Crystal structure of nitrated human manganese superoxide dismutase: Mechanism of inactivation

Quint, Patrick; Reutzel, Robbie; Mikulski, Rose; McKenna, Robert; Silverman, David N.

doi:10.1016/j.freeradbiomed.2005.08.045

Cited by 84 publications

(69 citation statements)

References 37 publications

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“…An illustrative example is the mitochondrial manganese superoxide dismutase (Mn-SOD), which catalyzes the disproportionation of superoxide to O 2 and H 2 O 2 . Mn-SOD was found to undergo almost complete inhibition when nitrated at Tyr 34 (MacMillan-Crow and Thompson, 1999;Quint et al, 2006;Xu et al, 2006). The crystal structures of native Mn-SOD and nitrated Mn-SOD were found to be closely superimposable; however, the nitration of Tyr 34 disrupts the Hbonding network at the active site, which may be the reason for protein inactivation (Quint et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…Mn-SOD was found to undergo almost complete inhibition when nitrated at Tyr 34 (MacMillan-Crow and Thompson, 1999;Quint et al, 2006;Xu et al, 2006). The crystal structures of native Mn-SOD and nitrated Mn-SOD were found to be closely superimposable; however, the nitration of Tyr 34 disrupts the Hbonding network at the active site, which may be the reason for protein inactivation (Quint et al, 2006). A crystal structure was also obtained for nitrated glutathione reductase (GR) (Savvides et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Proteomic analysis of age dependent nitration of rat cardiac proteins by solution isoelectric focusing coupled to nanoHPLC tandem mass spectrometry

Hong

Gokulrangan

Schöneich

2007

Experimental Gerontology

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Protein nitration occurs as a result of oxidative stress induced by reactive oxygen (ROS) and reactive nitrogen species (RNS). Therefore, protein nitration serves as a hallmark for protein oxidation in vivo. We have previously reported on age dependent protein nitration in cardiac tissue of Fisher 344 BN-F1 rats analyzed by two-dimensional gel electrophoresis; however, only one specific nitration site was identified (Kanski et al., 2005a). In the present report, we used solution phase isoelectric focusing (IEF) followed by nanoHPLC-ESI-MS/MS that allowed us to obtain good MS/MS data to identify specific sites of protein nitration in cardiac tissue. As expected, more nitrated proteins were detected in cardiac tissue of old rats, including myosin heavy chain, neurofibromin, tropomyosin and nebulin-related anchoring protein. The post-translational modification of these cytoskeletal proteins may provide some rationale for the age-dependent functional decline of the heart.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Proteomic analysis of age dependent nitration of rat cardiac proteins by solution isoelectric focusing coupled to nanoHPLC tandem mass spectrometry

Hong

Gokulrangan

Schöneich

2007

Experimental Gerontology

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“…its pK a drops from ϳ10.3 to 7.3) (41), and therefore, the reaction of O 2 . with manganese is hindered by both steric constraints and electrostatic repulsion (63,64). The nitration of Mn-SOD Tyr-34 is strongly supportive of the intramitochondrial peroxynitrite formation (65,66).…”

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confidence: 99%

Peroxynitrite, a Stealthy Biological Oxidant

Radí

2013

Journal of Biological Chemistry

714

444

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Peroxynitrite is the product of the diffusion-controlled reaction of nitric oxide and superoxide radicals. Peroxynitrite, a reactive short-lived peroxide with a pK a of 6.8, is a good oxidant and nucleophile. It also yields secondary free radical intermediates such as nitrogen dioxide and carbonate radicals. Much of nitric oxide-and superoxide-dependent cytotoxicity resides on peroxynitrite, which affects mitochondrial function and triggers cell death via oxidation and nitration reactions. Peroxynitrite is an endogenous toxicant but is also a cytotoxic effector against invading pathogens. The biological chemistry of peroxynitrite is modulated by endogenous antioxidant mechanisms and neutralized by synthetic compounds with peroxynitrite-scavenging capacity.

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“…5 Despite the accumulated evidence for protein nitration, its biological consequences are not well understood on a molecular level primarily due to scarcity of the 3D structures of nitrated proteins. So far crystal structures have been solved only for a few proteins with a nitrated tyrosine [6][7][8][9] and none with a nitrated tryptophan. To overcome the limited structural information on nitrated proteins, we employed a computational approach to probe the structural perturbations induced by protein nitration.…”

Section: Introductionmentioning

confidence: 99%

“…Molecular dynamics simulations of nitrated proteins. So far crystal structures have been solved only for a few proteins with a nitrotyrosine, i.e., Cu,Zn-superoxide dismutase (CuZn-SOD), 6 MnSOD, 7 glutathione reductase, 8 and laccase. 9 Structures of nitrotryptophan-containing proteins are not available yet.…”

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confidence: 99%

Force Field Parameters for 3-Nitrotyrosine and 6-Nitrotryptophan

Myung¹,

Han

2010

Bulletin of the Korean Chemical Society

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Nitration of tyrosine and tryptophan residues is common in cells under nitrative stress. However, physiological consequences of protein nitration are not well characterized on a molecular level due to limited availability of the 3D structures of nitrated proteins. Molecular dynamics (MD) simulation can be an alternative tool to probe the structural perturbations induced by nitration. In this study we developed molecular mechanics parameters for 3-nitrotyrosine (NIY) and 6-nitrotryptophan (NIW) that are compatible with the AMBER-99 force field. Partial atomic charges were derived by using a multi-conformational restrained electrostatic potential (RESP) methodology that included the geometry optimized structures of both α-and β-conformers of a capped tripeptide ACE-NIY-NME or ACE-NIW-NME. Force constants for bonds and angles were adopted from the generalized AMBER force field. Torsional force constants for the proper dihedral C-C-N-O and improper dihedral C-O-N-O of the nitro group in NIY were determined by fitting the torsional energy profiles obtained from quantum mechanical (QM) geometry optimization with those from molecular mechanical (MM) energy minimization. Force field parameters obtained for NIY were transferable to NIW so that they reproduced the QM torsional energy profiles of ACE-NIW-NME accurately. Moreover, the QM optimized structures of the tripeptides containing NIY and NIW were almost identical to the corresponding structures obtained from MM energy minimization, attesting the validity of the current parameter set. Molecular dynamics simulations of thioredoxin nitrated at the single tyrosine and tryptophan yielded well-behaved trajectories suggesting that the parameters are suitable for molecular dynamics simulations of a nitrated protein.

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Crystal structure of nitrated human manganese superoxide dismutase: Mechanism of inactivation

Cited by 84 publications

References 37 publications

Proteomic analysis of age dependent nitration of rat cardiac proteins by solution isoelectric focusing coupled to nanoHPLC tandem mass spectrometry

Proteomic analysis of age dependent nitration of rat cardiac proteins by solution isoelectric focusing coupled to nanoHPLC tandem mass spectrometry

Peroxynitrite, a Stealthy Biological Oxidant

Force Field Parameters for 3-Nitrotyrosine and 6-Nitrotryptophan

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