title: Radical S-adenosyl methionine epimerases: regioselective introduction of diverse D-amino acid patterns into peptide natural products.
abstract: PoyD is a radical S-adenosyl methionine epimerase that introduces multiple D-configured amino acids at alternating positions into the highly complex marine peptides polytheonamide A and B. This novel post-translational modification contributes to the ability of the polytheonamides to form unimolecular minimalistic ion channels and its cytotoxic activity at picomolar levels. Using a genome mining approach we have identified additional PoyD homologues in various bacteria. Three enzymes were expressed in E. coli with their cognate as well as engineered peptide precursors and shown to introduce diverse D-amino acid patterns into all-L peptides. The data reveal a family of architecturally and functionally distinct enzymes that exhibit high regioselectivity, substrate promiscuity, and irreversible action and thus provide attractive opportunities for peptide engineering.
authors.affiliation: Institute of Microbiology, Eigenössische Technische Hochschule (ETH) Zurich, Vladimir-Prelog-Weg 1-5/10, 8093 Zurich (Switzerland).
authors.forename: Brandon I
authors.initials: BI
authors.lastname: Morinaka
authors.forename: Anna L
authors.initials: AL
authors.lastname: Vagstad
authors.forename: Maximilian J
authors.initials: MJ
authors.lastname: Helf
authors.forename: Muriel
authors.initials: M
authors.lastname: Gugger
authors.forename: Carsten
authors.initials: C
authors.lastname: Kegler
authors.forename: Michael F
authors.initials: MF
authors.lastname: Freeman
authors.forename: Helge B
authors.initials: HB
authors.lastname: Bode
authors.forename: Jörn
authors.initials: J
authors.lastname: Piel
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D001688:Biological Products / Q000378:metabolism; D019998:Racemases and Epimerases / Q000737:chemistry*; D012436:S-Adenosylmethionine / Q000737:chemistry*; D013237:Stereoisomerism
chemical_list: D000596:Amino Acids; D001688:Biological Products; D012436:S-Adenosylmethionine; D019998:Racemases and Epimerases
keywords: D-amino acids; biosynthesis; enzymes; natural products; peptides