Production of the antitumor drug epirubicin (4′-epidoxorubicin) and its precursor by a genetically engineered strain of Streptomyces peucetius
Production of the antitumor drug epirubicin (4′-epidoxorubicin) and its precursor by a genetically engineered strain of Streptomyces peucetius
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DOI：
10.1038/nbt0198-69
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发表时间：
1998-01-01
影响因子：
46.9
通讯作者：
Hutchinson, CR
中科院分区：
文献类型：
--
作者：
Madduri, K;Kennedy, J;Hutchinson, CR
针对Streptomyces peucetius开发了一种发酵方法，绕过了重要的癌症化疗药物表柔比星（4'-表柔比星）和4'-表柔比星的低产半合成，该细菌通常产生蒽环类抗生素、阿霉素和柔红霉素； 4'-差向蒽环类抗生素是通过将异源阿维链霉菌 avrE 或糖多孢菌 eryBIV 基因引入到 S. peucetius dnmV 突变体中而形成的，该突变体阻断了道诺胺（这些抗生素的脱氧糖成分）的生物合成。通过用 avrE 替换 dnmV 的染色体拷贝并引入可增加野生型菌株中柔红霉素和阿霉素产量的进一步突变，产品产量显着提高。该方法表明，可以通过与细菌脱氧糖生物合成基因的组合生物合成来制备有价值的混合抗生素。
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.