Feedback control of polyketide metabolism during tylosin production

Tylosin is produced by Streptomyces fradiae via a combination of polyketide metabolism and synthesis of three deoxyhexose sugars, of which mycaminose is the first to be added to the polyketide aglycone, tylactone (protylonoli de). Previously, disruption of the gene (tylMII) encoding attachment of myc aminose to the aglycone unexpectedly abolished accumulation of the latter, raising the possibility of a link between polyketide metabolism and deoxyhe xose biosynthesis in S. fradiae. However, at that time, it was not possible to eliminate an alternative explanation, namely, that downstream effects o n the expression of other genes, not involved in mycaminose metabolism, mig ht have contributed to this phenomenon. Here, it is shown that disruption o f any of the four genes (tylMI-III and tylB) specifically involved in mycam inose biosynthesis elicits a similar response, confirming that production o f mycaminosyl-tylactone directly influences polyketide metabolism in S. fra diae. Under similar conditions, when mycaminose biosynthesis was specifical ly blocked by gene disruption, accumulation of tylactone could be restored by exogenous addition of glycosylated tylosin precursors. Moreover, certain other macrolides, not of the tylosin pathway, were also found to elicit qu alitatively similar effects. Comparison of the structures of stimulatory ma crolides will facilitate studies of the stimulatory mechanism.