Rational Biosynthetic Engineering for Optimization of Geldanamycin Analogues
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
2009-05-04
发表期刊CHEMBIOCHEM
卷号10期号:7页码:1243-1251
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.
关键词Biosynthesis Geldanamycin Natural Products Polyketides Site-directed Mutagenesis
学科领域Biochemistry & Molecular Biology ; Chemistry, Medicinal
DOI10.1002/cbic.200800763
收录类别SCI
语种英语
WOS研究方向Biochemistry & Molecular Biology ; Pharmacology & Pharmacy
WOS类目Biochemistry & Molecular Biology ; Chemistry, Medicinal
WOS记录号WOS:000266382900016
引用统计
被引频次:28[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.kib.ac.cn/handle/151853/14557
专题植物化学与西部植物资源持续利用国家重点实验室
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
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GB/T 7714
Kim, Woncheol,Lee, Dongho,Hong, Seong Su,et al. Rational Biosynthetic Engineering for Optimization of Geldanamycin Analogues[J]. CHEMBIOCHEM,2009,10(7):1243-1251.
APA Kim, Woncheol.,Lee, Dongho.,Hong, Seong Su.,Na, Zhu.,Shin, Jin Chul.,...&Hong, Young-Soo.(2009).Rational Biosynthetic Engineering for Optimization of Geldanamycin Analogues.CHEMBIOCHEM,10(7),1243-1251.
MLA Kim, Woncheol,et al."Rational Biosynthetic Engineering for Optimization of Geldanamycin Analogues".CHEMBIOCHEM 10.7(2009):1243-1251.
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