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Rational Biosynthetic Engineering for Optimization of Geldanamycin Analogues

Authors
Kim, WoncheolLee, DonghoHong, Seong SuNa, ZhuShin, Jin ChulRoh, Su HeunWu, Cheng-ZhuChoi, OksikLee, KyeongShen, Yue-MaoPaik, Sang-GiLee, Jung JoonHong, Young-Soo
Issue Date
4-5월-2009
Publisher
WILEY-V C H VERLAG GMBH
Keywords
biosynthesis; geldanamycin; natural products; polyketides; site-directed mutagenesis
Citation
CHEMBIOCHEM, v.10, no.7, pp.1243 - 1251
Indexed
SCIE
SCOPUS
Journal Title
CHEMBIOCHEM
Volume
10
Number
7
Start Page
1243
End Page
1251
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/120062
DOI
10.1002/cbic.200800763
ISSN
1439-4227
Abstract
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.
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