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- 作者：Yasushi Isashiki ; Katsuaki Kimura ; Norio Ohba
- 关键词：CHEMBIO ; PROTEINS ; MOLNEURO
- 刊名：American Journal of Ophthalmology
- 出版年：2008
- 期刊代码：7_00029394
- 类别：med
- 出版时间：July 2008
- 卷：146
- 期：1
- 页码：146-147
- 文件大小：45 K
摘要
Neurotrophic small molecules have the potential to aid in the treatment of neuronal injury and neurodegenerative diseases. The natural product fellutamide B, originally isolated from Penicillium fellutanum, potently induces nerve growth factor (NGF) release from fibroblasts and glial-derived cells, although the mechanism for this neurotrophic activity has not been elucidated. Here, we report that fellutamide B potently inhibits proteasome catalytic activity. High-resolution structural information obtained from cocrystallization of the 20S proteasome reveals novel aspects regarding β-subunit binding and adduct formation by fellutamide B to inhibit their hydrolytic activity. We demonstrate that fellutamide B and other proteasome inhibitors increased NGF gene transcription via a cis-acting element (or elements) in the promoter. These results demonstrate an unrecognized connection between proteasome inhibition and NGF production, suggesting a possible new strategy in the development of neurotrophic agents.