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Two-Step Reaction Mechanism Reveals New Antioxidant Capability of Cysteine Disulfides Against Hydroxyl Radical Attack

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Two-Step Reaction Mechanism Reveals New Antioxidant Capability of Cysteine Disulfides Against Hydroxyl Radical Attack Two-step reaction mechanism reveals new antioxidant capability of cysteine disulfides against hydroxyl radical attack Sarju Adhikaria, Ramon Crehuetb, Josep M. Angladab,1, Joseph S. Franciscoc,1, and Yu Xiaa,d,1 aDepartment of Chemistry, Purdue University, West Lafayette, IN 47907; bDepartment of Biological Chemistry, Institute of Advanced Chemistry of Catalonia, IQAC-CSIC, E-08034 Barcelona, Spain; cDepartment of Chemistry, University of Pennsylvania, Philadelphia, PA 19104; and dDepartment of Chemistry, Tsinghua University, Beijing 100084, China Contributed by Joseph S. Francisco, May 30, 2020 (sent for review April 9, 2020; reviewed by Richard A. O’Hair and Henry F. Schaefer III) Cysteine disulfides, which constitute an important component in group leads to H-atom transfer (13); thus-formed thiyl radicals are • biological redox buffer systems, are highly reactive toward the cycled in the –SS–/–SH/–S system via chemical reactions or en- • hydroxyl radical ( OH). The mechanistic details of this reaction, how- zymatic regulation (3). Although disulfide is not considered to be ever, remain unclear, largely due to the difficulty in characterizing an efficient antioxidant, due to its limited reactivity toward peroxyl • •− • unstable reaction products. Herein, we have developed a combined radicals (e.g., OOH and O2 ), the rate of its reaction with OH approach involving mass spectrometry (MS) and theoretical calcula- is under diffusion control (10); thus, its conversion to other sulfur • tions to investigate reactions of OH with cysteine disulfides (Cys– compounds directly impacts the steady state of –SS–/–SH redox S–S–R) in the gas phase. Four types of first-generation products system. It is believed that, in aqueous solutions, single-electron + were identified: protonated ions of the cysteine thiyl radical ( Cys– oxidation of the disulfide bond followed by bond cleavage into • + + • • • S ), cysteine ( Cys–SH), cysteine sulfinyl radical ( Cys–SO ), and cys- –S and –S+ is the dominant pathway by which OH reacts with + teine sulfenic acid ( Cys–SOH). The relative reaction rates and prod- disulfide bonds (14, 15). The disulfide cleavage products can uct branching ratios responded sensitively to the electronic property • − further react with O2, OH, OH , or other ROS, forming a series of the R group, providing key evidence to deriving a two-step reac- – • of oxyacids of sulfur, including sulfenic acid ( SOH), sulfinic acid tion mechanism. The first step involved OH conducting a back-side – – ( SO H), and sulfonic acid ( SO H) (3). For the reactions in CHEMISTRY – 2 3 attack on one of the sulfur atoms, forming sulfenic acid ( SOH) and nonpolar environments, such as at the interface of lipid membrane – • thiyl radical ( S ) product pairs. A subsequent H transfer step within and plasma or in the hydrophobic regions of protein tertiary the product complex was favored for protonated systems, generat- structures, the role of cysteine disulfides is less well understood. – • – ing sulfinyl radical ( SO )andthiol( SH) products. Because sulfenic More relevant information here can be gleaned from reactions of • • acid is a potent scavenger of peroxyl radicals, our results implied OH with organic disulfides in the gas phase. In general, OH that cysteine disulfide can form two lines of defense against reac- substitution at the disulfide bond occurs more readily than any tive oxygen species, one using the cysteine disulfide itself and the possible H abstraction or C–S bond cleavage in gas-phase reac- other using the sulfenic acid product of the conversion of cysteine tions (16, 17). Due to disagreement on the identities of the first- disulfide. This aspect suggested that, in a nonpolar environment, generation reaction products, different elementary steps have cysteine disulfides might play a more active role in the antioxidant been proposed for the mechanism by which the disulfide bond is network than previously appreciated. cleaved. For instance, the earliest description of the mechanism disulfide bond | hydroxyl radical | reaction intermediate | mass spectrometry | antioxidant Significance In this work, we harnessed mass spectrometry for online reac- he dynamic formation and cleavage of a disulfide linkage • between two cysteine amino acid residues has profound im- tion monitoring of hydroxyl radical ( OH) attack to cysteine T disulfide and acquired mechanistic details that had not been portance in cell biology, in particular for redox sensing, allosteric • regulation of protein functions, and enzyme catalysis (1, 2). achieved previously. Our findings suggest that OH substitution