title: An efficient method for the in vitro production of azol(in)e-based cyclic peptides.
abstract: Heterocycle-containing cyclic peptides are promising scaffolds for the pharmaceutical industry but their chemical synthesis is very challenging. A new universal method has been devised to prepare these compounds by using a set of engineered marine-derived enzymes and substrates obtained from a family of ribosomally produced and post-translationally modified peptides called the cyanobactins. The substrate precursor peptide is engineered to have a non-native protease cleavage site that can be rapidly cleaved. The other enzymes used are heterocyclases that convert Cys or Cys/Ser/Thr into their corresponding azolines. A macrocycle is formed using a macrocyclase enzyme, followed by oxidation of the azolines to azoles with a specific oxidase. The work is exemplified by the production of 17 macrocycles containing 6-9 residues representing 11 out of the 20 canonical amino acids.
authors.affiliation: Marine Biodiscovery Centre, Department of Chemistry, University of Aberdeen, Meston Walk, Aberdeen AB24 3UE (UK); Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD (UK); Pharmacognosy Department, Faculty of Pharmacy, Mansoura University, Mansoura 35516 (Egypt).
authors.forename: Wael E
authors.initials: WE
authors.lastname: Houssen
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Bent
authors.forename: Andrew R
authors.initials: AR
authors.lastname: McEwan
authors.forename: Nathalie
authors.initials: N
authors.lastname: Pieiller
authors.forename: Jioji
authors.initials: J
authors.lastname: Tabudravu
authors.forename: Jesko
authors.initials: J
authors.lastname: Koehnke
authors.forename: Greg
authors.initials: G
authors.lastname: Mann
authors.forename: Rosemary I
authors.initials: RI
authors.lastname: Adaba
authors.forename: Louise
authors.initials: L
authors.lastname: Thomas
authors.forename: Usama W
authors.initials: UW
authors.lastname: Hawas
authors.forename: Huanting
authors.initials: H
authors.lastname: Liu
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schwarz-Linek
authors.forename: Margaret C M
authors.initials: MC
authors.lastname: Smith
authors.forename: James H
authors.initials: JH
authors.lastname: Naismith
authors.forename: Marcel
authors.initials: M
authors.lastname: Jaspars
mesh_terms: D001393:Azoles / Q000737:chemistry / Q000378:metabolism*; D008968:Molecular Conformation; D010088:Oxidoreductases / Q000737:chemistry / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000737:chemistry / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000096:biosynthesis* / Q000737:chemistry; D019761:Phosphorus-Oxygen Lyases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D001393:Azoles; D010456:Peptides, Cyclic; D010088:Oxidoreductases; D010447:Peptide Hydrolases; D019761:Phosphorus-Oxygen Lyases
keywords: biosynthesis; cyanobactins; cyclic peptides; patellamides; ribosomal peptides