Nitro-oleic Acid, a Novel and Irreversible Inhibitor of Xanthine Oxidoreductase

Kelley, Eric E.; Batthyány, Carlos; Hundley, Nicholas J.; Woodcock, Steven R.; Bonacci, Gustavo; Rio, J. Mauricio Del; Schöpfer, Francisco J.; Lancaster, Jack R.; Freeman, Bruce Α.; Tarpey, Margaret M.

doi:10.1074/jbc.m802402200

Cited by 75 publications

(77 citation statements)

References 39 publications

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“…Consistent with this notion, nitroalkenes alkylate multiple functionally significant cysteines in the transcriptional regulatory protein Keap1, the p65 subunit of NFB, and the ligand binding domain of PPAR␥, leading to the regulation of Ͼ300 genes critical for metabolic, antioxidant defense, and tissue repair responses (12,15,52). Although electrophilic reactivity and signaling actions are often similar for NO 2 -OA, NO 2 -LA, NO 2 -CLA, and NO 2 -arachidonic acid, there are also unique and functionally significant reactions of NO 2 -OA with xanthine oxidoreductase and NO 2 -arachidonic acid with cyclooxygenase (53,54).…”

Section: Discussionmentioning

confidence: 99%

Modulation of Nitro-fatty Acid Signaling

Vitturi¹,

Chen²,

Woodcock³

et al. 2013

Journal of Biological Chemistry

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Background: Nitroalkenes are electrophilic anti-inflammatory mediators that signal via Michael addition and are metabolized in vivo. Results: Prostaglandin reductase-1 is identified as a nitroalkene reductase. Conclusion: Prostaglandin reductase-1 reduces fatty acid nitroalkenes to nitroalkanes, inactivating electrophilic reactivity. Significance: A mammalian enzyme is identified that metabolizes fatty acid nitroalkenes in vivo to silence their signaling reactions.

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Section: Discussionmentioning

confidence: 99%

Modulation of Nitro-fatty Acid Signaling

Vitturi¹,

Chen²,

Woodcock³

et al. 2013

Journal of Biological Chemistry

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“…Potential mechanisms underlying these actions include a ) inhibition of neutrophil function and platelet activation ( 43,44 ), b ) serving as partial agonists for PPAR ␥ ( 14,15,(45)(46)(47), c ) inhibition of cytokine expression via inhibition of DNA binding by the p65 unit of NF-B ( 48 ), and d ) upregulation of phase 2 gene expression via Keap1/Nrf2-dependent ( 5,49,50 ) and -independent mechanisms ( 51 ). Critical pro-infl ammatory enzymatic activities are also inhibited by fatty acid nitroalkenes, including xanthine oxidoreductase and cyclooxygenase-2 ( 52,53 ). These actions result in antiinfl ammatory responses in diverse animal models of disease including limiting restenosis after vessel injury ( 54 ), attenuation of weight gain and loss of insulin sensitivity in murine models of metabolic syndrome ( 6, 55 ), inhibition of sepsis-induced renal failure ( 56 ), prevention of ischemia-reperfusion injury ( 31,32,57 ), reduction of plaque formation in a murine ApoE Ϫ / Ϫ atherosclerosis model, and the reduction of chemically-induced infl ammatory bowel disease ( 47 ).…”

Section: Discussionmentioning

confidence: 99%

Characterization and quantification of endogenous fatty acid nitroalkene metabolites in human urine

Salvatore

Vitturi

Baker

et al. 2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org biomolecule nitration ( 1 ). Nitroalkene substituents are electrophilic and promote Michael addition of fatty acids with biological nucleophiles such as cysteine and histidine. The extent, rate, and reversibility of these reactions will be dictated both by the concentration and reactivity of individual nucleophiles. In this regard, protein structure and compartmentalization affect the reactivity of individual nucleophilic centers and will defi ne the molecular targets of electrophilic fatty acids.While enzymatically-oxygenated unsaturated fatty acids typically transduce anti-infl ammatory actions via specifi c g protein-coupled receptor ligand activity ( 2, 3 ), transcriptional responses to electrophilic fatty acids reveal that a broader array of signaling events are instigated ( 4, 5 ). The basis for this pleiotropy resides in the facile Michael addition of electrophilic fatty acid derivatives with nucleophilic centers of proteins that regulate structure and function ( 6 ). Functionally-signifi cant protein targets of electrophilic fatty acids include the transcriptional regulatory protein complex nuclear factor kappa B (NFkB), the

