Original Article

The Journal of Antibiotics (2008) 61, 365–371; doi:10.1038/ja.2008.51

Efrapeptin J, a New Down-regulator of the Molecular Chaperone GRP78 from a Marine Tolypocladium sp.

Yoichi Hayakawa1, Yuki Hattori1, Takashi Kawasaki1, Kaneo Kanoh2, Kyoko Adachi2, Yoshikazu Shizuri2 and Kazuo Shin-ya3

  1. 1Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan
  2. 2Marine Biotechnology Institute Co. Ltd., 3-75-1 Heita, Kamaishi, Iwate 026-0001, Japan
  3. 3Biological Information Research Center, National Institute of Advanced Industrial Science and Technology, 2-42 Aomi, Koto-ku, Tokyo 135-0064, Japan

Correspondence: Y. Hayakawa, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan. E-mail: hykw@rs.noda.tus.ac.jp

Received 31 March 2008; Accepted 29 May 2008.

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Abstract

A new down-regulator of the molecular chaperone GRP78, efrapeptin J, was isolated from a marine fungus, Tolypocladium sp. AMB18. The molecular formula of efrapeptin J was established as C81H139N18O16+ by high-resolution FAB-MS. The structure was elucidated to be a linear pentadecapeptide containing a hexahydropyrrolo[1,2-a]pyrimidinium moiety by NMR and MS analyses. Efrapeptins F, G and J dose-dependently inhibited 2-deoxyglucose-induced luciferase expression in HT1080 human fibrosarcoma cells transfected with a luciferase reporter plasmid containing the GRP78 promoter. Efrapeptin J also inhibited the protein expression of GRP78 in HT1080 cells and MKN-74 human gastric cancer cells. Efrapeptin J induced cell death in HT1080 cells under endoplasmic reticulum stress.

Keywords:

efrapeptin, GRP78, Tolypocladium, transcriptional down-regulator

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