伊藤昭博、前田里子、吉田稔
  • Organizer: 日本薬学会第135年会
  • Place of Presentation: 神戸学院大学（兵庫県神戸市）
  • Year and Date: 2015-03-26
  • Invited
• [Presentation] SIRT2 regulates cell migration through Keap1-mediated cell periphery localization of cortactin (2014)
  • Author(s): Akihiro Ito, Satoko Maeda, Minoru Yoshida
  • Organizer: Max Planck Joint Research Center for Systems Chemical Biology 3rd Annual Symposium
  • Place of Presentation: Schloss Ringberg, Kreuth, Germany
  • Year and Date: 2014-05-23
• [Book] 「NAD+関連タンパク質」、生体の化学 [増大特集]細胞シグナル操作方法 (2015)
  • Author(s): 伊藤昭博、八代田陽子、吉田稔
  • Publisher: 医学書院