title: Insights into the complex biosynthesis of the leupyrrins in Sorangium cellulosum So ce690.
abstract: The anti-fungal leupyrrins are secondary metabolites produced by several strains of the myxobacterium Sorangium cellulosum. These intriguing compounds incorporate an atypically substituted γ-butyrolactone ring, as well as pyrrole and oxazolinone functionalities, which are located within an unusual asymmetrical macrodiolide. Previous feeding studies revealed that this novel structure arises from the homologation of four distinct structural units, nonribosomally-derived peptide, polyketide, isoprenoid and a dicarboxylic acid, coupled with modification of the various building blocks. Here we have attempted to reconcile the biosynthetic pathway proposed on the basis of the feeding studies with the underlying enzymatic machinery in the S. cellulosum strain So ce690. Gene products can be assigned to many of the suggested steps, but inspection of the gene set provokes the reconsideration of several key transformations. We support our analysis by the reconstitution in vitro of the biosynthesis of the pyrrole carboxylic starter unit along with gene inactivation. In addition, this study reveals that a significant proportion of the genes for leupyrrin biosynthesis are located outside the core cluster, a 'split' organization which is increasingly characteristic of the myxobacteria. Finally, we report the generation of four novel deshydroxy leupyrrin analogues by genetic engineering of the pathway.
authors.affiliation: Helmholtz Institute for Pharmaceutical Research, Helmholtz Center for Infection Research and Department of Pharmaceutical Biotechnology, Saarland University, PO Box 151150, 66041 Saarbrücken, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Kopp
authors.forename: Herbert
authors.initials: H
authors.lastname: Irschik
authors.forename: Katja
authors.initials: K
authors.lastname: Gemperlein
authors.forename: Kathrin
authors.initials: K
authors.lastname: Buntin
authors.forename: Peter
authors.initials: P
authors.lastname: Meiser
authors.forename: Kira J
authors.initials: KJ
authors.lastname: Weissman
authors.forename: Helge B
authors.initials: HB
authors.lastname: Bode
authors.forename: Rolf
authors.initials: R
authors.lastname: Müller
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000737:chemistry; D000595:Amino Acid Sequence; D053898:Biosynthetic Pathways; D004269:DNA, Bacterial / Q000235:genetics; D004591:Electrophoresis, Polyacrylamide Gel; D008969:Molecular Sequence Data; D015394:Molecular Structure; D005810:Multigene Family / Q000235:genetics; D009231:Myxococcales / Q000235:genetics / Q000378:metabolism*; D010940:Plant Proteins / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D004269:DNA, Bacterial; D010940:Plant Proteins; C481579:leupyrrin A1; D015107:4-Butyrolactone