Decreased Zinc Affinity of Amyotrophic Lateral Sclerosis‐Associated Superoxide Dismutase Mutants Leads to Enhanced Catalysis of Tyrosine Nitration by Peroxynitrite

Crow, John P.; Sampson, Jacinda B.; Zhuang, Yingxin; Thompson, John A.; Beckman, Joseph S.

doi:10.1046/j.1471-4159.1997.69051936.x

Cited by 452 publications

(374 citation statements)

References 34 publications

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Section: Discussionsupporting

confidence: 61%

“…The inability of either compound to induce strong hepatic protein nitration in the SOD1-/-mice as in the WT indicates a general need for SOD1 to catalyze the process in vivo. Because the catalytic role of SOD1 in protein nitration has been shown in vitro [9,10,40,50], our results provide direct evidence for such a role of SOD1 in vivo.The diminished hepatic protein nitration in the SOD1-/-mice was unlikely due to a limited NO formation or secondary changes associated with SOD1 knockout. Both treatments of APAP and LPS resulted in similar differences in hepatic protein nitration between the SOD1-/-and WT mice, despite a large variation (0 to 79%) of genotype differences in plasma NO concentrations.…”

supporting

confidence: 61%

“…These paradoxical findings strongly suggest that SOD1 may exert functions more than just superoxide dismutation. In fact, SOD1 was shown to promote peroxynitrite-mediated nitrotyrosine formation in vitro [9,10]. …”

mentioning

confidence: 99%

“…Despite these pathological implications, the earlier observed in vitro catalytic role of SOD1 in nitrotyrosine formation [9,10] has been largely dismissed or neglected. There has been no experiment to test a cause-effect relationship between SOD1 and protein nitration in vivo.…”

mentioning

confidence: 99%

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Role of copper,zinc-superoxide dismutase in catalyzing nitrotyrosine formation in murine liver

Zhu

Zhang

Roneker

et al. 2008

Free Radical Biology and Medicine

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The solely known function of Cu,Zn-superoxide dismutase (SOD1) is to catalyze the dismutation of superoxide anion into hydrogen peroxide. Our objective was to determine if SOD1 catalyzed murine liver protein nitration induced by acetaminophen (APAP) and lipopolysaccharide (LPS). Liver and plasma samples were collected from young adult SOD1 knockout mice (SOD1-/-) and wild-type (WT) mice at 5 or 6 h after an ip injection of saline, APAP, or LPS. Hepatic nitrotyrosine formation was induced by APAP and LPS only in the WT mice. The diminished hepatic protein nitration in the SOD1-/-mice was not directly related to plasma nitrite and nitrate concentrations. Similar genotype differences were seen in liver homogenates treated with a bolus of peroxynitrite. Adding only the holo, but not the apo-SOD1 enzyme into the liver homogenates enhanced the reaction in an activity-dependent fashion and nearly eliminated the genotype difference at the high doses. Mass Spectrometry showed 4 more nitrotyrosine residues in bovine serum albumin and 10 more nitrated protein candidates in the SOD1-/-liver homogenates by peroxynitrite with added SOD1. In conclusion, the diminished hepatic protein nitration mediated by APAP or LPS in the SOD1-/-mice was due to the lack of SOD1 activity per se. Keywords SOD1; Protein nitration; Acetaminophen; Peroxynitrite; Lipopolysaccharide; Mouse Although copper,zinc-superoxide dismutase (SOD1) has been widely considered a major intracellular antioxidant enzyme in mammals, its solely known function is to catalyze the conversion of superoxide anion into less active hydrogen peroxide. Indeed, SOD1 is protective against oxidative stress associated with acute paraquat toxicity, myocardial ischemia/reperfusion injury, and N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurodegeneration [1][2][3]. Mice deficient in SOD1 develop Address correspondence to: Xin Gen Lei, Department of Animal Science, Cornell University, Ithaca, NY 14853, Tel. 607-254-4703; Fax. 607-255-9829; E-Mail: XL20@cornell.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. [7,8]. These paradoxical findings strongly suggest that SOD1 may exert functions more than just superoxide dismutation. In fact, SOD1 was shown to promote peroxynitrite-mediated nitrotyrosine formation in vitro [9,10]. NIH Public AccessPeroxynitrite is formed by a rapid diffusion-limited, radical-radical coupling reaction between nitric oxide (NO) and superoxide anion [11,12] [24,25,33,34] provide us with an unprecedented opportunity to study the in vivo role of SOD1 in nitrotyrosine formation. Furtherm...

