Poster Presentation RACI Biomolecular Division Conference 2013

Oxidant scavenging by selenium and sulfur compounds: absolute rate constants and assessment of biological relevance (#64)

Corin Storkey 1 , David I Pattison 1 , Ojia Skaff 1 , Luke Carroll 1 , Clare L Hawkins 1 , Shanlin Fu 2 , Carl H Schiesser 3 , Michael J Davies 1
  1. The Heart Research Institute, Newtown, Sydney, NSW, Australia
  2. Department of Chemistry and Forensic Science, University of Technology, Sydney, NSW, Australia
  3. School of Chemistry, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria, Australia

The human immune system uses powerful oxidants including peroxynitrous acid (ONOOH) and hypochlorous acid (HOCl) to kill invading pathogens. These oxidants also react with important biological targets including thiols, thioethers, lipids, proteins, carbohydrates and nucleic acids. Excessive, mistimed or inappropriate production of these species has been linked to human pathologies linked with chronic inflammation including cardiovascular disease, reperfusion injury, circulatory shock, inflammation and neurodegeneration.

            We have determined rate constants for reaction of these oxidants with low-molecular-mass selenium compounds to determine whether these can compete with endogenous thiols and thioethers, and thereby act as biological protective agents.

            Low-molecular-mass selenols such as selenocysteine (Sec) react with ONOOH with k ~2 x 105M-1s-1, considerably faster than those for the most susceptible biological targets including Cys residues (k 2 x 103 M-1s-1) and the key intracellular thiol tripeptide glutathione (GSH, k 8 x 102 M-1s-1). This enhanced reactivity of seleno species extends to the corresponding selenoethers / thioethers (cf. k 2 x 103 M-1s-1 for selenomethionine, 2 x 102 M-1s-1 for methionine).

            Rate constants for HOCl with seleno species were higher with k 1-2 x 108 M−1s−1. Those for the corresponding sulfur species are considerably lower (106–107 M−1s−1). Rate constants for hypobromous acid (HOBr) were ~10 times lower, and for hypothiocyanous acid (HOSCN) in the range 102–105M−1s−1.

            Product analysis indicates that micromolar concentrations of selenosugars can decrease damage to both isolated and human plasma proteins, as measured by decreased loss of Met, His, Trp, Lys, and Tyr residues and product formation.

            Selenol and selenoether oxidation is readily reversed by both low-molecular-mass thiols and enzymes, indicating that these species can act as catalytic protective agents. 

These data indicate that seleno compounds can modulate oxidative damage at sites of inflammation, and potentially protect against human disease.