title: Enzymatic N- and C-Protection in Cyanobactin RiPP Natural Products.
abstract: Recent innovations in peptide natural product biosynthesis reveal a surprising wealth of previously uncharacterized biochemical reactions that have potential applications in synthetic biology. Among these, the cyanobactins are noteworthy because these peptides are protected at their N- and C-termini by macrocyclization. Here, we use a novel bifunctional enzyme AgeMTPT to protect linear peptides by attaching prenyl and methyl groups at their free N- and C-termini. Using this peptide protectase in combination with other modular biosynthetic enzymes, we describe the total synthesis of the natural product aeruginosamide B and the biosynthesis of linear cyanobactin natural products. Our studies help to define the enzymatic mechanism of macrocyclization, providing evidence against the water exclusion hypothesis of transpeptidation and favoring the kinetic lability hypothesis.
authors.affiliation: Department of Medicinal Chemistry, University of Utah , Salt Lake City, Utah 84112, United States.
authors.forename: Debosmita
authors.initials: D
authors.lastname: Sardar
authors.affiliation: Department of Biochemistry, University of Illinois at Urbana-Champaign , Urbana, Illinois 61801, United States.
authors.forename: Yue
authors.initials: Y
authors.lastname: Hao
authors.affiliation: Department of Medicinal Chemistry, University of Utah , Salt Lake City, Utah 84112, United States.
authors.forename: Zhenjian
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Department of Medicinal Chemistry, University of Utah , Salt Lake City, Utah 84112, United States.
authors.forename: Maho
authors.initials: M
authors.lastname: Morita
authors.affiliation: Department of Biochemistry, University of Illinois at Urbana-Champaign , Urbana, Illinois 61801, United States.
authors.forename: Satish K
authors.identifier: 0000-0003-1790-1334
authors.initials: SK
authors.lastname: Nair
authors.affiliation: Department of Medicinal Chemistry, University of Utah , Salt Lake City, Utah 84112, United States.
authors.forename: Eric W
authors.identifier: 0000-0001-5839-694X
authors.initials: EW
authors.lastname: Schmidt
mesh_terms: D001688:Biological Products / Q000737:chemistry / Q000378:metabolism*; D008780:Methyltransferases / Q000737:chemistry / Q000378:metabolism*; D008968:Molecular Conformation; D010447:Peptide Hydrolases / Q000737:chemistry / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D014166:Transferases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D001688:Biological Products; D010455:Peptides; C000627240:AgeMTPT; D014166:Transferases; D008780:Methyltransferases; D010447:Peptide Hydrolases