Rational biosynthetic engineering for optimization of geldanamycin analogues

Woncheol Kim, Dongho Lee, Seong Su Hong, Zhu Na, Jin Chul Shin, Su Heun Roh, Cheng Zhu Wu, Oksik Choi, Kyeong Lee, Yue Mao Shen, Sang Gi Paik, Jung Joon Lee, Young Soo Hong

Research output: Contribution to journalArticlepeer-review

40 Citations (Scopus)


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 nonquinone 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.

Original languageEnglish
Pages (from-to)1243-1251
Number of pages9
Issue number7
Publication statusPublished - 2009 May 4


  • Biosynthesis
  • Geldanamycin
  • Natural products
  • Polyketides
  • Site-directed mutagenesis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry


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