Equally important is the disulfide (–SS–)/thiol (–SH)/thiyl radical at the disulfide bond is a fast and predominant reaction channel • (–S ) redox system of low–molecular-weight sulfur compounds, in the gas phase, while subsequent hydrogen transfer within the product pairs can be favorable in protonated systems. Notably, such as the redox pairs of glutathione and cysteine, the molar • ratios of which directly impact redox homeostasis in cells or by reacting with OH cysteine disulfide converts itself to a more potent antioxidant, sulfenic acid (–SOH), thus forming two lines plasma (3–5). Three types of reactions have been identified to be of defense against reactive oxygen species (ROS). These results responsible for chemical transformations between the –SS–, –SH, • provide insight into studying the antioxidant roles of cysteine and –S functional groups: nucleophilic substitution-eliminations, disulfide in nonpolar biological environment, such as at the in- specifically so-called thiol–disulfide interchange reactions (6), terface of lipid membrane and plasma. single-electron reactions of free thiols or disulfide bonds (7), and radical reactions (8). When the cell is under oxidative stress, Author contributions: J.M.A., J.S.F., and Y.X. designed research; S.A., R.C., J.M.A., J.S.F., low–molecular-weight sulfur compounds work synergistically with and Y.X. performed research; S.A., R.C., J.M.A., J.S.F., and Y.X. analyzed data; and S.A., other antioxidants (e.g., ascorbic acid and tocopherol) in the R.C., J.M.A., J.S.F., and Y.X. wrote the paper. “antioxidant network” to combat elevated concentrations of re- Reviewers: R.A.O., University of Melbourne; and H.F.S., University of Georgia. • active oxygen species (ROS) (9, 10). The hydroxyl radical ( OH) is The authors declare no competing interest. among the most oxidative species produced in aerobic systems, Published under the PNAS license. •− typically generated from superoxide anion (O2 )andH2O2 by 1To whom correspondence may be addressed. Email: [email protected], frjoseph@sas. Fenton and/or Haber–Weiss reactions (7). Besides, peroxynitrous upenn.edu, or [email protected]. • • acid (ONOOH) readily decomposes to OH and NO2 at neutral This article contains supporting information online at https://www.pnas.org/lookup/suppl/ • pH in biological systems, thus serving as an in situ source of OH doi:10.1073/pnas.2006639117/-/DCSupplemental. • (11, 12). Direct interaction between OH and the thiol functional www.pnas.org/cgi/doi/10.1073/pnas.2006639117 PNAS Latest Articles | 1of8 Downloaded by guest on September 30, 2021 • described a relatively simple picture, involving addition of OH onto the disulfide bond in R–S–S–R followed by rapid scission of • the disulfide bond into RS and RSOH (18). Butkovskaya and • Setser (19) later detected two product pairs: CH3SH/CH3SO and • CH3S /CH3SOH, with the former pair being found more favor- • able from reactions of dimethyl disulfide with OH. Bil et al. suggested H atom transfer in the product complex [CH3SOH– • • SCH3] to be a key step to account for the detection of CH3SO / • HSCH3 (20). However, the product pair CH3S /CH3SOH was not detected and thus ruled out in their mechanism. Obviously, the difficulties in identifying and quantifying the reactive inter- mediates have constituted a major hurdle for mechanistic studies of radical reactions. While electron paramagnetic resonance and other spectro- scopic methods are useful tools for detecting radical species (21), mass spectrometry (MS), which offers a distinct advantage in providing detailed molecular information, is increasingly being used to investigate the structure and reactivity of bio-radical ions in the gas phase (22–25). The recently developed electrospray ionization (ESI)–MS and direct MS for online reaction moni- toring have provided additional powerful tools for elucidating transient radical species in solution reactions (26–29). Given the • importance of –SS–/–SH/–S cycle in biology, we previously de- veloped an MS method to synthesize and characterize cysteine • • • thiyl (Cys–S ), perthiyl (Cys–SS ), and sulfinyl (Cys–SO )radicals in the gas phase (30–32). The method is based on performing radical reactions in the plume region of a nanoelectrospray ioni- zation (nano-ESI) source right before the sampling interface of a mass spectrometer. Such a setup provides a short sampling time Scheme 1. Online MS monitoring of reactions of OH• and cysteinyl disul- (submicrosecond to microsecond) so that bio-radicals can be de- fides (Cys–S–S–R) for various R groups with different electronic properties. tected and subsequently characterized using MS. For instance, two The Cys–S–S–R molecules became protonated at the amine group (+Cys–S– • pairs of reaction products, pep–S /pep–SOH and pep–SH/pep– S–R) when ionized using nano-ESI in positive ion mode. • SO resulting from disulfide bond cleavage in peptides (pep–S– •
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