2022 Fiscal Year Annual Research Report
Innovative chemical genetics on novel function of endogenous metabolites
Project/Area Number |
19H05640
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Research Institution | Institute of Physical and Chemical Research |
Principal Investigator |
吉田 稔 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, グループディレクター (80191617)
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Co-Investigator(Kenkyū-buntansha) |
西村 慎一 広島大学, 統合生命科学研究科(生), 教授 (30415260)
伊藤 昭博 東京薬科大学, 生命科学部, 教授 (40391859)
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Project Period (FY) |
2019-06-26 – 2024-03-31
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Keywords | 内在性代謝物 / 化学遺伝学 / 創薬標的分子 / 翻訳後修飾 / 代謝フェロモン |
Outline of Annual Research Achievements |
本研究では (1) エネルギー代謝、(2) 低酸素応答、 (3) アミノ酸代謝、(4) 脂質代謝、(5) タンパク質アシル化、(6) RNA代謝について化学遺伝学研究を推進した。 (1) エネルギー代謝: 解糖系酵素であるホスホフルクトキナーゼ1(PFK1)を阻害すると、β-酸化の増強とペントースリン酸経路への代謝変換による抗酸化活性増強により、ミトコンドリアの呼吸機能が高まることを明らかにしたので、PFK1阻害剤の探索のため、PFK1活性の簡便な測定方法を開発した。(2) 低酸素応答:低酸素応答を誘導するN-アシルドーパミンの生合成経路の解明を試み、リン脂質アシル基転移酵素として知られているPLAAT2をドーパミンアシル化酵素として同定した。(3)アミノ酸代謝:窒素カタボライト抑制(NCR)の解除分子としてシデロフォアであるフェリクローム(FC)を特定した。FCは高濃度のアンモニウム塩の存在下において、分裂酵母のロイシン要求性株の増殖を回復させた。この結果は鉄代謝と窒素代謝との緊密な関係性を示唆している。(4)脂質代謝:前年度までに、Hippo経路の転写因子TEADのリジン残基の長鎖アシル化は転写共役因子であるYAPとの結合に重要であることを見出した。そこで、TEADとYAPの結合を阻害する代謝物を探索し、複数のヒット化合物を得た。当該年度は、その中でも、植物アルカロイドであるエメチンの誘導体NPD689に注目し、NPD689はYAP依存的なTEADの転写活性を抑制することにより、悪性胸膜中皮腫や肺がん細胞の増殖を抑制することを見出した。(6) RNA代謝:スプライシング調節薬SSAによってイントロンを含むタンパク質の生産が認められ、これらの多くが凝集体を形成し、ストレス応答を引き起こすことを明らかにした。生じる細胞内の凝集体量を定量できるフィルターとラップ法を開発した。
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Research Progress Status |
翌年度、交付申請を辞退するため、記入しない。
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Strategy for Future Research Activity |
翌年度、交付申請を辞退するため、記入しない。
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[Journal Article] A specific G9a inhibitor unveils BGLT3 lncRNA as a universal mediator of chemically induced fetal globin gene expression2023
Author(s)
Shohei Takase, Takashi Hiroyama, Fumiyuki Shirai, Yuki Maemoto, Akiko Nakata, Mayumi Arata, Seiji Matsuoka, Takeshi Sonoda, Hideaki Niwa, Shin Sato, Takashi Umehara, Mikako Shirouzu, Yosuke Nishigaya, Tatsunobu Sumiya, Noriaki Hashimoto,... Minoru Yoshida, Akihiro Ito
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Journal Title
NATURE COMMUNICATIONS
Volume: 14
Pages: 23
DOI
Peer Reviewed / Open Access
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[Journal Article] Identification of a derivative of the alkaloid emetine as an inhibitor of the YAP-TEAD interaction and its potential as an anticancer agent2023
Author(s)
Saaya Sekine, Shohei Takase, Runa Hayase, Kota Noritsugu, Yuki Maemoto, Yasue Ichikawa, Kenji Ogawa, Yasumitsu Kondoh, Hiroyuki Osada, Minoru Yoshida, Akihiro Ito
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Journal Title
Bioscience, biotechnology, and biochemistry
Volume: 98
Pages: 501_510
DOI
Peer Reviewed
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[Journal Article] Discovery of Novel Substrate-Competitive Lysine Methyltransferase G9a Inhibitors as Anticancer Agents2023
Author(s)
Yosuke Nishigaya, Shohei Takase, Tatsunobu Sumiya, Ko Kikuzato, Tomohiro Sato, Hideaki Niwa, Shin Sato, Akiko Nakata, Takeshi Sonoda, Noriaki Hashimoto, Ryosuke Namie, Teruki Honma, Takashi Umehara, Mikako Shirouzu, Hiroo Koyama, Minoru Yoshida, Akihiro Ito, and Fumiyuki Shirai
