title: High divergence of the precursor peptides in combinatorial lanthipeptide biosynthesis.
abstract: Lanthionine-containing peptides (lanthipeptides) are a rapidly growing family of polycyclic peptide natural products belonging to the large class of ribosomally synthesized and post-translationally modified peptides (RiPPs). These compounds are widely distributed in taxonomically distant species, and their biosynthetic systems and biological activities are diverse. A unique example of lanthipeptide biosynthesis is the prochlorosin synthetase ProcM from the marine cyanobacterium Prochlorococcus MIT9313, which transforms up to 29 different precursor peptides (ProcAs) into a library of lanthipeptides called prochlorosins (Pcns) with highly diverse sequences and ring topologies. Here, we show that many ProcM-like enzymes from a variety of bacteria have the capacity to carry out post-translational modifications on highly diverse precursor peptides, providing new examples of natural combinatorial biosynthesis. We also demonstrate that the leader peptides come from different evolutionary origins, suggesting that the combinatorial biosynthesis is tied to the enzyme and not a specific type of leader peptide. For some precursor peptides encoded in the genomes, the leader peptides apparently have been truncated at the N-termini, and we show that these N-terminally truncated peptides are still substrates of the enzymes. Consistent with this hypothesis, we demonstrate that about two-thirds of the ProcA N-terminal sequence is not essential for ProcM activity. Our results also highlight the potential of exploring this class of natural products by genome mining and bioengineering.
authors.affiliation: Department of Chemistry, Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign , 600 South Mathews Avenue, Urbana, Illinois 61801, United States.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.forename: Xiao
authors.initials: X
authors.lastname: Yang
authors.forename: Huan
authors.initials: H
authors.lastname: Wang
authors.forename: Wilfred A
authors.initials: WA
authors.lastname: van der Donk
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000737:chemistry; D000595:Amino Acid Sequence; D020650:Combinatorial Chemistry Techniques; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D013440:Sulfides / Q000737:chemistry*
chemical_list: D010455:Peptides; D013440:Sulfides; C001520:lanthionine; D000409:Alanine