Lantibiotics are ribosomally synthesized peptides containing post-translationally installed lanthionine thioether bridges. Recently characterized class III lantibiotics have also revealed the occurrence of labionin, a novel carbacyclic variation of lanthionine, and highlighted the structural diversity within this group. Here we describe the discovery and characterization of curvopeptins produced by Thermomonospora curvata, the first class III lantibiotics of thermophilic origin. Furthermore, investigation of the modifying enzyme CurKC and in particular the characterization of its specificity toward phosphorylation co-substrates was performed. Remarkably, all investigated NTPs and dNTPs were accepted by the enzyme, although the purine nucleotides ATP/dATP and GTP/dGTP were the preferred co-substrates. This finding complements previous studies on the class III lantibiotic synthetases LabKC and EryKC and underlines the surprising promiscuity of the Ser/Thr-kinase domain. Enzymatic studies with a precursor peptide mutant allowed the assignment of all dehydration sites and further GC-MS analysis revealed the presence of lanthionine as the main type of intramolecular ring.
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