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Journal Title
J. Med. Chem.
Volume: 66
Pages: 4059_4085
DOI
Peer Reviewed / Open Access
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[Journal Article] Pivotal role 1 for S-nitrosylation of DNA methyltransferase in epigenetic regulation2023
Author(s)
Okuda K, Nakahara K, Ito A, Kumar A, Nomura R, Iijima Y, Takasugi N, Adachi K, Shimada Y, Fujio S, Onuma K, Osaki M, Okada F, Ukegawa T, Takeuchi Y, Yasui N, Yamashita A, Marusawa H, Katagiri T, Shibata T, Uchida K, Nakamura T, Zhang KYZ, Lipton SA, Uehara T
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Journal Title
Nature Communications
Volume: 14
Pages: 621
DOI
Peer Reviewed / Open Access
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[Journal Article] A specific G9a inhibitor unveils BGLT3 lncRNA as a universal mediator of chemically induced 2023年 fetal globin gene expression2023
Author(s)
S. Takase, T. Hiroyama, F. Shirai, Y. Maemoto, A. Nakata, M. Arata, S. Matsuoka, T. Sonoda, H. 14 Niwa, S. Sato, T. Umehara, M. Shirouzu, Y. Nishigaya, T. Sumiya, N. Hashimoto, R. Namie, M. Usui, T. Ohishi, S. Ohba, M. Kawada, Y. Hayashi, H. Harada, T. Yamaguchi, Y. Shinkai, Y. Nakamura, M. Yoshida, A. Ito
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Journal Title
Nat. Commun.
Volume: 14
Pages: 23
DOI
Peer Reviewed
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[Journal Article] Visualization of the dynamic interaction between nucleosomal histone H3K9 tri-methylation and HP1α chromodomain in living cells2022
Author(s)
Sasaki K, Suzuki M, Sonoda T, Schneider-Poetsch T, Ito A, Takagi M, Fujishiro S, Sohtome Y, Dodo K, Umehara T, Aburatani H, Shin-ya K, Nakao Y, Sodeoka M, Yoshida M
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Journal Title
Cell Chem. Biol.
Volume: 29
Pages: 1153-1161.e5
DOI
Peer Reviewed / Open Access
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[Journal Article] Recognition of pathogen-derived sphingolipids in Arabidopsis2022
Author(s)
Kato Hiroaki, Nemoto Keiichiro, Shimizu Motoki, Abe Akira, Asai Shuta, Ishihama Nobuaki, Matsuoka Seiji, Daimon Takaaki, Ojika Makoto,Kawakita Kazuhito, Onai Kiyoshi, Shirasu Ken, Yoshida Minoru, Ishiura Masahiro, Takemoto Daigo, Takano Yoshitaka, Terauchi Ryohei
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Journal Title
Science
Volume: 376
Pages: 857-860
DOI
Peer Reviewed / Open Access
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[Journal Article] A Novel Class of HIV-1 Inhibitors Targeting the Vpr-Induced G2-Arrest in Macrophages by New Yeast- and Cell-Based High-Throughput Screening2022
Author(s)
Sato Hirotaka ,Murakami Tomoyuki, Matsuura Ryosuke, Abe Masako, Matsuoka Seiji, Yashiroda Yoko, Yoshida Minoru, Akari Hirofumi , Nagasawa Yosuke , Takei Masami, Aida Yoko
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Journal Title
Viruses
Volume: 14
Pages: 1321
DOI
Peer Reviewed / Open Access
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[Journal Article] Phenylboronic Ester-Activated Aryl Iodide-Selective Buchwald-Hartwig-Type Amination toward Bioactivity Assay2022
Author(s)
Raghu N. Dhital, Abhijit Sen, Hao Hu, Rikako Ishii, Takuma Sato,Yoko Yashiroda, Hiromi Kimura,Charles Boone, Minoru Yoshida, Yushi Futamura, Hiroyuki Hirano, Hiroyuki Osada,Daisuke Hashizume, Yasuhiro Uozumi, and Yoichi M.A. Yamada
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Journal Title
ACS Omega
Volume: -
Pages: -
DOI
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Targeting fungal membrane homeostasis with imidazopyrazoindoles impairs azole resistance and biofilm formation2022
Author(s)
Nicole M. Revie, Kali R. Iyer, Michelle E. Maxson, Jiabao Zhang, Su Yan, Caroline M. Fernandes, Kirsten J. Meyer , Xuefei Chen, Iwona Skulska, Meea Fogal , Hiram Sanchez, Saif Hossain, Sheena Li, Yoko Yashiroda, Hiroyuki Hirano, Minoru Yoshida, Hiroyuki Osada, Charles Boone, ... Leah E. Cowen
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Journal Title
NATURE COMMUNICATIONS
Volume: 13
Pages: 3634
DOI
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Discovery of Benzylpiperazine Derivatives as CNS-Penetrant and Selective Histone Deacetylase 6 Inhibitors2022
