Mechanism of copper-catalyzed autoxidation of cysteine

Kachur, Alexander V.; Koch, Cameron J.; Biaglow, John E.

doi:10.1080/10715769900300571

Cited by 105 publications

(110 citation statements)

References 14 publications

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“…One possibility is the scheme proposed in Reactions 4 -6, in which the sulfenic acid would react with more thiol to give the disulfide and the SOD would be available to complex more cysteine. This is similar to the inner sphere mechanism proposed for free Cu 2ϩ , although there is equivocal evidence for at least some superoxide production (13,(15)(16)(17)30 By generating hydrogen peroxide, the reaction between Cu,Zn-SOD and thiols is a potential source of reactive oxidants in biological systems. The toxicity of thiols to cells is well documented, with the aminothiols, cysteine and cysteamine, being most potent (18,19,(33)(34)(35)(36)(37)(38).…”

Section: Fig 4 Rates Of Oxidation Of Cysteine (Q) and Cysteamine (E)mentioning

confidence: 75%

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Thiol Oxidase Activity of Copper,Zinc Superoxide Dismutase

Winterbourn

Peskin

Parsons-Mair

2002

Journal of Biological Chemistry

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The ability of copper,zinc superoxide dismutase (Cu,Zn-SOD) to catalyze autoxidation of cysteine and other thiols was investigated by measuring thiol loss and oxygen consumption. The reaction occurred equally well with the bovine and human enzymes and produced hydrogen peroxide and the corresponding disulfide. It did not occur with manganese SOD and is not, therefore, due to the dismutase activity of the enzyme. Cysteine and cysteamine were highly reactive: the K m for cysteine was 1.4 mM and V max (with 40 g/ml SOD) 35 M/ min; the equivalent values for cysteamine (with 20 g/ml SOD) were 1.4 mM and 36 M/min. With 1 mM thiol and 40 g/ml SOD, rates of oxidation of other thiols (M/min) were as follows: GSH, 1.0; dithiothreitol, 2.1; dihydrolipoic acid, 1.7; homocysteine, 1.6; cys-gly, 1.4; penicillamine, 0.6; and N-acetylcysteine, 0.1. SOD-mediated oxidation of cysteine, in the absence of chelating agents, proceeded only after a variable lag phase. The lag was decreased but not eliminated with Chelex-treated reagents and is attributed to interference by submicromolar concentrations of iron and possibly other transition metal ions. SOD-catalyzed oxidation of the other thiols was variably affected by adventitious metal ions and chelating agents. Reactions were all performed in the presence of desferrioxamine to obviate these effects. SOD-catalyzed oxidation of GSH and homocysteine was enhanced by cysteine through a thiol-disulfide exchange mechanism. This study characterizes a novel pro-oxidant thiol oxidase activity of Cu,Zn-SOD. It is a potential source of reactive oxidants and may contribute to the cytotoxicity of reactive thiols such as cysteine and cysteamine.

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Section: Fig 4 Rates Of Oxidation Of Cysteine (Q) and Cysteamine (E)mentioning

confidence: 75%

“…GSH and other thiols can also scavenge radicals and in combination with SOD constitute an efficient radical removal system (8 -12). However, thiols can act as pro-oxidants by undergoing autoxidation to produce hydrogen peroxide (13)(14)(15)(16)(17). The reaction is metal-catalyzed, with copper being a particularly effective catalyst.…”

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confidence: 99%

Thiol Oxidase Activity of Copper,Zinc Superoxide Dismutase

Winterbourn

Peskin

Parsons-Mair

2002

Journal of Biological Chemistry

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“…Initially, copper-DTT complexes rapidly form in a reversible and ROS-independent fashion. Then, the copper-DTT complexes oxidize and generate ROS (38,40). This ROS production, however, is characterized by comparatively slow kinetics and can be significantly inhibited by a molar excess of DTT over copper (40), as reflected by low copper/DTT ratios in our cell-free system.…”

Section: Figurementioning

confidence: 98%

Liver mitochondrial membrane crosslinking and destruction in a rat model of Wilson disease

Zischka

Lichtmannegger²,

Schmitt³

et al. 2011

J. Clin. Invest.

177

168

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Wilson disease (WD) is a rare hereditary condition that is caused by a genetic defect in the copper-transportingATPase ATP7B that results in hepatic copper accumulation and lethal liver failure. The present study focuses on the structural mitochondrial alterations that precede clinical symptoms in the livers of rats lacking Atp7b, an animal model for WD. Liver mitochondria from these Atp7b -/-rats contained enlarged cristae and widened intermembrane spaces, which coincided with a massive mitochondrial accumulation of copper. These changes, however, preceded detectable deficits in oxidative phosphorylation and biochemical signs of oxidative damage, suggesting that the ultrastructural modifications were not the result of oxidative stress imposed by copper-dependent Fenton chemistry. In a cell-free system containing a reducing dithiol agent, isolated mitochondria exposed to copper underwent modifications that were closely related to those observed in vivo. In this cell-free system, copper induced thiol modifications of three abundant mitochondrial membrane proteins, and this correlated with reversible intramitochondrial membrane crosslinking, which was also observed in liver mitochondria from Atp7b -/-rats. In vivo, copper-chelating agents reversed mitochondrial accumulation of copper, as well as signs of intra-mitochondrial membrane crosslinking, thereby preserving the functional and structural integrity of mitochondria. Together, these findings suggest that the mitochondrion constitutes a pivotal target of copper in WD.

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“…47 Transition metal ions catalyze the cysteine oxidation by generating reactive intermediates such as radicals. 9,10 Copper plays the role of electron carrier from thiol to oxygen where the complexation of copper(II) is the first step in the oxidation process. In both experiments with the copper electrode and with the copper(II) salt, the oxidations were important, even though they were rather higher in the presence of copper(II) salt.…”

Section: Kctcca Reactions With Zn 2+ and Other Reactionsmentioning

confidence: 99%

The role of copper in cysteine oxidation: study of intra- and inter-molecular reactions in mass spectrometry

Prudent

Girault

2009

Metallomics

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Cysteine-containing peptide oxidation was studied both by using an inert platinum electrode and a sacrificial electrode (copper or zinc) generating metallic ions in electrospray ionization mass spectrometry (ESI-MS). Using peptides containing one, two and three cysteines, we have compared the different chemical and electrochemical oxidation pathways of cysteine (RS ÀII H) to cystine (RS ÀI S ÀI R) and to sulfenic, sulfinic and sulfonic acid (RS 0 OH, RS II O 2 H and RS IV O 3 H, respectively). In the absence of copper ions, intra-molecular reactions were the most abundant, whereas inter-molecular reactions were found to be enhanced by the presence of copper ions. These cations favor the formation of 2 : 1 (peptide : copper) complexes compared to 1 : 1 complexes, thus enhancing the formation of inter-molecular bridges. This study highlights the importance of the position of cysteine inside a peptide during disulfide bridge formation.

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Mechanism of copper-catalyzed autoxidation of cysteine

Cited by 105 publications

References 14 publications

Thiol Oxidase Activity of Copper,Zinc Superoxide Dismutase

Thiol Oxidase Activity of Copper,Zinc Superoxide Dismutase

Liver mitochondrial membrane crosslinking and destruction in a rat model of Wilson disease

The role of copper in cysteine oxidation: study of intra- and inter-molecular reactions in mass spectrometry

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