Development of a Streptomyces venezuelae-based combinatorial biosynthetic system for the production of glycosylated derivatives of doxorubicin and its biosynthetic intermediates

Ah Reum Han, Je Won Park, Mi Kyeong Lee, Yeon Hee Ban, Young Ji Yoo, Eun Ji Kim, Eunji Kim, Byung Gee Kim, Jae Kyung Sohng, Yeo Joon Yoon

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Doxorubicin, one of the most widely used anticancer drugs, is composed of a tetracyclic polyketide aglycone and L-daunosamine as a deoxysugar moiety, which acts as an important determinant of its biological activity. This is exemplified by the fewer side effects of semisynthetic epirubicin (4′-epi-doxorubicin). An efficient combinatorial biosynthetic system that can convert the exogenous aglycone ∈-rhodomycinone into diverse glycosylated derivatives of doxorubicin or its biosynthetic intermediates, rhodomycin D and daunorubicin, was developed through the use of Streptomyces venezuelae mutants carrying plasmids that direct the biosynthesis of different nucleotide deoxysugars and their transfer onto aglycone, as well as the postglycosylation modifications. This system improved epirubicin production from ∈-rhodomycinone by selecting a substrate flexible glycosyltransferase, AknS, which was able to transfer the unnatural sugar donors and a TDP-4-ketohexose reductase, AvrE, which efficiently supported the biosynthesis of TDP-4-epi-L-daunosamine. Furthermore, a range of doxorubicin analogs containing diverse deoxysugar moieties, seven of which are novel rhodomycin D derivatives, were generated. This provides new insights into the functions of deoxysugar biosynthetic enzymes and demonstrates the potential of the S. venezuelae-based combinatorial biosynthetic system as a simple biological tool for modifying structurally complex sugar moieties attached to anthracyclines as an alternative to chemical syntheses for improving anticancer agents.

Original languageEnglish
Pages (from-to)4912-4923
Number of pages12
JournalApplied and Environmental Microbiology
Volume77
Issue number14
DOIs
Publication statusPublished - 2011 Jul 1
Externally publishedYes

Fingerprint

Streptomyces venezuelae
deoxysugars
doxorubicin
Streptomyces
Doxorubicin
sugar
Epirubicin
production technology
chemical derivatives
plasmid
antineoplastic agents
Polyketides
Glycosyltransferases
Daunorubicin
drug
Anthracyclines
enzyme
substrate
daunorubicin
Antineoplastic Agents

ASJC Scopus subject areas

  • Biotechnology
  • Food Science
  • Applied Microbiology and Biotechnology
  • Ecology

Cite this

Development of a Streptomyces venezuelae-based combinatorial biosynthetic system for the production of glycosylated derivatives of doxorubicin and its biosynthetic intermediates. / Han, Ah Reum; Park, Je Won; Lee, Mi Kyeong; Ban, Yeon Hee; Yoo, Young Ji; Kim, Eun Ji; Kim, Eunji; Kim, Byung Gee; Sohng, Jae Kyung; Yoon, Yeo Joon.

In: Applied and Environmental Microbiology, Vol. 77, No. 14, 01.07.2011, p. 4912-4923.

Research output: Contribution to journalArticle

Han, Ah Reum ; Park, Je Won ; Lee, Mi Kyeong ; Ban, Yeon Hee ; Yoo, Young Ji ; Kim, Eun Ji ; Kim, Eunji ; Kim, Byung Gee ; Sohng, Jae Kyung ; Yoon, Yeo Joon. / Development of a Streptomyces venezuelae-based combinatorial biosynthetic system for the production of glycosylated derivatives of doxorubicin and its biosynthetic intermediates. In: Applied and Environmental Microbiology. 2011 ; Vol. 77, No. 14. pp. 4912-4923.
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