The Alleged Role of Nitroxyl in Certain Reactions of Aldehydes and Alkyl Halides<sup>1</sup>

Smith, Peter A.; Hein, George E.

doi:10.1021/ja01506a043

Cited by 103 publications

(69 citation statements)

References 2 publications

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“…Similarly, the incubation of a nitroxyl donor, Angeli's salt (26,36), with ferri-cyt c⅐TOCL complexes caused the formation of typical EPR signals of heme-Fe(II)-nitrosylated species (Fig. 1B).…”

Section: Resultsmentioning

confidence: 86%

“…These established that the native hexacoordinate state includes axial ligation of Met 80 to the heme that can be ruptured and replaced by His 26 and His 33 under destabilizing conditions (1, 47). Five cooperative and hierarchic folding units of different stabilities have been revealed in horse heart cyt c such that substructures of higher stability are dependent on the unfolding of lower stability substructures whereby destabilization of Met 80 -containing domain displays the lowest stability (46,48).…”

Section: Discussionmentioning

confidence: 99%

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Nitric Oxide Inhibits Peroxidase Activity of Cytochrome c· Cardiolipin Complex and Blocks Cardiolipin Oxidation

Vlasova

Tyurin

Kapralov

et al. 2006

Journal of Biological Chemistry

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The increased production of NO during the early stages of apoptosis indicates its potential involvement in the regulation of programmed cell death through yet to be identified mechanisms. Recently, an important role for catalytically competent peroxidase form of pentacoordinate cytochrome c (cyt c) in a complex with a mitochondriaspecific phospholipid, cardiolipin (CL), has been demonstrated during execution of the apoptotic program. Because the cyt c⅐CL complex acts as CL oxygenase and selectively oxidizes CL in apoptotic cells in a reaction dependent on the generation of protein-derived (tyrosyl) radicals, we hypothesized that binding and nitrosylation of cyt c regulates CL oxidation. Here we demonstrate by low temperature electron paramagnetic resonance spectroscopy that CL facilitated interactions of ferro-and ferri-states of cyt c with NO and NO ؊ , respectively, to yield a mixture of penta-and hexa-coordinate nitrosylated cyt c. In the nitrosylated cyt c⅐CL complex, NO chemically reacted with H 2 O 2 -activated peroxidase intermediates resulting in their reduction. A dose-dependent quenching of H 2 O 2 -induced protein-derived radicals by NO donors was shown using direct electron paramagnetic resonance measurements as well as immuno-spin trapping with antibodies against protein 5,5-dimethyl-1-pyrroline N-oxide-nitrone adducts. In the presence of NO donors, H 2 O 2 -induced oligomeric forms of cyt c positively stained for 3-nitrotyrosine confirming the reactivity of NO toward tyrosyl radicals of cyt c. Interaction of NO with the cyt c⅐CL complex inhibited its peroxidase activity with three different substrates: CL, etoposide, and 3,3-diaminobenzidine. Given the importance of CL oxidation in apoptosis, mass spectrometry analysis was utilized to assess the effects of NO on oxidation of 1,12,2-tertalinoleoyl cardiolipin. NO effectively inhibited 1,12,2-tertalinoleoyl cardiolipin oxidation catalyzed by the peroxidase activity of cyt c. Thus, NO can act as a regulator of peroxidase activity of cyt c⅐CL complexes.

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Section: Resultsmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Nitric Oxide Inhibits Peroxidase Activity of Cytochrome c· Cardiolipin Complex and Blocks Cardiolipin Oxidation

Vlasova

Tyurin

Kapralov

et al. 2006

Journal of Biological Chemistry

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“…Gas chromatographic headspace analysis [16] confirmed a 13% yield of N 2 O, which forms upon dehydration of the HNO dimer (Eq. 3) [39,40].…”

Section: Resultsmentioning

confidence: 99%

Generation of nitroxyl by heme protein-mediated peroxidation of hydroxylamine but not N-hydroxy-L-arginine

Donzelli

Espey

Flores-Santana

et al. 2008

Free Radical Biology and Medicine

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The chemical reactivity, toxicology and pharmacological responses to nitroxyl (HNO) are often distinctly different from those of nitric oxide (NO). The discovery that HNO donors may have pharmacological utility for treatment of cardiovascular disorders such as heart failure and ischemia reperfusion has led to increased speculation of potential endogenous pathways for HNO biosynthesis. Here, the ability of heme proteins to utilize H 2 O 2 to oxidize hydroxylamine (NH 2 OH) or N-hydroxy-L-arginine (NOHA) to HNO was examined. Formation of HNO was evaluated with a recently developed selective assay in which the reaction products in the presence of reduced glutathione (GSH) were quantified by HPLC. Release of HNO from the heme pocket was indicated by formation of sulfinamide (GS(O)NH 2 ), while the yields of nitrite and nitrate signified the degree of intramolecular recombination of HNO with the heme. Formation of GS(O)NH 2 was observed upon oxidation of NH 2 OH, whereas NOHA, the primary intermediate in oxidation of L-arginine by NO synthase, was apparently resistant to oxidation by the heme proteins utilized. In the presence of NH 2 OH, the highest yields of GS(O)NH 2 were observed with proteins in which the heme was coordinated to a histidine (horseradish peroxidase, lactoperoxidase, myeloperoxidase, myoglobin and hemoglobin) in contrast to a tyrosine (catalase) or cysteine (cytochrome P450). That peroxidation of NH 2 OH by horseradish peroxidase produced free HNO, which was able to affect intracellular targets, was verified by conversion of 4,5-diaminofluorescein to the corresponding fluorophore within intact cells.

