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. 2002 May;46(5):1174-82.
doi: 10.1128/AAC.46.5.1174-1182.2002.

Biosynthetic gene cluster of simocyclinone, a natural multihybrid antibiotic

A Trefzer  1 , S Pelzer, J Schimana, S Stockert, C Bihlmaier, H-P Fiedler, K Welzel, A Vente, A Bechthold
Affiliations

Biosynthetic gene cluster of simocyclinone, a natural multihybrid antibiotic

A Trefzer et al. Antimicrob Agents Chemother. 2002 May.

Abstract

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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Figures

FIG. 1.
FIG. 1.
Biosynthetic scheme for simocyclinone D8. Domain organization and biosynthetic intermediates for SimC1A, SimC1B, and SimC1C are shown on top. Domain designations: KS, ketosynthase; AT, acyltransferase; ACP, acyl carrier protein; DH, dehydratase; KR, ketoreductase; ER, enoyl reductase; TE, thioesterase. The ER domain, shown in grey, is believed to be inactive. Single enzymatic steps are indicated by a single arrow, and multiple reactions steps are indicated by two arrows.
FIG. 2.
FIG. 2.
Organization of the simocyclinone biosynthetic gene cluster from S. antibioticus Tü6040. Cosmid clones isolated are shown above the map. The solid line indicates the region sequenced during this study, and letters above the line give the position of probes used for hybridization. ORFs are shown as arrows indicating the size and direction of transcription. Fragments A and B were used for insertional inactivation.
FIG. 3.
FIG. 3.
HPLC traces of simocyclinones produced by S. antibioticus Tü6040 (wild type), mutant Sim-C2, and mutant Sim-PKSII. HPLC conditions were as indicated in the text. The retention times were as follows: simocyclinone D8, 10.8 min; simocyclinone A1, 5.8 min. UV/Vis spectra of simocyclinone D8 and simocyclinone A1 are shown above the HPLC chromatograms.
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