Rational Biosynthetic Engineering for Optimization of Geldanamycin Analogues

CORC > 昆明植物研究所 > 中国科学院昆明植物研究所 > 植物化学与西部植物资源持续利用国家重点实验室

	Rational Biosynthetic Engineering for Optimization of Geldanamycin Analogues
	Kim, Woncheol 1,2; Lee, Dongho 3; Hong, Seong Su 3; Na, Zhu 1,4,5; Shin, Jin Chul 1,2; Roh, Su Heun 1; Wu, Cheng-Zhu 1; Choi, Oksik 1; Lee, Kyeong 1; Shen, Yue-Mao 4
刊名	CHEMBIOCHEM
	2009-05-04
卷号	10 期号:7 页码:1243-1251
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.
学科主题	Biochemistry & Molecular Biology; Chemistry, Medicinal
类目[WOS]	Biochemistry & Molecular Biology ; Chemistry, Medicinal
研究领域[WOS]	Biochemistry & Molecular Biology ; Pharmacology & Pharmacy
关键词[WOS]	HSP90 MOLECULAR CHAPERONE ; SHOCK-PROTEIN 90 ; COMBINATORIAL BIOSYNTHESIS ; POLYKETIDE SYNTHASE ; ANTITUMOR AGENT ; IN-VIVO ; NAD(P)H-QUINONE OXIDOREDUCTASE-1 ; BENZOQUINONE ANSAMYCINS ; CRYSTAL-STRUCTURE ; NATURAL-PRODUCTS
收录类别	SCI
语种	英语
WOS记录号	WOS:000266382900016
公开日期	2012-07-25
内容类型	期刊论文
源URL	[http://ir.kib.ac.cn/handle/151853/14557]
专题	昆明植物研究所_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.