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“…Negative ion LC-MS analysis of the resulting product mixtures shows complete conversion of quercetin (301 m∕z) to a new dominant product ion (134 m∕z) that matches a C 7 H 4 O 2 N − anion; LC-MS retention time and fragmentation pattern is consistent with 3,4-dihydroxybenzonitrile, as confirmed with an authentic sample of the product. The use of 15 N-labeled AS (specifically ½O 15 N 14 NO 2 −2 , SI Text, Synthesis and characterization of 15 N-labeled Angeli's Salt) (28) in analogous anaerobic assays results in 15 N-labeled product with 135 m∕z peak observable in the LC-MS (Fig. 2).…”

Section: Resultsmentioning

confidence: 99%

Nitrosyl hydride (HNO) replaces dioxygen in nitroxygenase activity of manganese quercetin dioxygenase

Kumar

Zapata

Ramirez

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Quercetin dioxygenase (QDO) catalyzes the oxidation of the flavonol quercetin with dioxygen, cleaving the central heterocyclic ring and releasing CO. The QDO from Bacillus subtilis is unusual in that it has been shown to be active with several divalent metal cofactors such as Fe, Mn, and Co. Previous comparison of the catalytic activities suggest that Mn(II) is the preferred cofactor for this enzyme. We herein report the unprecedented substitution of nitrosyl hydride (HNO) for dioxygen in the activity of Mn-QDO, resulting in the incorporation of both N and O atoms into the product. Turnover is demonstrated by consumption of quercetin and other related substrates under anaerobic conditions in the presence of HNO-releasing compounds and the enzyme. As with dioxygenase activity, a nonenzymatic base-catalyzed reaction of quercetin with HNO is observed above pH 7, but no enhancement of this basal reactivity is found upon addition of divalent metal salts. Unique and regioselective N-containing products ( 14 N∕ 15 N) have been characterized by MS analysis for both the enzymatic and nonenzymatic reactions. Of the several metallo-QDO enzymes examined for nitroxygenase activity under anaerobic condition, only the Mn(II) is active; the Fe(II) and Co(II) substituted enzymes show little or no activity. This result represents an enzymatic catalysis which we denote nitroxygenase activity; the unique reactivity of the Mn-QDO suggests a metalmediated electron transfer mechanism rather than metal activation of the substrate's inherent base-catalyzed reactivity.nitroxyl | quercetinase D ioxygenases are enzymes that incorporate both atoms of dioxygen into a targeted substrate, e.g., the enzyme catechol 1,2-dioxygenase cleaves the C-C bond between catechol's two hydroxyl groups forming the dicarboxylate cis,cis-muconic acid (1). Although highly divergent, there are two broadly defined classes of nonheme dioxygenases: those that directly bind dioxygen at the metal center or those in which dioxygen binds to the substrate that has been activated by interaction with the metal center (2). Such questions also apply to quercetin dioxygenase (QDO), which catalyzes the oxidation of the flavonol quercetin (1) with dioxygen ( Fig. 1). During turnover, QDO cleaves the central heterocyclic ring of quercetin, releasing CO, and yielding the corresponding depside. The QDO from Bacillus subtilis is unusual in that it has been shown to be active with several divalent metal cofactors such as Cu, Fe, Mn, and Co. Comparison of the catalytic activities suggest that Mn(II) is the preferred cofactor for this enzyme (3).The simple molecule nitrosyl hydride (HNO) is the singly reduced and protonated form of nitric oxide, NO. HNO has garnered much interest because it demonstrates a physiological reactivity distinctly different from its congener nitric oxide (4, 5). In a series of papers, we have reported the preparation and characterization of the HNO adduct of myoglobin (HNO-Mb) by reduction of 7) and by trapping of free HNO by deoxymyoglobin (Mb-Fe II ) (8)...

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The Alleged Role of Nitroxyl in Certain Reactions of Aldehydes and Alkyl Halides¹

Cited by 103 publications

References 2 publications

Nitric Oxide Inhibits Peroxidase Activity of Cytochrome c· Cardiolipin Complex and Blocks Cardiolipin Oxidation

Nitric Oxide Inhibits Peroxidase Activity of Cytochrome c· Cardiolipin Complex and Blocks Cardiolipin Oxidation

Generation of nitroxyl by heme protein-mediated peroxidation of hydroxylamine but not N-hydroxy-L-arginine

Nitrosyl hydride (HNO) replaces dioxygen in nitroxygenase activity of manganese quercetin dioxygenase

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The Alleged Role of Nitroxyl in Certain Reactions of Aldehydes and Alkyl Halides1

Cited by 103 publications

References 2 publications

Nitric Oxide Inhibits Peroxidase Activity of Cytochrome c· Cardiolipin Complex and Blocks Cardiolipin Oxidation

Nitric Oxide Inhibits Peroxidase Activity of Cytochrome c· Cardiolipin Complex and Blocks Cardiolipin Oxidation

Generation of nitroxyl by heme protein-mediated peroxidation of hydroxylamine but not N-hydroxy-L-arginine

Nitrosyl hydride (HNO) replaces dioxygen in nitroxygenase activity of manganese quercetin dioxygenase

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The Alleged Role of Nitroxyl in Certain Reactions of Aldehydes and Alkyl Halides¹