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Two new tailoring enzymes, a glycosyltransferase and an oxygenase, involved in biosynthesis of the angucycline antibiotic urdamycin A in Streptomyces fradiae Tü2717

Universität Tübingen, Pharmazeutisches Institut, Auf der Morgenstelle 8, D-72076 Tübingen, Germany¹
Hoechst Marion Roussel Deutschland GmbH, Process Development, D-65926 Frankfurt, Germany^2
3Medical University of South Carolina, Department of Pharmaceutical Sciences, 171 Ashley Avenue, Charleston, SC 29425-2303, USA³

Author for correspondence: A. Bechthold. Tel.: +49 7071 2975483. Fax: +49 7071 295250. e-mail: andreas.bechthold{at}uni-tuebingen.de

Urdamycin A, the principal product of Streptomyces fradiae Tü2717, is an angucycline-type antibiotic and anticancer agent containing C-glycosidically linked D-olivose. To extend knowledge of the biosynthesis of urdamycin A the authors have cloned further parts of the urdamycin biosynthetic gene cluster. Three new ORFs (urdK, urdJ and urdO) were identified on a 3·35 kb fragment, and seven new ORFs (urdL, urdM, urdJ2, urdZ1, urdGT2, urdG and urdH) on an 8·05 kb fragment. The deduced products of these genes show similarities to transporters (urdJ and urdJ2), regulatory genes (urdK), reductases (urdO), cyclases (urdL) and deoxysugar biosynthetic genes (urdG, urdH and urdZ1). The product of urdM shows striking sequence similarity to oxygenases (N-terminal sequence) as well as reductases (C-terminal sequence), and the deduced amino acid sequence of urdGT2 resembles those of glycosyltransferases. To determine the function of urdM and urdGT2, targeted gene inactivation experiments were performed. The resulting urdM deletion mutant strains accumulated predominantly rabelomycin, indicating that UrdM is involved in oxygenation at position 12b of urdamycin A. A mutant in which urdGT2 had been deleted produced urdamycin I, urdamycin J and urdamycin K instead of urdamycin A. Urdamycins I, J and K are tetracyclic angucyclinones lacking a C–C connected deoxysugar moiety. Therefore UrdGT2 must catalyse the earliest glycosyltransfer step in the urdamycin biosynthetic pathway, theC-glycosyltransfer of one NDP-D-olivose.

Keywords: glycosyltransferase, oxygenase, angucycline, urdamycin A, Streptomyces

Abbreviations: PKS polyketide synthase

This paper is dedicated to Professor Heinz Floss, a pioneer in the field of antibiotics, on the occasion of his 65th birthday.

The GenBank accession numbers for the sequences reported in this paper are AF164960 and AF164961.

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