title: Structure and biosynthesis of a macrocyclic peptide containing an unprecedented lysine-to-tryptophan crosslink.
abstract: Streptococcal bacteria use peptide signals as a means of intraspecies communication. These peptides can contain unusual post-translational modifications, providing opportunities for expanding our understanding of nature's chemical and biosynthetic repertoires. Here, we have combined tools from natural products discovery and mechanistic enzymology to elucidate the structure and biosynthesis of streptide, a streptococcal macrocyclic peptide. We show that streptide bears an unprecedented post-translational modification involving a covalent linkage between two unactivated carbons within the side chains of lysine and tryptophan. The biosynthesis of streptide was addressed by genetic and biochemical studies. The former implicated a new SPASM-domain-containing radical SAM enzyme StrB, while the latter revealed that StrB contains two [4Fe-4S] clusters and installs the unusual lysine-to-tryptophan crosslink in a single step. By intramolecularly stitching together the side chains of lysine and tryptophan, StrB provides a new route for biosynthesizing macrocyclic peptides.
authors.affiliation: Department of Chemistry, Princeton University, Princeton, New Jersey, USA.
authors.forename: Kelsey R
authors.initials: KR
authors.lastname: Schramma
authors.affiliation: Department of Chemistry, Princeton University, Princeton, New Jersey, USA.
authors.forename: Leah B
authors.initials: LB
authors.lastname: Bushin
authors.affiliation: Department of Chemistry, Princeton University, Princeton, New Jersey, USA.|Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA.
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Seyedsayamdost
mesh_terms: D055162:Biocatalysis; D002851:Chromatography, High Pressure Liquid; D008239:Lysine / Q000737:chemistry*; D047028:Macrocyclic Compounds / Q000737:chemistry*; D008958:Models, Molecular; D010456:Peptides, Cyclic / Q000096:biosynthesis / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization; D014364:Tryptophan / Q000737:chemistry*
chemical_list: D047028:Macrocyclic Compounds; D010456:Peptides, Cyclic; D014364:Tryptophan; D008239:Lysine