ISOLATION AND CHARACTERIZATION OF A GENE FROM STREPTOMYCES SP STRAIN C5 THAT CONFERS THE ABILITY TO CONVERT DAUNOMYCIN TO DOXORUBICIN ON STREPTOMYCES-LIVIDANS TK24

DNA sequence analysis of a region of the Streptomyces sp. strain C5 da unomycin biosynthesis gene cluster, located between the daunomycin pol yketide biosynthesis gene cluster and a durl (transcriptional activato r) homolog, revealed the presence of a gene encoding a P-450-like enzy me with a deduced M(r) of 46,096. Expression of this gene, named herei n doxA, in Streptomyces lividans TK24 resulted in in vivo bioconversio n of daunomycin to doxorubicin. DoxA showed specificity for only dauno mycin and 13-dihydrodaunomycin, both of which were converted to doxoru bicin. Daunomycinone (daunomycin aglycone), carminomycin, 13-dihydroca rminomycin, idarubicin, and aklavin were not apparent substrates for D oxA. In vector controls or in vectors in which doxA was poorly express ed, S. lividans catalyzed the reduction of daunomycin and other 13-oxo -anthracyclines and -anthracyclinones to their 13-dihydro homologs.