Graduate Thesis Or Dissertation
 

Alkylation of peptides and proteins by S-(2-chloroethyl)glutathione and characterization of adducts by mass spectrometry

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  • Glutathione, a ubiquitous intracellular tripeptide, protects cells by reacting with electrophiles and radicals that can damage cellular macromolecules. However, glutathione conjugation is now recognized as one mechanism by which drugs and xenobiotics can also be converted to reactive intermediates having toxic consequences to cells. The halogenated alkane 1,2-dichloroethane forms S-(2-chloroethyl) glutathione (CEG) upon glutathione conjugation which can cyclize to an episulfonium ion. The episulfonium ion of CEG is a potent electrophile that can alkylate the N7 position of guanine in DNA. To investigate the possible role of protein alkylation by CEG as a determinant in the toxicity of 1,2-dichloroethane, it is necessary to better understand the alkylation chemistry of CEG toward proteins. Although covalent binding has been known to be correlated with the toxicity of many chemicals, it is now thought covalent binding is selective towards specific protein targets. My work has attempted to determine if the alkylation event is also selective for certain amino acids in a protein. To answer the specific question of where the adducts derived from the episulfonium ion of CEG have formed, a combination of mass spectrometric techniques, including tandem mass spectrometry, were employed. As models, I employed one peptide, oxytocin, and two proteins, human hemoglobin and E. coli thioredoxin. The results of my work show that for the episulfonium ion of CEG, alkylation is highly selective for cysteine over other amino acids with tyrosine being the next most reactive amino acid residue. However, the episulfonium ion is also selective amongst protein thiols as certain cysteine residues are not alkylated, possibly due to steric hindrance and/or charge effects.
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