S-Adenosyl-L-methionine: macrocin O-methyltransferase activities in a series of Streptomyces fradiae mutants that produce different levels of the macrolide antibiotic tylosin.

A series of mutants of Streptomyces fradiae selected for increased production of the macrolide antibiotic tylosin was analyzed for levels of expression of macrocin O-methyltransferase, the enzyme which catalyzes the final step in the biosynthesis of tylosin. Increased tylosin production was accompanied by increased macrocin O-methyltransferase in some of the mutants. Increased expression of macrocin O-methyltransferase was due to more rapid early biosynthesis of the enzyme, to reduced decay of enzyme specific activity late in the fermentation, or to combinations of both. Mutant strains which showed rapid loss of enzyme specific activity late in the fermentation converted large amounts of tylosin to relomycin. The most productive mutants, which synthesized elevated levels of macrocin O-methyltransferase, also produced large amounts of macrocin, the substrate for the enzyme. Incomplete conversion of macrocin to tylosin by these mutants may be due to substrate and product inhibition (E. T. Seno and R. H. Baltz, Antimicrob. Agents Chemother. 20:370-377, 1981). The results suggest that both the levels of precursors and the levels of expression of tylosin biosynthetic enzymes are important for efficient production of tylosin.