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Title 

Rational biosynthetic engineering for optimization of geldanamycin analogues

Authors 

W KimD LeeS S HongZ NaJin Chul ShinSu Heun RohC Z WuOkSik ChoiKyeong LeeY M ShenS G PaikJung Joon LeeYoung-Soo Hong

Publisher 

Wiley-Blackwell

Issue Date 

2009

Citation 

ChemBioChem, vol. 10, no. 7, pp. 1243-1251

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.

ISSN 

1439-4227

Link 

http://dx.doi.org/10.1002/cbic.200800763

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2017-04-19


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