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

Donzelli, Sonia; Espey, Michael Graham; Flores-Santana, Wilmarie; Switzer, Christopher; Yeh, Grace Chao; Huang, Jinming; Stuehr, Dennis J.; King, S. Bruce; Miranda, Katrina M.; Wink, David A.

doi:10.1016/j.freeradbiomed.2008.04.036

Cited by 76 publications

(74 citation statements)

References 67 publications

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“…Both NH 2 OH and hydroxyurea can be oxidized by peroxidases (33,69) [ Fig. 5 for NH 2 OH; a related two step process is suggested for hydroxyurea (69)].…”

Section: Pathways For Formation Of Endogenous Hnomentioning

confidence: 99%

“…Whether HNO will be capable of escaping the heme pocket seems to be protein dependent. A survey of heme proteins (33) showed that proteins such as Mb and myeloperoxidase, which have proximal histidine residues, can generate free HNO, as indicated by formation of sulfinamide. A lower affinity of the ferric heme for HNO may also correlate to a lower affinity for NO upon reductive nitrosylation.…”

Section: Pathways For Formation Of Endogenous Hnomentioning

confidence: 99%

“…HNO has been assumed to be an intermediate of SAHA oxidation by a peroxidase mechanism (139). Addition of HRP/H 2 O 2 /NH 2 OH to cells loaded with DAF resulted in an increase in fluorescence (33), indicating that HNO produced by this reaction can migrate into cells (42). Interestingly, HNO pharmacology has been shown to be effective with cardiovascular conditions in which inflammation will produce H 2 O 2 .…”

Section: Pathways For Formation Of Endogenous Hnomentioning

confidence: 99%

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The Specificity of Nitroxyl Chemistry Is Unique Among Nitrogen Oxides in Biological Systems

Flores-Santana

Salmon

Donzelli

et al. 2011

Antioxidants & Redox Signaling

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The importance of nitric oxide in mammalian physiology has been known for nearly 30 years. Similar attention for other nitrogen oxides such as nitroxyl (HNO) has been more recent. While there has been speculation as to the biosynthesis of HNO, its pharmacological benefits have been demonstrated in several pathophysiological settings such as cardiovascular disorders, cancer, and alcoholism. The chemical biology of HNO has been identified as related to, but unique from, that of its redox congener nitric oxide. A summary of these findings as well as a discussion of possible endogenous sources of HNO is presented in this review.

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“…Both NH 2 OH and hydroxyurea can be oxidized by peroxidases (33,69) [ Fig. 5 for NH 2 OH; a related two step process is suggested for hydroxyurea (69)].…”

Section: Pathways For Formation Of Endogenous Hnomentioning

confidence: 99%

Section: Pathways For Formation Of Endogenous Hnomentioning

confidence: 99%

Section: Pathways For Formation Of Endogenous Hnomentioning

confidence: 99%

See 1 more Smart Citation

The Specificity of Nitroxyl Chemistry Is Unique Among Nitrogen Oxides in Biological Systems

Flores-Santana

Salmon

Donzelli

et al. 2011

Antioxidants & Redox Signaling

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“…However, more recent evidence suggests that HNO may also be active endogenously (22,33,35,38), and therefore likely to be of physiological significance. Indeed a number of potential biosynthetic pathways for HNO generation have been identified, including a) direct oxidation of the nitric oxide synthase (NOS) intermediates hydroxylamine (8) and Nhydroxy-L-arginine (19); b) nitrosothiol decomposition (44); c) direct reduction of NO by either mitochondrial cytochrome c, ubiquinol, and=or xanthine oxidase (20,36), and d) by NOS in the absence of the cofactor tetrahydrobiopterin (BH 4 ) (1).…”

Section: Introductionmentioning

confidence: 99%

A Novel Role for HNO in Local and Spreading Vasodilatation in Rat Mesenteric Resistance Arteries

Yuill

Yarova

Kemp-Harper

et al. 2011

Antioxidants & Redox Signaling

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Nitric oxide-mediated vasodilatation has previously been attributed to the uncharged form of the molecule (NO ), but increasing evidence suggests that nitroxyl (HNO) may play a significant role in endothelium-dependent relaxation. The aim of this study was to investigate the mechanisms underlying HNO-mediated vasodilatation in phenylephrine pre-constricted pressurized (70 mmHg) mesenteric arteries, and on membrane currents in isolated smooth muscle cells using whole cell and perforated patch clamp recordings. Angeli's salt (AS: nitroxyl donor), evoked concentration-dependent vasodilatation that was insensitive to the NO scavengers carboxy-PTIO and hydroxocobalamin (HXC), but sensitive to either the HNO scavenger L-cysteine, K-channel blockers (4-AP and iberiotoxin), raised [K + ] o , or inhibition of soluble guanylyl cyclase (ODQ). AS-evoked smooth muscle hyperpolarization significantly augmented K V current in an ODQ sensitive manner, and also increased the BK Ca current. Importantly, 30 mM AS initiated conducted or spreading vasodilatation, and following blockade of endothelial K-channels (TRAM-34 and apamin), ACh was able to evoke similar L-cysteine-sensitive conducted dilatation. These data show that vasodilatation induced by HNO is mediated by both K V and BK Ca channels, and suggest a physiological role in vasodilatation through the vasculature.

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“…But the significance of "free" HNO in nature is as yet uncertain (22). Although several biological pathways for HNO formation have been suggested, e.g., via nitrosothiol decomposition (23,24) or enzymatic malfunction (25)(26)(27), no true physiological role for endogenous HNO has been accepted. Following our previous characterization of the trapping of free HNO by various O 2 -binding globins (11), we hypothesized that HNO might similarly interact with O 2 -dependent oxygenases; we herein report the unprecedented substitution of HNO for O 2 in the activity of Mn-QDO, resulting in the incorporation of the nitroxyl-derived N atom into the product, which we denote as nitroxygenase activity.…”

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

Cited by 76 publications

References 67 publications

The Specificity of Nitroxyl Chemistry Is Unique Among Nitrogen Oxides in Biological Systems

The Specificity of Nitroxyl Chemistry Is Unique Among Nitrogen Oxides in Biological Systems

A Novel Role for HNO in Local and Spreading Vasodilatation in Rat Mesenteric Resistance Arteries

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

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