Author(s)
Kosuke Hashimoto, Soichiro Ide, Mayumi Arata, Akiko Nakata, Akihiro Ito, Takashi K. Ito, Norio Kudo, Bangzhong Lin, Kazuto Nunomura, Keiko Tsuganezawa, Minoru Yoshida, Yasuo Nagaoka, Takaaki Sumiyoshi
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Journal Title
ACS Medicinal Chemistry Letters
Volume: 13
Pages: 1077-1082
DOI
Peer Reviewed
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[Journal Article] Genome-based discovery and total synthesis of janustatins, potent cytotoxins from a plant-associated bacterium2022
Author(s)
Reiko Ueoka, Philipp Sondermann, Stefan Leopold-Messer, Yizhou Liu, Rei Suo, Agneya Bhushan, Lida Vadakumchery, Ute Greczmiel, Yoko Yashiroda, Hiromi Kimura, Shinichi Nishimura, Yojiro Hoshikawa, Minoru Yoshida, Annette Oxenius, Shigeki Matsunaga, R Thomas Williamson, Erick M Carreira, Jorn Piel
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Journal Title
Nature chemistry
Volume: 14
Pages: 1193-1201
DOI
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Isoquercitrin from Apocynum venetum L. produces an anti-obesity effect on obese mice by targeting C-1-tetrahydrofolate synthase, carbonyl reductase, and glutathione S-transferase P and modification of the AMPK/SREBP-1c/FAS/CD36 signaling pathway in mice in vivo2022
Author(s)
Majid Manzoor, Makoto Muroi, Haruna Nishimura, Danni Chen, Naoko Ogawa, Hiroki Kobayashi, Opeyemi B. Fasina, Jianyu Wang, Hiroyuki Osada, Minoru Yoshida, Lan Xiang, Jianhua Qi
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Journal Title
Food & Function
Volume: 13
Pages: 10923-10936
DOI
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] N-(3,4-dimethoxyphenethyl)-6-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-amine inhibits bladder cancer progression by suppressing YAP1/TAZ2022
Author(s)
Yusuke Shiraishi, Tomohiko Maehama, Miki Nishio, Junji Otani, Hiroki Hikasa, Tak Wah Mak, Takehiko Sasaki, Teruki Honma, Yasumitsu Kondoh, Hiroyuki Osada, Minoru Yoshida, Masato Fujisawa, Akira Suzuki
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Journal Title
Genes to Cells
Volume: 27
Pages: 602-612
DOI
Peer Reviewed / Open Access
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[Journal Article] MDMX elevation by a novel Mdmx_p53 interaction inhibitor mitigates neuronal damage after ischemic stroke2022
Author(s)
Haomin Yan, Tsutomu Sasaki, Hideaki Kanki, Yoshiyuki Hirata, Kumiko Nishiyama, Sunao Hisada, Shigenobu Matsumura, Yasuo Nagaoka, Takaaki Sumiyoshi, Seiichi Nagano, Akiko Nakata, Minoru Yoshida, Shinichi Uesato, Hideki Mochizuki
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Journal Title
Scientific Reports
Volume: 12
Pages: 21110
DOI
Peer Reviewed / Open Access
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[Journal Article] Retusone A, a Guaiane-Type Sesquiterpene Dimer from Wikstroemia retusa and its Inhibitory Effects on Histone Acetyltransferase HBO1 Expression2022
Author(s)
Yun YS, Nakano T, Fukaya H, Hitotsuyanagi Y, Nakamura M, Umetsu M, Matsushita N, Miyake K, Fuchino H, Kawahara N, Moriya F, Ito A, Takahashi Y, Inoue H
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Journal Title
Molecules
Volume: 27
Pages: 2909
DOI
Peer Reviewed / Open Access
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[Journal Article] Differential Biosynthesis and Roles of Two Ferrichrome-Type Siderophores, ASP2397/AS2488053 and Ferricrocin, in Acremonium persicinum2022
Author(s)
Asai, Y., Hiratsuka, T., Ueda, M., Kawamura, Y., Asamizu, S., Onaka, H., Arioka, M., Nishimura, S., Yoshida, M.
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Journal Title
ACS Chem. Biol.
Volume: 17
Pages: 207-216
DOI
Peer Reviewed
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[Presentation] Identifying the targets of novel compounds using high throughput chemical-genomics screening2022
Author(s)
Lien Pham, Yuichi Shichino,Sheena Li, Yoko Yashiroda, Mami Yoshimura, Hiromi Kimura, Yumi Kawamura,Luis Alberto Vega Isuhuaylas,Norio Kudo, Minoru Yoshida,Shintaro Iwasaki, and Charles Boone
Organizer
酵母遺伝学フォーラム第55回研究報告会
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