title: Post-translational modification of therapeutic peptides by NisB, the dehydratase of the lantibiotic nisin.
abstract: Post-translationally introduced dehydroamino acids often play an important role in the activity and receptor specificity of biologically active peptides. In addition, a dehydroamino acid can be coupled to a cysteine to yield a cyclized peptide with increased biostability and resistance against proteolytic degradation and/or modified specificity. The lantibiotic nisin is an antimicrobial peptide produced by Lactococcus lactis. Its post-translational enzymatic modification involves NisB-mediated dehydration of serines and threonines and NisC-catalyzed coupling of cysteines to dehydroresidues, followed by NisT-mediated secretion. Here, we demonstrate that a L. lactis strain containing the nisBTC genes effectively dehydrates and secretes a wide range of medically relevant nonlantibiotic peptides among which variants of adrenocorticotropic hormone, vasopressin, an inhibitor of tripeptidyl peptidase II, enkephalin, luteinizing hormone-releasing hormone, angiotensin, and erythropoietin. For most of these peptides, ring formation was demonstrated. These data show that lantibiotic enzymes can be applied for the modification of peptides, thereby enabling the biotechnological production of dehydroresidue-containing and/or thioether-bridged therapeutic peptides with enhanced stability and/or modulated activities.
authors.affiliation: BiOMaDe Technology Foundation, Nijenborgh 4, 9747 AG Groningen, The Netherlands.
authors.forename: Leon D
authors.initials: LD
authors.lastname: Kluskens
authors.forename: Anneke
authors.initials: A
authors.lastname: Kuipers
authors.forename: Rick
authors.initials: R
authors.lastname: Rink
authors.forename: Esther
authors.initials: E
authors.lastname: de Boef
authors.forename: Susan
authors.initials: S
authors.lastname: Fekken
authors.forename: Arnold J M
authors.initials: AJ
authors.lastname: Driessen
authors.forename: Oscar P
authors.initials: OP
authors.lastname: Kuipers
authors.forename: Gert N
authors.initials: GN
authors.lastname: Moll
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D001426:Bacterial Proteins / Q000378:metabolism*; D006836:Hydro-Lyases / Q000378:metabolism*; D013294:Lactococcus lactis / Q000201:enzymology; D008565:Membrane Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D009561:Nisin / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013440:Sulfides / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D008565:Membrane Proteins; C079126:NisB protein, Lactococcus lactis; D010456:Peptides, Cyclic; D013440:Sulfides; D009561:Nisin; D006836:Hydro-Lyases