@misc{10481/57343,
year = {2019},
month = {7},
url = {http://hdl.handle.net/10481/57343},
abstract = {Introducing one or more intramolecular thioether bridges in a peptide provides a
promising approach to create more stable molecules with improved pharmacodynamic
properties and especially to protect peptides against proteolytic degradation.
Lanthipeptides are compounds that naturally possess thioether bonds in their structure.
The model lanthipeptide, nisin, is produced by Lactococcus lactis as a core peptide
fused to a leader peptide. The modification machinery responsible for nisin production,
including the Ser/Thr-dehydratase NisB and the cyclase NisC, can be applied for
introducing a thioether bridge into peptides fused to the nisin leader peptide, e.g., to
replace a disulfide bond. Vasopressin plays a key role in water homeostasis in the
human body and helps to constrict blood vessels. There are two cysteine residues in the
structure of wild type vasopressin, which form a disulfide bridge in the mature peptide.
Here, we show it is possible to direct the biosynthesis of vasopressin variants in such a
way that the disulfide bridge is replaced by a thioether bridge using the nisin modification
machinery NisBTC, albeit at low efficiency. Vasopressin mutants were fused either to the
nisin leader peptide directly (Type A), after the first three rings of nisin (Type B/C), or after
full nisin (Type D). The type B strategy was optimal for expression. LC-MS/MS data
verified the formation of a thioether bridge, which provides proof of principle for this
modification in vasopressin. This is a first step prior to the necessary increase of the
production yield and further purification of these peptides to finally test their biological
activity in tissue and animal models.},
organization = {Chinese Scholarship Council (No.
201306770012)},
organization = {MM-L was supported by a grant of the EU
FW7 Project SynPeptide.},
publisher = {Frontiers in Microbiology},
keywords = {thioether bridge},
keywords = {lanthipeptides},
keywords = {Vasopressin},
keywords = {nisin modification machinery},
keywords = {Mass spectrometry},
title = {Feasability of Introducing a Thioether Ring in Vasopressin by nisBTC Co-expression in Lactococcus lactis},
doi = {10.3389/fmicb.2019.01508},
author = {Li, Qian and Montalbán-López, Manuel and Kuipers, Oscar P.},
}