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“…In target tissues, NO 2 -FAs react with susceptible nucleophilic amino acids and post-translationally modify protein structure, function, and/or subcellular distribution. To date, NO 2 -FAs have been reported to inhibit xanthine oxidase (20) and nuclear factor jB (NFjB)-regulated gene expression, with the latter being the consequence of adduction of a critical cysteine in the p65 subunit (8). Simultaneously, NO 2 -FAs are partial agonists of the peroxisome proliferator-activated receptor (PPAR)-c (23,34), and Nrf2-dependent phase 2 gene expression can be activated by the NO 2 -FA-mediated adduction of select cysteine residues in the Nrf2 regulatory protein, Keap1 (19).…”

Section: Introductionmentioning

confidence: 99%

Electrophilic Fatty Acid Species Inhibit 5-Lipoxygenase and Attenuate Sepsis-Induced Pulmonary Inflammation

Awwad

Steinbrink²,

Frömel³

et al. 2014

Antioxidants & Redox Signaling

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Aims: The reaction of nitric oxide and nitrite-derived species with polyunsaturated fatty acids yields electrophilic fatty acid nitroalkene derivatives (NO 2 -FA), which display anti-inflammatory properties. Given that the 5-lipoxygenase (5-LO, ALOX5) possesses critical nucleophilic amino acids, which are potentially sensitive to electrophilic modifications, we determined the consequences of NO 2 -FA on 5-LO activity in vitro and on 5-LOmediated inflammation in vivo. Results: Stimulation of human polymorphonuclear leukocytes (PMNL) with nitro-oleic (NO 2 -OA) or nitro-linoleic acid (NO 2 -LA) (but not the parent lipids) resulted in the concentrationdependent and irreversible inhibition of 5-LO activity. Similar effects were observed in cell lysates and using the recombinant human protein, indicating a direct reaction with 5-LO. NO 2 -FAs did not affect the activity of the platelet-type 12-LO (ALOX12) or 15-LO-1 (ALOX15) in intact cells or the recombinant protein. The NO 2 -FAinduced inhibition of 5-LO was attributed to the alkylation of Cys418, and the exchange of Cys418 to serine rendered 5-LO insensitive to NO 2 -FA. In vivo, the systemic administration of NO 2 -OA to mice decreased neutrophil and monocyte mobilization in response to lipopolysaccharide (LPS), attenuated the formation of the 5-LO product 5-hydroxyeicosatetraenoic acid (5-HETE), and inhibited lung injury. The administration of NO 2 -OA to 5-LO knockout mice had no effect on LPS-induced neutrophil or monocyte mobilization as well as on lung injury. Innovation: Prophylactic administration of NO 2 -OA to septic mice inhibits inflammation and promotes its resolution by interfering in 5-LO-mediated inflammatory processes. Conclusion: NO 2 -FAs directly and irreversibly inhibit 5-LO and attenuate downstream acute inflammatory responses. Antioxid. Redox Signal. 20, 2667Signal. 20, -2680

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Nitro-oleic Acid, a Novel and Irreversible Inhibitor of Xanthine Oxidoreductase

Cited by 75 publications

References 39 publications

Modulation of Nitro-fatty Acid Signaling

Modulation of Nitro-fatty Acid Signaling

Characterization and quantification of endogenous fatty acid nitroalkene metabolites in human urine

Electrophilic Fatty Acid Species Inhibit 5-Lipoxygenase and Attenuate Sepsis-Induced Pulmonary Inflammation

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