title: Biosynthetic Timing and Substrate Specificity for the Thiopeptide Thiomuracin.
abstract: The biosynthesis of the thiopeptide thiomuracin is a well-orchestrated process involving a multitude of posttranslational modifications. We show that six Cys residues of a precursor peptide are first cyclodehydrated and oxidized to thiazoles in an ordered, but nonlinear fashion that is leader-peptide-dependent. Then four alcohols are glutamylated and converted to alkenes in a C-to-N terminal directional process that is leader-peptide-independent. Finally, two of these alkenes undergo a formal [4 + 2] cycloaddition to form a trithiazole-substituted pyridine macrocycle. We describe here the factors that govern the substrate specificity and order of biosynthetic events that turn a ribosomal peptide into a powerful antibiotic.
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.
authors.forename: Zhengan
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.
authors.forename: Graham A
authors.initials: GA
authors.lastname: Hudson
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.|Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 1206 West Gregory Drive, Urbana, Illinois 61801, USA.
authors.forename: Nilkamal
authors.initials: N
authors.lastname: Mahanta
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.
authors.forename: Jonathan I
authors.initials: JI
authors.lastname: Tietz
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.|Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 1206 West Gregory Drive, Urbana, Illinois 61801, USA.
authors.forename: Wilfred A
authors.initials: WA
authors.lastname: van der Donk
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.|Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 1206 West Gregory Drive, Urbana, Illinois 61801, USA.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Mitchell
mesh_terms: D008968:Molecular Conformation; D010453:Peptide Synthases / Q000737:chemistry / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000096:biosynthesis* / Q000737:chemistry; D013379:Substrate Specificity; D013844:Thiazoles / Q000737:chemistry
chemical_list: D010456:Peptides, Cyclic; D013844:Thiazoles; C576049:thiomuracin A; D010453:Peptide Synthases