Madduri K, Kennedy J, Rivola G, Inventi-Solari A, Filippini S, Zanuso G, Colombo A L, Gewain K M, Occi J L, MacNeil D J, Hutchinson C R
School of Pharmacy, University of Wisconsin, Madison 53706, USA.
Nat Biotechnol. 1998 Jan;16(1):69-74. doi: 10.1038/nbt0198-69.
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.
已为产黄青霉开发出一种发酵方法，该方法绕过了表柔比星（4'-表阿霉素）和4'-表柔红霉素这两种重要癌症化疗药物产量较低的半合成过程。这种细菌通常会产生蒽环类抗生素阿霉素和柔红霉素；通过将来自阿维链霉菌的avrE基因或来自糖多孢红霉菌的eryBIV基因导入产黄青霉中因氨基糖生物合成受阻的dnmV突变体中，可形成4'-差向异构蒽环类抗生素。通过用avrE替代dnmV的染色体拷贝，并引入能提高野生型菌株中柔红霉素和阿霉素产量的进一步突变，产物产量得到了显著提高。该方法表明，通过与细菌脱氧糖生物合成基因进行组合生物合成，可以制备出有价值的杂合抗生素。