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Section: Discussionsupporting

confidence: 61%

supporting

confidence: 61%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Role of copper,zinc-superoxide dismutase in catalyzing nitrotyrosine formation in murine liver

Zhu

Zhang

Roneker

et al. 2008

Free Radical Biology and Medicine

View full text Add to dashboard Cite

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“…15 Absorbance at 500 nm was measured using a spectrofluorometer (SpectraMAX-Gemini, Molecular Devices, Sunnyvale, CA, USA). PAR in the absence of Zn 2 þ is associated with low basal absorbance.…”

Section: Zinc Assaymentioning

confidence: 99%

Genetic Elimination of eNOS Reduces Secondary Complications of Experimental Subarachnoid Hemorrhage

Sabri

Lass

et al. 2013

J Cereb Blood Flow Metab

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Delayed complications of subarachnoid hemorrhage (SAH) such as angiographic vasospasm, cortical spreading ischemia, microcirculatory dysfunction, and microthrombosis are reported in both patients and animal models of SAH. We demonstrated previously that SAH is associated with increased oxidative stress in the brain parenchyma, and that this correlates with dysfunction of endothelial nitric oxide synthase (eNOS) (homodimeric uncoupling). Uncoupling of eNOS exacerbated oxidative stress and enhanced nitric oxide (NO) depletion, and was associated with multiple secondary complications such as microthrombosis, neuronal apoptosis, and release of reactive oxygen species. Thus, we hypothesized that genetic abbrogation of eNOS would confer a beneficial effect on the brain after SAH. Using a prechiasmatic injection model of SAH, we show here that eNOS knockout (KO) significantly alleviates vasospasm of the middle cerebral artery and reduces superoxide production. Endothelial nitric oxide synthase KO also affected other nitric oxide synthase isoforms. It significantly increases neuron nitric oxide synthase expression but has no effect on inducible nitric oxide synthase. Endothelial nitric oxide synthase KO decreases Zn 2 þ release after SAH, reduces microthrombi formation, and prevent neuronal degeneration. This work is consistent with our findings where, after SAH, increased oxidative stress can uncouple eNOS via Zn 2 þ thiolate oxidation, or theoretically by depletion or oxidation of tetrahydrobiopterin, resulting in a paradoxical release of superoxide anion radical, further exacerbating oxidative stress and microvascular damage.

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Light and electron microscopic distribution of the AMPA receptor subunit, GluR2, in the spinal cord of control and G86R mutant superoxide dismutase transgenic mice

et al. 1998

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Excitotoxicity has been hypothesized to contribute to amyotrophic lateral sclerosis (ALS) neurodegeneration. The similar pattern of vulnerability in the spinal cord of mutant superoxide dismutase (SOD-1) transgenic mice and mice treated with excitotoxins supports a role for excitotoxicity in the mechanism of degeneration. The distribution of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) class of glutamate receptors (GluRs) with different calcium permeabilities has been proposed as an explanation for this differential vulnerability. GluR2 appears to be the dominant determinant of calcium permeability for AMPA receptors; thus, it is critical for their contribution to excitotoxic mechanisms. In this study, we investigate the distribution of GluR2 immunoreactivity in the spinal cord of control and SOD-1 transgenic mice. GluR2 immunoreactivity is present equally within vulnerable neurons (i.e., motor neurons and calretinin-immunoreactive neurons) as well as nonvulnerable neurons (i.e., calbindin-immunoreactive neurons and dorsal horn neurons). In addition, postembedding immunoelectron microscopy reveals that GluR2 is present in synapses of dorsal and ventral horn neurons and that the percentage of labeled synapses and numbers of immunogold particles per synapse do not vary between these spinal cord regions. Comparing control mice with SOD-1 transgenic mice, at both the light and the electron microscopic levels, the distribution and intensity of GluR2-immunoreactivity do not appear to be altered. These results suggest that the cellular and synaptic distribution of GluR2 is not a determinant of the selective vulnerability observed in SOD-1 transgenic mice or in ALS patients.

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Decreased Zinc Affinity of Amyotrophic Lateral Sclerosis‐Associated Superoxide Dismutase Mutants Leads to Enhanced Catalysis of Tyrosine Nitration by Peroxynitrite

Cited by 452 publications

References 34 publications

Role of copper,zinc-superoxide dismutase in catalyzing nitrotyrosine formation in murine liver

Role of copper,zinc-superoxide dismutase in catalyzing nitrotyrosine formation in murine liver

Genetic Elimination of eNOS Reduces Secondary Complications of Experimental Subarachnoid Hemorrhage

Light and electron microscopic distribution of the AMPA receptor subunit, GluR2, in the spinal cord of control and G86R mutant superoxide dismutase transgenic mice

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