Identification of novel disulfide adducts between the thiol containing leaving group of the nerve agent VX and cysteine containing tripeptides derived from human serum albumin

Medientyp: E-Artikel

Titel: Identification of novel disulfide adducts between the thiol containing leaving group of the nerve agent VX and cysteine containing tripeptides derived from human serum albumin

Beteiligte: Kranawetvogl, Andreas; Küppers, Jim; Gütschow, Michael; Worek, Franz; Thiermann, Horst; Elsinghorst, Paul W.; John, Harald

Erschienen: Wiley, 2017

Sprache: Englisch

DOI: 10.1002/dta.2144

ISSN: 1942-7603; 1942-7611

Schlagwörter: Spectroscopy ; Pharmaceutical Science ; Environmental Chemistry ; Analytical Chemistry

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Beschreibung: Chemical warfare agents represent a continuous and considerable threat to military personnel and the civilian population. Such compounds are prohibited by the Chemical Weapons Convention, to which adherence by the member states is strictly controlled. Therefore, reliable analytical methods for verification of an alleged use of banned substances are required. Accordingly, current research focuses on long‐term biomarkers derived from covalent adducts with biomolecules such as proteins. Recently, we have introduced a microbore liquid chromatography/electrospray ionization high‐resolution tandem mass spectrometry method allowing for the investigation of two different classes of adducts of the nerve agent VX with human serum albumin (HSA). Phosphonylated tyrosine residues and novel disulfide adducts at cysteine residues of HSA were produced by enzymatic cleavage with pronase and detected simultaneously. Notably, the thiol containing leaving group of VX (2‐(diisopropylamino)ethanethiol, DPAET) formed disulfide adducts that were released as cysteine and proline containing dipeptides originating from at least two different sites of HSA. Aim of this study was to identify assumed and novel adducts of DPAET with HSA using synthetic peptide reference compounds. Two novel tripeptides were identified representing disulfide adducts with DPAET (Met‐Pro‐Cys‐DPAET, MPC‐DPAET and Asp‐Ile‐Cys‐DPAET, DIC‐DPAET). MPC‐DPAET was shown to undergo partial in‐source decay during electrospray ionization for MS detection thereby losing the N‐terminal Met residue. This results in the more stable Pro‐Cys‐DPAET (PC‐DPAET) dipeptide detectable as protonated ion. The limit of detection for MPC‐DPAET was evaluated, revealing toxicologically relevant VX plasma concentrations. The results provide novel insights into the reactivity of VX and its endogenous targets. Copyright © 2016 John Wiley & Sons, Ltd.

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