Mustard gas crosslinking of proteins through preferential alkylation of cysteines

Byrne, Michael; Broomfield, Clarence A.; Stites, Wesley E.

doi:10.1007/bf01887394

Cited by 31 publications

(11 citation statements)

References 29 publications

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“…This behavior may hint at unforeseen mechanisms for the interaction of the mercury(II) ion with biological structures, ultimately leading to cellular and organ toxicity, since episulfonium species are considered the key biologically active intermediates, e.g., in the alkylation of bio-nucleophiles by mustard gas [25,26].…”

Section: Discussionmentioning

confidence: 99%

Molecular characterization of homo- and heterodimeric mercury(II)-bis-thiolates of some biologically relevant thiols by electrospray ionization and triple quadrupole tandem mass spectrometry

Rubino

Verduci

Giampiccolo

et al. 2004

J. Am. Soc. Mass Spectrom.

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A series of 24 compounds of general formula R(1)S-Hg-SR(2), R(1) and R(2) being biologically relevant thiol-containing amino acids and peptides (cysteine, homo-cysteine, penicillamine, N-acetyl-cysteine, N-acetyl-penicillamine, cysteinyl-glycine, gamma-glutamyl-cysteine and glutathione) were prepared by direct reaction of mercury(II) ions and thiols in water at millimolar concentration. The obtained products were characterized by electrospray ionization and triple quadrupole tandem mass spectrometry. The source spectra of equimolar mixtures of two different thiols reacting with a stoichiometric amount of mercury(II) show the peak clusters of the three theoretically expected bis-thiolato-mercury(II) complexes with relative intensities close to the theoretically expected 1:2:1 ratio, thus pointing at lack of substantial discrimination between the different thiols, the only observed exception being homo-cysteine, which is less reactive than cysteine and penicillamine. The fragment spectra are structure-specific for the different ligands bound to the metal ion and allow a stand-alone discrimination of some constitutional isomer pairs. Among the peculiar fragmentation processes observed, loss of neutral ammonia from protonated symmetrical and unsymmetrical mercury(II)-bis-thiolates with free, protonizable amino groups leads to the formation of thiirane-carboxylic bound species; this process is suppressed when the protonated amino group is in the gamma-position with respect to the sulfur atom, as in the case of compounds with homo-cysteine. This unusual behavior may hint at unforeseen mechanisms for the interaction of mercury(II) with biological structures, ultimately leading to cellular and organ toxicity. Compounds with N-acetylated amino acids show distinctive fragment ions to which the connectivity of a protonated 2-methyl-oxazoline-5-carboxylic acid may be proposed on the basis of the loss of water and of the elements of formic acid. Finally, the adducts of mercury(II) with glutathione and gamma-glutamyl-cysteine feature a distinctive decomposition channel by loss of a pyroglutamic unit, much the same as protonated glutathione, glutathione disulfide, the S-glutathionyl adducts of biologically occurring electrophiles and other (pseudo)-peptides with gamma-glutamyl bonds.

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Section: Discussionmentioning

confidence: 99%

Molecular characterization of homo- and heterodimeric mercury(II)-bis-thiolates of some biologically relevant thiols by electrospray ionization and triple quadrupole tandem mass spectrometry

Rubino

Verduci

Giampiccolo

et al. 2004

J. Am. Soc. Mass Spectrom.

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“…Reactivity toward proteins is thought to occur preferentially at cysteines [20,22], although reactivity at the alpha-amino group (ie, the amino terminus), the imino group of histidine, and carboxylic acid groups of aspartic and glutamic acid has been demonstrated [23][24][25][26][27].…”

Section: Introductionmentioning

confidence: 99%

Treatment of keratin intermediate filaments with sulfur mustard analogs

Hess

Fitzgerald

2007

Biochemical and Biophysical Research Communications

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Sulfur mustard (SM) is an alkylating agent with a history of use as a chemical weapon. The chemical reactivity of sulfur mustard toward both proteins and nucleic acids coupled with the hours long delay between exposure and appearance of blisters has prevented the determination of the mechanism of blister formation. We have treated assembled keratin intermediate filaments with analogs of sulfur mustard to simulate exposure to SM. We find that treatment of intact filaments with chloroethyl ethyl sulfide (CEES) or mechlorethamine (MEC) produces aggregates of keratin filaments with little native appearing structure. Treatment of a mix of epidermal keratins 1/10 (keratin pair 1 and 10) and keratins 5/14 with a sulfhydryl-specific modification reagent also results in filament abnormalities. Our results are consistent with the hypothesis that modification of keratins by SM would result in keratin filament destruction, leading to lysis of epidermal basal cells and skin blistering.

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“…Thus, the most likely nucleophile target regions within GSH and NAC are the thiol group. Cysteine to cysteine crosslinks in SMexposed proteins and possibly the deprotonated carboxy group(s) have been described (Byrne et al, 1996). Under the pre-treatment regimen, GSH or NAC did not have the chance for extracellular interaction with SM.…”

Section: Discussionmentioning

confidence: 96%

Protective effects of the thiol compounds GSH and NAC against sulfur mustard toxicity in a human keratinocyte cell line

et al. 2016

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Mustard gas crosslinking of proteins through preferential alkylation of cysteines

Cited by 31 publications

References 29 publications

Molecular characterization of homo- and heterodimeric mercury(II)-bis-thiolates of some biologically relevant thiols by electrospray ionization and triple quadrupole tandem mass spectrometry

Molecular characterization of homo- and heterodimeric mercury(II)-bis-thiolates of some biologically relevant thiols by electrospray ionization and triple quadrupole tandem mass spectrometry

Treatment of keratin intermediate filaments with sulfur mustard analogs

Protective effects of the thiol compounds GSH and NAC against sulfur mustard toxicity in a human keratinocyte cell line

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