Original articleInteraction kinetics of selenium-containing compounds with oxidants
Graphical abstract
Introduction
Organic selenium compounds have been identified as potential oxidant scavengers (‘antioxidants’) due to their high nucleophilicity, and the ease of oxidation of the Se centre. Some of these materials have been reported to have high rate constants for reaction with HOCl and other oxidants [[1], [2], [3], [4], [5], [6], [7], [8]]. Selenium-containing compounds have also been reported to react more rapidly than their sulfur analogues, with this being consistent across a range of oxidants and a number of selenium-containing compounds. Thus, selenols (RSeH) have been reported to react 10–80 times faster with HOSCN, and 250–830 fold faster for ONOOH, than the analogous thiols (RSH) [[1], [2], [3], [4],8].
Selenium compounds have generated interest as potential therapeutic agents against oxidative damage, due to these high rate constants and their capacity to be recycled (i.e. act as catalytic scavenging agents) [1,[9], [10], [11], [12], [13]]. Diselenides (RSeSeR′) may react directly with oxidants, or alternatively be reduced to selenols by the action of both low-molecular-mass thiols [14], including the abundant cellular thiol-containing cofactor glutathione (GSH), and also by antioxidant enzymes such as thioredoxin [9,10]. The resulting selenols may then act as an oxidant scavenger, regenerating the diselenide [5,14,15]. Oxidation of selenides (RSeR′) yields selenoxides [RSe(=O)R’] that, in turn, can be reduced by thiols including glutathione (GSH), or Cys residues present in redox enzymes such as thioredoxin, to reform the parent selenide [1,11,12,16,17]. Thus, both the selenol/diselenide, and selenide/selenoxide pairs may act as catalytic scavengers.
Hypochlorous acid (HOCl) is a powerful oxidant produced by the mammalian innate immune system, and is used to destroy invading pathogens [[18], [19], [20]]. Neutrophils release myeloperoxidase, an enzyme that catalyzes the reaction between hydrogen peroxide (H2O2) and chloride ions (Cl−) to produce hypochlorous acid (HOCl) [[18], [19], [20]]. However, HOCl can also damage host tissue if produced at inappropriate concentrations, times or locations. Proteins are major targets for HOCl in biological systems due to their abundance, and high rate constants for reaction [19,21,22]. HOCl reacts with a number of amino acid side chains, though reactions with the sulfur-containing amino acids are kinetically favored, with rate constants, k, of 3.1 and 1.5 × 108 M−1 s−1 for Cys and Met, respectively [23]. Rate constants for reaction of HOCl with disulfides show a considerable variation (104 - 108 M−1 s−1) with this variation arising from steric and electronic effects [24]. HOCl can also react with the aromatic moieties of Tyr, Trp and His [19,21,22,25], to yield oxygenated or chlorinated products, with these processes being essentially irreversible [19,20]. As a result of these reactions, HOCl can inhibit enzyme function via modification of residues in the active site of proteins [19,26], via alterations to protein structure (e.g. unfolding), and/or induction of aggregation via crosslink formation [19,26].
In the light of the high reactivity of some disulfides with a number of oxidants, and the variation in the rate constants for these reactions [24], we have determined rate constants for the reaction of HOCl, H2O2, amino acid hydroperoxides and 1O2 with a variety of selenium-containing compounds, including diselenides, selenides and selenols (see Table 1 for structures), as these species might be expected to show greater, or equal, reactivity when compared to the corresponding sulfur species. We show that these rate constants cover a wide range, with the data providing valuable insights into the putative role of selenium compounds as oxidant scavengers in biological systems.
Section snippets
Reagents
Solutions were prepared in 0.1 M sodium phosphate buffer, pH 7.4 unless otherwise specified. The selenides, 2,2′-selenodiacetic acid (SeDA), 3,3′-selenodipropionic acid (SePA), 4,4′-selenodibutanoic acid (SeBA), and the diselenide, 3,3′-diselenodipropionic acid (DSePA) were generously supplied by Prof. Indira Priyadarsini (Bhabha Atomic Research Centre, Mumbai, India) and Prof. Vimal Jain (UM-DAE Centre for Excellence in Basic Sciences, University of Mumbai, Mumbai, India). The diselenide,
Diselenides react slowly with H2O2 and other peroxides
The second order rate constant for two diselenides were determined by pseudo-first order kinetics. SeCA and DSePA (1 mM) were mixed with 10–50 mM H2O2 and absorbance monitored between 295 and 315 nm over 16 h (Fig. 1A and B). Exponential curves were fitted to the resulting absorbance vs time plots to determine the observed reaction rate (kobs). Rate constants were then determined from the gradient of kobs vs [H2O2] (Fig. 1 C, D). The rate constant for the reaction between SeCA and H2O2 was
Discussion
HOCl, H2O2 and 1O2 can induce damage to cellular constituents and induce dysfunction and cell death; these reactions contribute to both the killing of pathogens by the innate immune system and also human disease [19,26,37]. Antioxidants have been proposed to modulate damage in various human pathologies. Selenium-containing compounds have generated particular interest, because of their high rate constants for reaction with some oxidants [5,8,[38], [39], [40], [41], [42]]. This study has
Acknowledgements
The authors gratefully acknowledge generous financial support from the Novo Nordisk Foundation (grant no: NNF13OC0004294 to MJD) and a WHRI International Fellow co-funded by Marie Curie Actions (PCOFUND-GA-2013-608765) to LC. Prof. K. Indira Priyadarsini (Bhabha Atomic Research Centre, Mumbai, India) and Prof. Vimal Jain (UM-DAE Centre for Excellence in Basic Sciences, University of Mumbai, Mumbai, India) are gratefully acknowledged for providing samples of some of the selenium compounds used
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