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Production of the antitumor drug epirubicin (4′-epidoxorubicin) and its precursor by a genetically engineered strain of Streptomyces peucetius

Nature Biotechnology volume 16, pages 69–74 (1998)Cite this article

Abstract

A fermentation method that bypasses the low-yielding semisynthesis of epirubicin (4′-epidoxorubicin) and 4′-epidaunorubicin, important cancer chemotherapy drugs, has been developed for Streptomyces peucetius. This bacterium normally produces the anthracycline antibiotics, doxorubicin and daunorubicin; the 4′-epimeric anthracyclines are formed by introducing the heterologous Streptomyces avermitilis avrE or Saccharopolyspora eryBIV genes into an S. peucetius dnmV mutant blocked in the biosynthesis of daunosamine, the deoxysugar component of these antibiotics. Product yields were enhanced considerably by replacing the chromosomal copy of dnmV with avrE and by introducing further mutations that can increase daunorubicin and doxorubicin yields in the wild-type strain. This method demonstrates that valuable hybrid antibiotics can be made by combinatorial biosynthesis with bacterial deoxysugar biosynthesis genes.

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Author notes

  1. Krishnamurthy Madduri and Jonathan Kennedy: These authors contributed equally to this work.

Authors and Affiliations

  1. School of Pharmacy, University of Wisconsin, Madison, WI, 53706

    Krishnamurthy Madduri, Jonathan Kennedy & C.Richard Hutchinson

  2. Department of Bacteriology, University of Wisconsin, Madison, WI, 53706

    C.Richard Hutchinson

  3. Technical Operations, Pharmacia and Upjohn, Viale Pasteur 10, 20014, Nerviano, Milan, Italy

    Giovanni Rivola, Augusto Inventi-Solari, Silvia Filippini, Giovanna Zanuso & Anna Luisa Colombo

  4. Department of Molecular Pharmacology and Biochemistry, Merck Sharpe and Dohme Research Labs, Rahway, NJ, 07065

    Keith M. Gewain, James L. Occi & Douglas J. MacNeil

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  1. Krishnamurthy Madduri
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Correspondence to C.Richard Hutchinson.

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Madduri, K., Kennedy, J., Rivola, G. et al. Production of the antitumor drug epirubicin (4′-epidoxorubicin) and its precursor by a genetically engineered strain of Streptomyces peucetius. Nat Biotechnol 16, 69–74 (1998). https://doi.org/10.1038/nbt0198-69

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