title: Comparative study of the oxidation behavior of sulfur-containing amino acids and glutathione by electrochemistry-mass spectrometry in the presence and absence of cisplatin.
abstract: Small sulfur-containing compounds are involved in several important biochemical processes, including-but not limited to-redox regulation and drug conjugation/detoxification. While methods for stable redox pairs of such compounds (thiols/disulfides) are available, analytical data on more labile and short-lived redox intermediates are scarce, due to highly challenging analytical requirements. In this study, we employ the direct combination of reagentless electrochemical oxidation and mass spectrometric (EC-MS) identification for monitoring oxidation reactions of cysteine, N-acetylcysteine, methionine, and glutathione under simulated physiological conditions (pH 7.4, 37 °C). For the first time, all theoretically expected redox intermediates-with only one exception-are detected simultaneously and in situ, including sulfenic, sulfinic, and sulfonic acids, disulfides, thiosulfinates, thiosulfonates, and sulfoxides. By monitoring the time/potential-dependent interconversion of sulfur species, mechanistic oxidation routes are confirmed and new reactions detected, e.g., sulfenamide formation due to reaction with ammonia from the buffer. Furthermore, our results demonstrate a highly significant impact of cisplatin on the redox reactivity of sulfur species. Namely, the amount of thiol oxidation to sulfonic acid via sulfenic and sulfinic acid intermediates is diminished for glutathione in the presence of cisplatin in favor of the disulfide formation, while for N-acetylcysteine the contrary applies. N-acetylcysteine is the only ligand which displays enhanced oxidation currents upon cisplatin addition, accompanied by increased levels of thiosulfinate and thiosulfonate species. This is traced back to thiol reactivity and highlights the important role of sulfenic acid intermediates, which may function as a switch between different oxidation routes.
authors.affiliation: Leibniz-Institut für Analytische Wissenschaften - ISAS e.V., Otto-Hahn-Str. 6b, 44227, Dortmund, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Zabel
authors.affiliation: Leibniz-Institut für Analytische Wissenschaften - ISAS e.V., Otto-Hahn-Str. 6b, 44227, Dortmund, Germany. guenther.weber@isas.de.
authors.forename: Günther
authors.initials: G
authors.lastname: Weber
mesh_terms: D000111:Acetylcysteine / Q000737:chemistry; D000596:Amino Acids / Q000737:chemistry*; D002945:Cisplatin / Q000737:chemistry* / Q000378:metabolism; D004563:Electrochemistry / Q000379:methods*; D005978:Glutathione / Q000737:chemistry*; D013058:Mass Spectrometry / Q000379:methods*; D008715:Methionine / Q000737:chemistry; D010084:Oxidation-Reduction; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000378:metabolism; D013455:Sulfur / Q000737:chemistry
chemical_list: D000596:Amino Acids; D013438:Sulfhydryl Compounds; D013455:Sulfur; D008715:Methionine; D005978:Glutathione; D002945:Cisplatin; D000111:Acetylcysteine
keywords: Cisplatin; Electrochemistry; Intermediate; Mass spectrometry; Redox; Thiol