| 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 |
| DOI | 10.1002/cbic.200800763 |
| 收录类别 | SCI |
| 语种 | 英语 |
| WOS记录号 | WOS:000266382900016 |
| 引用统计 | |
| 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 |
| 推荐引用方式 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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