title: SylC catalyzes ureido-bond formation during biosynthesis of the proteasome inhibitor syringolin A.
abstract: Syringolins are a class of cyclic tripeptide natural products that are potent and irreversible inhibitors of the eukaryotic proteasome. In addition to being hybrid NRPS/PKS molecules, they also feature an unusual ureido-linkage (red) between two amino acid monomers. Here we report the first in vitro characterization of enzymatic ureido-linkage formation which is catalyzed by an NRPS, SylC. Using (13)C- and (18)O-labeling studies, we show that biosynthesis occurs via N-carboxylation to form an initial N-carboxy-aminoacyl-S-Ppant enzyme intermediate which undergoes intramolecular cyclization followed by condensation with a second amino acid to form the ureido-containing dipeptide product.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115. USA.
authors.forename: Heidi J
authors.initials: HJ
authors.lastname: Imker
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Walsh
authors.forename: William M
authors.initials: WM
authors.lastname: Wuest
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D002384:Catalysis; D010456:Peptides, Cyclic / Q000096:biosynthesis* / Q000138:chemical synthesis; D061988:Proteasome Inhibitors; D014508:Urea / Q000737:chemistry
chemical_list: D000596:Amino Acids; D010456:Peptides, Cyclic; D061988:Proteasome Inhibitors; C407267:syringolin A; D014508:Urea