title: Post-translational Claisen Condensation and Decarboxylation en Route to the Bicyclic Core of Pantocin A.
abstract: Pantocin A (PA) is a member of the growing family of ribosomally encoded and post-translationally modified peptide natural products (RiPPs). PA is much smaller than most known RiPPs, a tripeptide with a tight bicyclic core that appears to be cleaved from the middle of a larger 30-residue precursor peptide. We show here that the enzyme PaaA catalyzes the double dehydration and decarboxylation of two glutamic acid residues in the 30-residue precursor PaaP. Further truncates of PaaP leader and follower peptide sequences demonstrate the different impacts of these two regions on PaaA-mediated tailoring and delineate an essential role for the follower sequence in the decarboxylation step. The crystal structure of apo PaaA is reported, allowing identification of structural features that set PaaA apart from other homologous enzymes that typically do not catalyze such extended post-translational chemistry. Together, these data reveal how additional chemistry can be extracted from a ubiquitous enzyme family toward ribosomally derived peptide natural product biosynthesis and suggest that more examples of such enzymes likely exist in untapped genomic space.
authors.affiliation: Division of Chemical Biology and Medicinal Chemistry, University of North Carolina at Chapel Hill , Eshelmann School of Pharmacy, Chapel Hill, North Carolina 27599, United States.
authors.forename: Swapnil V
authors.initials: SV
authors.lastname: Ghodge
authors.affiliation: Department of Chemistry, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
authors.forename: Kristen A
authors.initials: KA
authors.lastname: Biernat
authors.affiliation: Division of Chemical Biology and Medicinal Chemistry, University of North Carolina at Chapel Hill , Eshelmann School of Pharmacy, Chapel Hill, North Carolina 27599, United States.
authors.forename: Sarah Jane
authors.initials: SJ
authors.lastname: Bassett
authors.affiliation: Department of Chemistry, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Redinbo
authors.affiliation: Division of Chemical Biology and Medicinal Chemistry, University of North Carolina at Chapel Hill , Eshelmann School of Pharmacy, Chapel Hill, North Carolina 27599, United States.
authors.forename: Albert A
authors.initials: AA
authors.lastname: Bowers
mesh_terms: D001643:Bridged Bicyclo Compounds / Q000737:chemistry*; D018360:Crystallography, X-Ray; D003653:Decarboxylation; D006020:Glycopeptides / Q000737:chemistry*; D011499:Protein Processing, Post-Translational
chemical_list: D001643:Bridged Bicyclo Compounds; D006020:Glycopeptides; C482694:pantocin A