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Antimicrobial Agents and Chemotherapy, June 2006, p. 2113-2121, Vol. 50, No. 6
0066-4804/06/$08.00+0     doi:10.1128/AAC.00007-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Biosynthetic Gene Cluster for the Polyenoyltetramic Acid -Lipomycin

Albert-Ludwigs-Universität Freiburg, Institut für Pharmazeutische Wissenschaften, Pharmazeutische Biologie und Biotechnologie, Stefan-Meier-Straße 19, D-79194 Freiburg, Germany,¹ Combinature Biopharm AG, Robert-Rössle-Straße 10, 13125 Berlin, Germany,² Albert-Ludwigs-Universität Freiburg, Institut für Pharmazeutische Wissenschaften, Pharmazeutische und Medizinische Chemie, Stefan-Meier-Straße 19, D-79194 Freiburg, Germany,³ Technische Universität München, Institut für Organische Chemie und Biochemie II, Lichtenbergstraße 4, 85747 München, Germany⁴

Received 4 January 2006/ Returned for modification 2 March 2006/ Accepted 28 March 2006

The gram-positive bacterium Streptomyces aureofaciens Tü117 produces the acyclic polyene antibiotic -lipomycin. The entire biosynthetic gene cluster (lip gene cluster) was cloned and characterized. DNA sequence analysis of a 74-kb region revealed the presence of 28 complete open reading frames (ORFs), 22 of them belonging to the biosynthetic gene cluster. Central to the cluster is a polyketide synthase locus that encodes an eight-module system comprised of four multifunctional proteins. In addition, one ORF shows homology to those for nonribosomal peptide synthetases, indicating that -lipomycin belongs to the classification of hybrid peptide-polyketide natural products. Furthermore, the lip cluster includes genes responsible for the formation and attachment of D-digitoxose as well as ORFs that resemble those for putative regulatory and export functions. We generated biosynthetic mutants by insertional gene inactivation. By analysis of culture extracts of these mutants, we could prove that, indeed, the genes involved in the biosynthesis of lipomycin had been cloned, and additionally we gained insight into an unusual biosynthesis pathway.

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