title: Enhanced toxicity of the protein cross-linkers divinyl sulfone and diethyl acetylenedicarboxylate in comparison to related monofunctional electrophiles.
abstract: Previously, we determined that diethyl acetylenedicarboxylate (DAD), a protein cross-linker, was significantly more toxic than analogous monofunctional electrophiles. We hypothesized that other protein cross-linkers enhance toxicity similarly. In agreement with this hypothesis, the bifunctional electrophile divinyl sulfone (DVSF) was 6-fold more toxic than ethyl vinyl sulfone (EVSF) in colorectal carcinoma cells and greater than 10-fold more toxic in Saccharomyces cerevisiae. DVSF and DAD caused oligomerization of yeast thioredoxin 2 (Trx2p) in vitro and promoted Trx2p cross-linking to other proteins in yeast at cytotoxic doses. Our results suggest that protein cross-linking is considerably more detrimental to cellular homeostasis than simple alkylation.
authors.affiliation: Biochemistry & Molecular Biology Program, Departments of Biology and Chemistry, The College of Wooster, Wooster, Ohio 44691, USA. jwest@wooster.edu
authors.forename: James D
authors.initials: JD
authors.lastname: West
authors.forename: Chelsea E
authors.initials: CE
authors.lastname: Stamm
authors.forename: Haley A
authors.initials: HA
authors.lastname: Brown
authors.forename: Samantha L
authors.initials: SL
authors.lastname: Justice
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Morano
mesh_terms: D000478:Alkylation; D000480:Alkynes / Q000633:toxicity*; D045744:Cell Line, Tumor; D003432:Cross-Linking Reagents / Q000633:toxicity*; D003603:Cytotoxins / Q000633:toxicity*; D006801:Humans; D011506:Proteins / Q000737:chemistry*; D012441:Saccharomyces cerevisiae / Q000166:cytology; D013450:Sulfones / Q000633:toxicity*
chemical_list: D000480:Alkynes; D003432:Cross-Linking Reagents; D003603:Cytotoxins; D011506:Proteins; D013450:Sulfones; C009873:divinyl sulfone; C022918:acetylenedicarboxylic acid dimethyl ester