Site-Selective Oxidative Degradation of the Conserved Disulfide Bridge in Oxytocin and Vasopressin: Chemical Transformations and Structural Destabilization
- 1National Research Council of Italy Via Marzolo 1 , , ,
- 2Harwell Science and Innovation Campus , , ,
Abstract
Reactive oxygen species (ROS) are major mediators of oxidative stress and represent an important source of chemical instability for biologically relevant molecules, including disulfide-containing peptides. Oxytocin and vasopressin are important signaling neuropeptides whose biological activity critically depends on the structural integrity of a conserved Cys1–Cys6 disulfide bridge. Here, we investigated the oxidative degradation pathways of both peptides under controlled ROS-generating conditions using UV–C irradiation as a reproducible source of radical stress. Structural and chemical changes were monitored by circular dichroism spectroscopy and HPLC–mass spectrometry. Both peptides underwent progressive degradation with prominent modifications of the disulfide bridge, which emerged as a major site of radical attack. Oxidative degradation produced thioether and polysulfide-containing species consistent with disulfide-bridge modification involving cysteine desulfurization and rearrangement, while CD spectroscopy revealed early loss of the disulfide-constrained cyclic structure before extensive degradation occurred. Control experiments employing thiol- and disulfide-reactive reagents further supported the key role of the disulfide bridge in determining peptide susceptibility to oxidative damage. Removal or modification of the sulfur-containing residues significantly altered degradation kinetics and product distribution. These results identify the conserved Cys1–Cys6 disulfide bridge as a major target of ROS-induced degradation in oxytocin and vasopressin under oxidative conditions and provide new insight into the chemical pathways associated with oxidative modification of cyclic disulfide-containing peptides. More broadly, these findings establish a framework for future investigations into whether redox chemistry and oxidative stress contribute to the regulation or dysregulation of oxytocin and vasopressin stability and signaling.
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BibTeX
@article{tartaggia2026siteselective,
title = {{Site-Selective Oxidative Degradation of the Conserved Disulfide Bridge in Oxytocin and Vasopressin: Chemical Transformations and Structural Destabilization}},
author = {Stefano Tartaggia and Claudia Honisch and Rohanah Hussain and Giuliano Siligardi and Paolo Ruzza},
journal = {ACS Omega},
year = {2026},
month = nov,
doi = {10.1021/acsomega.6c09201},
url = {https://pubs.acs.org/acsodf/article/doi/10.1021/acsomega.6c09201/5463452/Site-Selective-Oxidative-Degradation-of-the},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Site-Selective Oxidative Degradation of the Conserved Disulfide Bridge in Oxytocin and Vasopressin: Chemical Transformations and Structural Destabilization
AU - Stefano Tartaggia
AU - Claudia Honisch
AU - Rohanah Hussain
AU - Giuliano Siligardi
AU - Paolo Ruzza
PY - 2026
DA - 2026/11/04
JO - ACS Omega
DO - 10.1021/acsomega.6c09201
UR - https://pubs.acs.org/acsodf/article/doi/10.1021/acsomega.6c09201/5463452/Site-Selective-Oxidative-Degradation-of-the
AB - Reactive oxygen species (ROS) are major mediators of oxidative stress and represent an important source of chemical instability for biologically relevant molecules, including disulfide-containing peptides. Oxytocin and vasopressin are important signaling neuropeptides whose biological activity critically depends on the structural integrity of a conserved Cys1–Cys6 disulfide bridge. Here, we investigated the oxidative degradation pathways of both peptides under controlled ROS-generating conditions using UV–C irradiation as a reproducible source of radical stress. Structural and chemical changes were monitored by circular dichroism spectroscopy and HPLC–mass spectrometry. Both peptides underwent progressive degradation with prominent modifications of the disulfide bridge, which emerged as a major site of radical attack. Oxidative degradation produced thioether and polysulfide-containing species consistent with disulfide-bridge modification involving cysteine desulfurization and rearrangement, while CD spectroscopy revealed early loss of the disulfide-constrained cyclic structure before extensive degradation occurred. Control experiments employing thiol- and disulfide-reactive reagents further supported the key role of the disulfide bridge in determining peptide susceptibility to oxidative damage. Removal or modification of the sulfur-containing residues significantly altered degradation kinetics and product distribution. These results identify the conserved Cys1–Cys6 disulfide bridge as a major target of ROS-induced degradation in oxytocin and vasopressin under oxidative conditions and provide new insight into the chemical pathways associated with oxidative modification of cyclic disulfide-containing peptides. More broadly, these findings establish a framework for future investigations into whether redox chemistry and oxidative stress contribute to the regulation or dysregulation of oxytocin and vasopressin stability and signaling.
SN - 2470-1343
ER -