Sequencing and analysis of the biosynthetic gene cluster of the lipopeptide antibiotic Friulimicin in Actinoplanes friuliensis.

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Muller C, Nolden S, Gebhardt P, Heinzelmann E, Lange C, Puk O, Welzel K, Wohlleben W, Schwartz D

Sequencing and analysis of the biosynthetic gene cluster of the lipopeptide antibiotic Friulimicin in Actinoplanes friuliensis.

Antimicrob Agents Chemother. 2007 Mar;51(3):1028-37. Epub 2007 Jan 12.

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17220414 [ View in PubMed
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Abstract

Actinoplanes friuliensis produces the lipopeptide antibiotic friulimicin, which is a cyclic peptide with one exocyclic amino acid linked to a branched-chain fatty acid acyl residue. The structural relationship to daptomycin and the excellent antibacterial performance of friulimicin make the antibiotic an attractive drug candidate. The complete friulimicin biosynthetic gene cluster of 24 open reading frames from A. friuliensis was sequenced and analyzed. In addition to genes for regulation, self-resistance, and transport, the cluster contains genes encoding peptide synthetases, proteins involved in the synthesis and linkage of the fatty acid component of the antibiotic, and proteins involved in the synthesis of the nonproteinogenic amino acids pipecolinic acid, methylaspartic acid, and 2,3-diaminobutyric acid. By using heterologous gene expression in Escherichia coli, we provide biochemical evidence for the stereoselective synthesis of L-pipecolinic acid by the deduced protein of the lysine cyclodeaminase gene pip. Furthermore, we show the involvement of the dabA and dabB genes in the biosynthesis of 2,3-diaminobutyric acid by gene inactivation and subsequent feeding experiments.

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