TY - JOUR

T1 - Preventing protein oxidation with sugars

T2 - scavenging of hypohalous acids by 5-selenopyranose and 4-selenofuranose derivatives

AU - Storkey, Corin

AU - Pattison, David I

AU - White, Jonathan M

AU - Schiesser, Carl H

AU - Davies, Michael Jonathan

PY - 2012/11/19

Y1 - 2012/11/19

N2 - Heme peroxidases including myeloperoxidase (MPO) are released at sites of inflammation by activated leukocytes. MPO generates hypohalous acids (HOX, X = Cl, Br, SCN) from H(2)O(2); these oxidants are bactericidal and are key components of the inflammatory response. However, excessive, misplaced or mistimed production can result in host tissue damage, with this implicated in multiple inflammatory diseases. We report here methods for the conversion of simple monosaccharide sugars into selenium- and sulfur-containing species that may act as potent water-soluble scavengers of HOX. Competition kinetic studies show that the seleno species react with HOCl with rate constants in the range 0.8-1.0 × 10(8) M(-1) s(-1), only marginally slower than those for the most susceptible biological targets including the endogenous antioxidant, glutathione. The rate constants for the corresponding sulfur-sugars are considerably slower (1.4-1.9 × 10(6) M(-1) s(-1)). Rate constants for reaction of the seleno-sugars with HOBr are ~8 times lower than those for HOCl (1.0-1.5 × 10(7) M(-1) s(-1)). These values show little variation with differing sugar structures. Reaction with HOSCN is slower (~10(2) M(-1) s(-1)). The seleno-sugars decreased the extent of HOCl-mediated oxidation of Met, His, Trp, Lys, and Tyr residues, and 3-chlorotyrosine formation, on both isolated bovine serum albumin and human plasma proteins, at concentrations as low as 50 μM. These studies demonstrate that novel selenium (and to a lesser extent, sulfur) derivatives of monosaccharides could be potent modulators of peroxidase-mediated damage at sites of acute and chronic inflammation, and in multiple human pathologies.

AB - Heme peroxidases including myeloperoxidase (MPO) are released at sites of inflammation by activated leukocytes. MPO generates hypohalous acids (HOX, X = Cl, Br, SCN) from H(2)O(2); these oxidants are bactericidal and are key components of the inflammatory response. However, excessive, misplaced or mistimed production can result in host tissue damage, with this implicated in multiple inflammatory diseases. We report here methods for the conversion of simple monosaccharide sugars into selenium- and sulfur-containing species that may act as potent water-soluble scavengers of HOX. Competition kinetic studies show that the seleno species react with HOCl with rate constants in the range 0.8-1.0 × 10(8) M(-1) s(-1), only marginally slower than those for the most susceptible biological targets including the endogenous antioxidant, glutathione. The rate constants for the corresponding sulfur-sugars are considerably slower (1.4-1.9 × 10(6) M(-1) s(-1)). Rate constants for reaction of the seleno-sugars with HOBr are ~8 times lower than those for HOCl (1.0-1.5 × 10(7) M(-1) s(-1)). These values show little variation with differing sugar structures. Reaction with HOSCN is slower (~10(2) M(-1) s(-1)). The seleno-sugars decreased the extent of HOCl-mediated oxidation of Met, His, Trp, Lys, and Tyr residues, and 3-chlorotyrosine formation, on both isolated bovine serum albumin and human plasma proteins, at concentrations as low as 50 μM. These studies demonstrate that novel selenium (and to a lesser extent, sulfur) derivatives of monosaccharides could be potent modulators of peroxidase-mediated damage at sites of acute and chronic inflammation, and in multiple human pathologies.

KW - Free Radical Scavengers

KW - Hypochlorous Acid

KW - Molecular Structure

KW - Monosaccharides

KW - Organoselenium Compounds

KW - Oxidation-Reduction

KW - Peroxidase

KW - Thiocyanates

U2 - 10.1021/tx3003593

DO - 10.1021/tx3003593

M3 - Journal article

C2 - 23075063

VL - 25

SP - 2589

EP - 2599

JO - Chemical Research in Toxicology

JF - Chemical Research in Toxicology

SN - 0893-228X

IS - 11

ER -