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The mycarose-biosynthetic genes of Streptomyces fradiae, producer of tylosin

Department of Biochemistry, University of Leicester, Leicester LE1 7RH, UK¹

Author for correspondence: Eric Cundliffe. Tel: +44 116 252 3451. Fax: +44 116 252 3369. e-mail: ec13{at}le.ac.uk

The tylCK region of the Streptomyces fradiae genome was sequenced, revealing an incomplete set of five tylC genes encoding all-but-one of the enzymes involved in the biosynthesis of mycarose. The latter is a 6-deoxyhexose sugar required during production of the macrolide antibiotic, tylosin. The missing mycarose-biosynthetic gene, tylCVI, was found about 50 kb distant from its functional partners, on the other side of the tylG (polyketide synthase) gene complex. Mutational analysis, involving targeted gene transplacement, was employed to confirm the functions of specific genes, including tylCVI. Particularly interesting was the similarity between the tylosin-biosynthetic mycarosyltransferase enzyme, TylCV, and proteins of the macrolide glycosyltransferase (MGT) family that inactivate macrolides via glycosylation of attached sugar residues and are involved in resistance and/or antibiotic efflux. The arrangement of genes within the ‘mycarose cluster’ would allow their expression as two short operons with divergent, and perhaps co-regulated, promoters. Whether displacement of tylCVI relative to the other tylC genes provides additional regulatory opportunities remains to be established.

Keywords: tylosin production, Streptomyces fradiae, mycarose biosynthesis, deoxyhexose metabolism

Abbreviations: MGT, macrolide glycosyltransferase

The GenBank accession number for the sequence determined in this work is AF147704.

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