Biosynthesis of the macrolide antibiotic tylosin. A preferred pathway from tylactone to tylosin.

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Abstract
The efficiencies of bioconversion of 23 potential intermediates in the biosynthesis of tylosin were determined with a mutant strain blocked only in tylactone biosynthesis. Tylactone, the 1st intermediate excreted by Streptomyces fradiae, was converted to tylosin by a preferred sequence of reactions which include addition of mycaminose to the C-5 hydroxyl position of the lactone; hydroxylation of the C-20 methyl group to a hydroxymethyl group; dehydrogenation of the C-20 hydroxymethyl group to a formyl group; hydroxylation of the C-23 methyl group to a hydroxymethyl group; addition of 6-deoxy-D-allose to the C-23 hydroxymethyl group; addition of mycarose to the 4''-hydroxyl group of mycaminose; addition of a methyl group to the 2''''''-hydroxyl position of demethylmacrocin; and addition of a methyl group to the 3''''''-hydroxyl position of macrocin to produce tylosin. The intermediates which lacked both neutral sugars (mycarose and 6-deoxy-D-allose) were biologically unstable; substantial quantities of these compounds were degraded during standard bioconversion experiments. The amount of 1 such intermediate (O-mycaminosyltylonolide) degraded was substantially reduced when low concentrations of the compound were used for bioconversion; under these conditions, much higher efficiencies of bioconversion to tylosin were obtained. A mutant blocked in hydroxylation of the C-20 methyl group was also blocked in the further dehydrogenation of the C-20 hydroxymethyl group to a formyl group. In vitro studies showed that the 2''''''-O-methylation of demethylmacrocin must precede the 3''''''-O-methylation of macrocin to produce tylosin.