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Methionine(329) in human serum albumin: A novel target for alkylation by sulfur mustard

TitleMethionine(329) in human serum albumin: A novel target for alkylation by sulfur mustard
Publication TypeJournal Article
Year of Publication2019
AuthorsSiegert M., Gandor F., Kranawetvogl A., Borner H., Thiermann H., John H.
JournalDrug Test Anal
Volume11
Issue5
Pagination659-668
Date PublishedMay
ISBN Number1942-7603 (Linking)
Accession Number30468304
KeywordsAlbumin-adducts, Alkylation, High-resolution mass spectrometry, methionyl sulfonium, Sulfur Mustard
Abstract

Exposure to the vesicant sulfur mustard (SM) may lead to erythema and blistering. Toxicity of SM is hypothesized due to the alkylation of DNA bases and nucleophilic amino acid side chains in proteins (adducts) by forming the hydroxyethylthioethyl (HETE) moiety. Despite its prohibition by the chemical weapons convention, SM still represents a serious threat to military personnel and civilians. Therefore, development and improvement of forensic analytical methods for the verification of SM exposure is of high interest. Protein adducts have been shown to be highly suitable and beneficial biomarkers of poisoning. Herein we present methionine(329) in human serum albumin (HSA) as a novel target of SM forming a HETE-methionyl sulfonium ion. The alkylated tetrapeptide LeuGlyMet(329) (-HETE)Phe, LGM(-HETE)F, was detected after pepsin-mediated proteolysis and subsequent analysis by microbore liquid chromatography-electrospray ionization-high-resolution tandem-mass spectrometry. Compound identity was confirmed by a synthetic reference. Proteolysis conditions for HSA were optimized towards maximum yield of LGM(-HETE)F and its limit of identification (32.3 nM SM in serum) was similar to those of the established HSA-derived biomarkers HETE-CysPro and HETE-CysProPhe (15.6 nM SM in serum). Stability of the alkylated Met(329) in vitro and in vivo was limited to 5 days making this modification a beneficial short-time biomarker. Furthermore, it was found that the HETE-methionyl sulfonium ion can transfer its HETE moiety to the side chain of cysteine and glutamic acid as well as to the N-terminus of peptides and proteins in vitro thus revealing novel insights into the molecular toxicity of SM.

URLhttps://www.ncbi.nlm.nih.gov/pubmed/30468304
DOI10.1002/dta.2548
Short TitleMethionine(329) in human serum albumin: A novel target for alkylation by sulfur mustard

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