Biosynthesis of anthracydines: enzymic conversion of aklanonic acid to aklavinone and -rhodomycinone by anthracycline-producing streptomycetes

Abstract

Alklanonic acid, a substituted anthraquinone, is the earliest stable intermediate isolated so far in the biosynthesis of anthracycline antibiotics. Desalted, soluble cell extracts of Streptomyces sp. C5 and Streptomyces peucetius (ATCC 29050) converted aklanonic acid to .epsilon.-rhodomycinone in an S-adenosyl-L-methionine- and NADPH-dependent sequence of reactions. Alkanonic acid was methylated to form aklanonic acid methyl ester (AAME), which was cyclized to form aklaviketone. Aklaviketone was reduced to aklavinone by an NADPH-linked reductase. When extracts of Streptomyces sp. C5 and S. peucetius were used, aklavinone was hydroxylated at C-11 by an NADPH- and oxygen-dependent reaction to form .epsilon.-rhodomycinone. Cell extracts of Streptomyces galilaeus strains ATCC 31133 and 31671 converted aklanonic acid to aklavinone in the same manner, but neither of the S. galilaeus strains hydroxylated aklavinone to .EPSILON.-rhodomycinone. Mutants of Streptomyces sp. C5 blocked at steps in the conversion of aklanonic acid to aklavinone, and which accumulated aklanonic acid (SC5-39; duaC), AAME (SC5-138; dauD, dauE), and aklaviketone (SC5-159; dauE, dauF), lacked the expected enzymic activities. In a mutant (SC5-24; dauE) lacking aklaviketone reductase, but retaining aklavinone 11-hydroxylase activity, maggiemycin was formed as an apparent shunt product. An enzymic pathway for .epsilon.-rhodomycinone and maggiemycin formation is consistent with the data presented.