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 journalArticle

34 Citations (Scopus)

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 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
JournalChemBioChem
Volume10
Issue number7
DOIs
Publication statusPublished - 2009 May 4

Fingerprint

Polyketide Synthases
Rifabutin
Pharmacology
Derivatives
Mutagenesis
Biosynthesis
Site-Directed Mutagenesis
Hydroxyl Radical
Antineoplastic Agents
Toxicity
Adenosine Triphosphatases
geldanamycin
Genes
benzoquinone

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Medicine(all)

Cite this

Kim, W., Lee, D., Hong, S. S., Na, Z., Shin, J. C., Roh, S. H., ... Hong, Y. S. (2009). Rational biosynthetic engineering for optimization of geldanamycin analogues. ChemBioChem, 10(7), 1243-1251. https://doi.org/10.1002/cbic.200800763

Rational biosynthetic engineering for optimization of geldanamycin analogues. / Kim, Woncheol; Lee, Dongho; Hong, Seong Su; Na, Zhu; Shin, Jin Chul; Roh, Su Heun; Wu, Cheng Zhu; Choi, Oksik; Lee, Kyeong; Shen, Yue Mao; Paik, Sang Gi; Lee, Jung Joon; Hong, Young Soo.

In: ChemBioChem, Vol. 10, No. 7, 04.05.2009, p. 1243-1251.

Research output: Contribution to journalArticle

Kim, W, Lee, D, Hong, SS, Na, Z, Shin, JC, Roh, SH, Wu, CZ, Choi, O, Lee, K, Shen, YM, Paik, SG, Lee, JJ & Hong, YS 2009, 'Rational biosynthetic engineering for optimization of geldanamycin analogues', ChemBioChem, vol. 10, no. 7, pp. 1243-1251. https://doi.org/10.1002/cbic.200800763
Kim, Woncheol ; Lee, Dongho ; Hong, Seong Su ; Na, Zhu ; Shin, Jin Chul ; Roh, Su Heun ; Wu, Cheng Zhu ; Choi, Oksik ; Lee, Kyeong ; Shen, Yue Mao ; Paik, Sang Gi ; Lee, Jung Joon ; Hong, Young Soo. / Rational biosynthetic engineering for optimization of geldanamycin analogues. In: ChemBioChem. 2009 ; Vol. 10, No. 7. pp. 1243-1251.
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