Rational biosynthetic engineering for optimization of geldanamycin analogues

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Title
Rational biosynthetic engineering for optimization of geldanamycin analogues
Author(s)
W Kim; D Lee; S S Hong; Z Na; Jin Chul Shin; Su Heun Roh; C Z Wu; OkSik Choi; Kyeong Lee; Y M Shen; S G Paik; Jung Joon Lee; Young-Soo Hong
Bibliographic Citation
Chembiochem, vol. 10, no. 7, pp. 1243-1251
Publication Year
2009
Abstract
Tailor made: We report the rational 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. Rational biosynthetic engineering allowed the generation of geldanamycin derivatives, such as DHQ3 illustrated in the figure, which had superior pharmacological properties in comparison to the parent compound. 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.
Keyword
biosynthesisgeldanamycinnatural productspolyketidessite-directed mutagenesis
ISSN
1439-4227
Publisher
Wiley
DOI
http://dx.doi.org/10.1002/cbic.200800763
Type
Article
Appears in Collections:
Ochang Branch Institute > Chemical Biology Research Center > 1. Journal Articles
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