title: An acyl-CoA dehydrogenase is involved in the formation of the Delta cis3 double bond in the acyl residue of the lipopeptide antibiotic friulimicin in Actinoplanes friuliensis.
abstract: The lipopeptide antibiotic friulimicin, produced by Actinoplanes friuliensis, is an effective drug against Gram-positive bacteria, such as methicillin-resistant Staphylococcus epidermidis and Staphylococcus aureus strains. Friulimicin consists of a cyclic peptide core of ten amino acids and an acyl residue linked to an exocyclic amino acid. The acyl residue is essential for antibiotic activity, varies in length from C13 to C15, and carries a characteristic double bond at position Delta cis3. Sequencing of a DNA fragment adjacent to a previously described fragment encoding some of the friulimicin biosynthetic genes revealed several genes whose gene products resemble enzymes of lipid metabolism. One of these genes, lipB, encodes an acyl-CoA dehydrogenase homologue. To elucidate the function of the LipB protein, a lipB insertion mutant was generated and the friulimicin derivative (FR242) produced by the mutant was purified. FR242 had antibiotic activity lower than friulimicin in a bioassay. Gas chromatography showed that the acyl residue of wild-type friulimicin contains a double bond, whereas a saturated bond was present in FR242. These results were confirmed by the heterologous expression of lipB in Streptomyces lividans T7, which led to the production of unsaturated fatty acids not found in the S. lividans T7 parent strain. These results indicate that the acyl-CoA dehydrogenase LipB is involved in the introduction of the unusual Delta cis3 double bond into the acyl residue of friulimicin.
authors.affiliation: Fakultät Biologie, Mikrobiologisches Institut, Mikrobiologie/Biotechnologie, Eberhard-Karls-Universität Tübingen, Auf der Morgenstelle 28, 72076 Tübingen, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Heinzelmann
authors.affiliation: Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie-Hans-Knöll-Institut, Beutenbergstrasse 11, 07745 Jena, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Berger
authors.affiliation: Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie-Hans-Knöll-Institut, Beutenbergstrasse 11, 07745 Jena, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Müller
authors.affiliation: Fakultät Biologie, Mikrobiologisches Institut, Mikrobiologie/Biotechnologie, Eberhard-Karls-Universität Tübingen, Auf der Morgenstelle 28, 72076 Tübingen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Härtner
authors.affiliation: Fakultät Biologie, Mikrobiologisches Institut, Mikrobiologie/Biotechnologie, Eberhard-Karls-Universität Tübingen, Auf der Morgenstelle 28, 72076 Tübingen, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Poralla
authors.affiliation: Fakultät Biologie, Mikrobiologisches Institut, Mikrobiologie/Biotechnologie, Eberhard-Karls-Universität Tübingen, Auf der Morgenstelle 28, 72076 Tübingen, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wohlleben
authors.affiliation: Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie-Hans-Knöll-Institut, Beutenbergstrasse 11, 07745 Jena, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schwartz
mesh_terms: D042964:Acyl-CoA Dehydrogenase / Q000378:metabolism*; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides; D001426:Bacterial Proteins / Q000235:genetics*; D002849:Chromatography, Gas; D003001:Cloning, Molecular; D004269:DNA, Bacterial / Q000737:chemistry / Q000235:genetics; D024881:Drug Resistance, Bacterial; D005231:Fatty Acids, Unsaturated / Q000032:analysis / Q000302:isolation & purification; D017353:Gene Deletion; D023061:Gene Order; D005798:Genes, Bacterial; D008848:Micromonosporaceae / Q000201:enzymology*; D008969:Molecular Sequence Data; D015394:Molecular Structure; D016254:Mutagenesis, Insertional; D010455:Peptides / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism* / Q000494:pharmacology; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D048170:Streptomyces lividans / Q000235:genetics / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D001426:Bacterial Proteins; D004269:DNA, Bacterial; D005231:Fatty Acids, Unsaturated; D010455:Peptides; C416817:friulimicin A; C088618:lipase activator protein, Bacteria; D042964:Acyl-CoA Dehydrogenase