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Antimicrobial Agents and Chemotherapy, May 2002, p. 1174-1182, Vol. 46, No. 5
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.5.1174-1182.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Biosynthetic Gene Cluster of Simocyclinone, a Natural Multihybrid Antibiotic

Pharmazeutische Biologie, Albert-Ludwigs-Universität Freiburg, 79104 Freiburg,¹ Institut für Mikrobiologie und Biotechnologie,² Mikrobiologisches Institut, Eberhard-Karls-Universität Tübingen, 72076 Tübingen,⁴ Combinature Biopharm AG, 13125 Berlin, Germany³

Received 6 August 2001/ Returned for modification 25 November 2001/ Accepted 9 February 2002

The entire simocyclinone biosynthetic cluster (sim gene cluster) from the producer Streptomyces antibioticus Tü6040 was identified on six overlapping cosmids (1N1, 5J10, 2L16, 2P6, 4G22, and 1K3). In total, 80.7 kb of DNA from these cosmids was sequenced, and the analysis revealed 49 complete open reading frames (ORFs). These ORFs include genes responsible for the formation and attachment of four different moieties originating from at least three different pools of primary metabolites. Also in the sim gene cluster, four ORFs were detected that resemble putative regulatory and export functions. Based on the putative function of the gene products, a model for simocyclinone D8 biosynthesis was proposed. Biosynthetic mutants were generated by insertional gene inactivation experiments, and culture extracts of these mutants were analyzed by high-performance liquid chromatography. Production of simocyclinone D8 was clearly detectable in the wild-type strain but was not detectable in the mutant strains. This indicated that indeed the sim gene cluster had been cloned.

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