title: Thiopeptide biosynthesis featuring ribosomally synthesized precursor peptides and conserved posttranslational modifications.
abstract: Thiopeptides, with potent activity against various drug-resistant pathogens, contain a characteristic macrocyclic core consisting of multiple thiazoles, dehydroamino acids, and a 6-membered nitrogen heterocycle. Their biosynthetic pathways remain elusive, in spite of great efforts by in vivo feeding experiments. Here, cloning, sequencing, and characterization of the thiostrepton and siomycin A gene clusters unveiled a biosynthetic paradigm for the thiopeptide specific core formation, featuring ribosomally synthesized precursor peptides and conserved posttranslational modifications. The paradigm generality for thiopeptide biosynthesis was supported by genome mining and ultimate confirmation of the thiocillin I production in Bacillus cereus ATCC 14579, a strain that was previously unknown as a thiopeptide producer. These findings set the stage to accelerate the discovery of thiopeptides by prediction at the genetic level and to generate structural diversity by applying combinatorial biosynthesis methods.
authors.affiliation: State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Rd., Shanghai 200032, China.
authors.forename: Rijing
authors.initials: R
authors.lastname: Liao
authors.forename: Lian
authors.initials: L
authors.lastname: Duan
authors.forename: Chun
authors.initials: C
authors.lastname: Lei
authors.forename: Haixue
authors.initials: H
authors.lastname: Pan
authors.forename: Ying
authors.initials: Y
authors.lastname: Ding
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.forename: Daijie
authors.initials: D
authors.lastname: Chen
authors.forename: Ben
authors.initials: B
authors.lastname: Shen
authors.forename: Yi
authors.initials: Y
authors.lastname: Yu
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
mesh_terms: D001407:Bacillus / Q000235:genetics / Q000378:metabolism; D001426:Bacterial Proteins / Q000096:biosynthesis* / Q000235:genetics*; D003001:Cloning, Molecular; D005798:Genes, Bacterial; D005810:Multigene Family; D010455:Peptides / Q000235:genetics* / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D012270:Ribosomes / Q000378:metabolism*; D013302:Streptomyces / Q000235:genetics / Q000378:metabolism; D013883:Thiostrepton / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D010455:Peptides; C025311:siomycin; C012574:thiocillin; D013883:Thiostrepton