title: Bioinspired strategy for the ribosomal synthesis of thioether-bridged macrocyclic peptides in bacteria.
abstract: Inspired by the biosynthetic logic of lanthipeptide natural products, a new methodology was developed to direct the ribosomal synthesis of macrocyclic peptides constrained by an intramolecular thioether bond. As a first step, a robust and versatile strategy was implemented to enable the cyclization of ribosomally derived peptide sequences via a chemoselective reaction between a genetically encoded cysteine and a cysteine-reactive unnatural amino acid (O-(2-bromoethyl)-tyrosine). Combination of this approach with intein-catalyzed protein splicing furnished an efficient route to achieve the spontaneous, post-translational formation of structurally diverse macrocyclic peptides in bacterial cells. The present peptide cyclization strategy was also found to be amenable to integration with split intein-mediated circular ligation, resulting in the intracellular synthesis of conformationally constrained peptides featuring a bicyclic architecture.
authors: Department of Chemistry, University of Rochester , Rochester, New York 14627, United States.
authors: Nina
authors: N
authors: Bionda
authors: Abby L
authors: AL
authors: Cryan
authors: Rudi
authors: R
authors: Fasan
mesh_terms: D000595:Amino Acid Sequence; D000604:Amino Acyl-tRNA Synthetases / Q000378:metabolism; D003500:Cyclization; D003545:Cysteine / Q000737:chemistry; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D047668:Inteins; D008969:Molecular Sequence Data; D009154:Mutation; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D014176:Protein Biosynthesis; D011499:Protein Processing, Post-Translational; D019154:Protein Splicing; D014443:Tyrosine / Q000031:analogs & derivatives / Q000737:chemistry
chemical_list: D010455:Peptides; D010456:Peptides, Cyclic; D014443:Tyrosine; D000604:Amino Acyl-tRNA Synthetases; D003545:Cysteine