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题名: Rational Biosynthetic Engineering for Optimization of Geldanamycin Analogues
作者: Kim, Woncheol1, 2; Lee, Dongho3; Hong, Seong Su3; Na, Zhu1, 4, 5; Shin, Jin Chul1, 2; Roh, Su Heun1; Wu, Cheng-Zhu1; Choi, Oksik1; Lee, Kyeong1; Shen, Yue-Mao4; Paik, Sang-Gi2; Lee, Jung Joon1; Hong, Young-Soo1
刊名: CHEMBIOCHEM
关键词: biosynthesis ; geldanamycin ; natural products ; polyketides ; site-directed mutagenesis
英文摘要: A rational biosynthetic engineering approach was applied to the optimization of the pharmacological properties of the benzoquinone ansamycin, geldanamycin. Geldanamycin and its natural or semisynthetic derivatives have the potential to serve as anticancer chemotherapeutic agents. However, these first-generation Hsp90 inhibitors share an unfavorable structural feature that causes both reduced efficacy and toxicity during clinical evaluation. We report the rationally designed biosynthesis of C15 hydroxylated non-quinone geldanamycin analogues by site-directed mutagenesis of the geldanamycin polyketide synthase (PKS), together with a combination of post-PKS tailoring genes. A 15-hydroxyl-17-demethoxy non-quinone analogue, DHQ3, exhibited stronger inhibition of Hsp90 ATPase activity (4.6-fold) than geldanamycin. Taken together, the results of the present study indicate that rational biosynthetic engineering allows the generation of derivatives of geldanamycin with superior pharmacological properties.
出版日期: 2009-05-04
卷号: 10, 期号:7, 页码:1243-1251
DOI标识: 10.1002/cbic.200800763
语种: 英语
收录类别: SCI
学科分类: Biochemistry & Molecular Biology; Chemistry, Medicinal
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内容类型: 期刊论文
URI标识: http://ir.kib.ac.cn/handle/151853/14557
Appears in Collections:植物化学与西部植物资源持续利用国家重点实验室_期刊论文

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作者单位: 1.Korea Res Inst Biosci & Biotechnol, Taejon 305806, South Korea
2.Chungnam Natl Univ, Taejon 305764, South Korea
3.Korea Univ, Sch Life Sci & Biotechnol, Seoul 136713, South Korea
4.Chinese Acad Sci, State Key Lab Phytochem & Plant Resources W China, Kunming Inst Bot, Kunming 650204, Peoples R China
5.Chinese Acad Sci, Grad Univ, Beijing 100049, Peoples R China

Recommended Citation:
Kim, W; Lee, D; Hong, SS; Na, Z; Shin, JC; Roh, SH; Wu, CZ; Choi, O; Lee, K; Shen, YM; Paik, SG; Lee, JJ; Hong, YS.Rational Biosynthetic Engineering for Optimization of Geldanamycin Analogues,CHEMBIOCHEM,2009,10(7):1243-1251
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