Feedback control of polyketide metabolism during tylosin production

• Published in: Microbiology (Society for General Microbiology) 2001-04, Vol.147 (4), p.795-801
• Main Authors: Butler, Andrew R, Flint, Simon A, Cundliffe, Eric
• Format: Article
• Language: English
• Subjects: Bacterial Proteins; Biological and medical sciences; Biology of microorganisms of confirmed or potential industrial interest; Biotechnology; Carbohydrate Sequence; Chromatography, High Pressure Liquid; Feedback; Fundamental and applied biological sciences. Psychology; Fungal Proteins - genetics; Fungal Proteins - metabolism; Genetic Complementation Test; Glucosamine - analogs & derivatives; Glucosamine - biosynthesis; Glucosamine - genetics; Glucosamine - metabolism; Glycosylation; Mission oriented research; Molecular Sequence Data; Mutagenesis, Site-Directed; Mycaminose; Physiology and metabolism; Polyketides; Streptomyces - metabolism; Streptomyces fradiae; Transaminases; Tylactone; tylB gene; tylMI gene; tylMII gene; tylMIII gene; Tylosin - analogs & derivatives; Tylosin - metabolism
• ISSN: 1350-0872; 1465-2080
• DOI: 10.1099/00221287-147-4-795

Department of Biochemistry, University of Leicester, Leicester LE1 7RH, UK 1 Author for correspondence: Eric Cundliffe. Tel: [phone]. Fax: [phone]. e-mail: ec13{at}le.ac.uk 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 (protylonolide). Previously, disruption of the gene ( tylMII ) encoding attachment of mycaminose to the aglycone unexpectedly abolished accumulation of the latter, raising the possibility of a link between polyketide metabolism and deoxyhexose biosynthesis in S. fradiae . However, at that time, it was not possible to eliminate an alternative explanation, namely, that downstream effects on the expression of other genes, not involved in mycaminose metabolism, might have contributed to this phenomenon. Here, it is shown that disruption of any of the four genes ( tylMI–III and tylB ) specifically involved in mycaminose biosynthesis elicits a similar response, confirming that production of mycaminosyl-tylactone directly influences polyketide metabolism in S. fradiae . Under similar conditions, when mycaminose biosynthesis was specifically 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 qualitatively similar effects. Comparison of the structures of stimulatory macrolides will facilitate studies of the stimulatory mechanism. Keywords: mycaminose biosynthesis, polyketide, Streptomyces fradiae , tylactone, tylosin production Abbreviations: OMT, O -mycaminosyltylonolide; PKS, polyketide synthase a These authors made equal contributions to this work.