The nature of heme/iron-induced protein tyrosine nitration

Bian, Ka; Gao, Zhonghong; Weisbrodt, Norman W.; Murad, Ferid

doi:10.1073/pnas.0931291100

Cited by 169 publications

(142 citation statements)

References 51 publications

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“…Alternatively, based on a previous report (41), it was tempting to consider that PMAboosted production of reactive oxygen species, associated with iron knocked out from an IRP-1-disrupted [Fe-S] cluster, would favor local nitration through Fenton chemistry. Indeed, in vitro studies previously showed that redox metals, particularly iron, can catalyze protein tyrosine nitration promoted by peroxynitrite (42) or by nitrite/H 2 O 2 (41,43). However, our results showing that myeloperoxidase inhibitors completely abrogated nitration strongly suggest that "autocatalytic" nitration of IRP-1 by its own iron was not relevant under these conditions.…”

Section: Endogenous Irp-1 Nitration In Activated Macrophagescontrasting

confidence: 53%

Endogenous Nitration of Iron Regulatory Protein-1 (IRP-1) in Nitric Oxide-producing Murine Macrophages

González

Drapier

Bouton

2004

Journal of Biological Chemistry

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Iron regulatory protein-1 (IRP-1) is a bifunctional [4Fe-4S] protein that functions as a cytosolic aconitase or as a trans-regulatory factor controlling iron homeostasis at a post-transcriptional level. Because IRP-1 is a sensitive target protein for nitric oxide (NO), we investigated whether this protein is nitrated in inflammatory macrophages and whether this post-transcriptional modification changes its activities. RAW 264.7 macrophages were first stimulated with interferon-␥ and lipopolysaccharide (IFN-␥/LPS) and then triggered by phorbol 12-myristate 13-acetate (PMA) in order to promote co-generation of NO In mammalian cells, iron regulatory proteins (IRP-1 and -2) 1 marshal iron trafficking, storage, and availability by modulating ferritin and transferrin receptor expression at a post-transcriptional level (1). They operate by interacting with one or several specific stem-loop RNA structures called iron-responsive elements (IREs), which are located in untranslated regions (UTR) of several mRNAs. At low intracellular iron concentration, IRPs bind to the IRE of ferritin mRNA at its 5Ј-UTR and block translation, whereas they stabilize transferrin receptor mRNA through direct interactions with several IRE motifs in the 3Ј-UTR. One critical discrepancy between the two IRPs is that only IRP-1 functions as a cytosolic aconitase when holding a [4Fe-4S] cluster, which masks the IRE-binding domain. In this case, holo-IRP-1 catalyzes the interconversion of citrate into isocitrate via the intermediate formation of cis-aconitate, as does its mitochondrial counterpart in the Krebs cycle (2).It is well documented that nitric oxide (NO ⅐ ) also stimulates the trans-regulatory activity of IRP-1 and consequently disturbs iron homeostasis in various cellular systems exposed to inflammatory conditions (3). More specifically, NO ⅐ converts IRP-1 from an aconitase to a trans-regulatory factor by directly targeting its [Fe-S] cluster leading to its complete disassembly (4 -6). In this way, the apoprotein generated by NO ⅐ , in a reducing environment, tightly binds to IRE(s) and exerts its iron-regulatory function (7,8). In the early 1990s, it was reported that simultaneous production of NO ⅐ and superoxide (O 2 . ) by activated macrophages led to intracellular formation of peroxynitrite (9). Since NO ⅐ can turn into a powerful oxidizing and nitrating agent such as peroxynitrite in vivo, its reactivity toward key enzymes of cellular metabolism has become an active area of investigation (10, 11). Regarding IRP-1, in vitro studies have demonstrated that peroxynitrite causes the direct inhibition of its aconitase activity by promoting complete disruption of the [4Fe-4S] cluster but, unlike NO ⅐ , without stimulating the IRE-binding activity of IRP-1 (5-6, 12). These data suggest that peroxynitrite might generate additional posttranslational modifications of IRP-1 in comparison with NO ⅐ . Interestingly, recent biochemical and resonance Raman studies have allowed the detection of tyrosine nitration on pure recombinant IRP-1 by sy...

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Section: Endogenous Irp-1 Nitration In Activated Macrophagescontrasting

confidence: 53%

Endogenous Nitration of Iron Regulatory Protein-1 (IRP-1) in Nitric Oxide-producing Murine Macrophages

González

Drapier

Bouton

2004

Journal of Biological Chemistry

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“…For example, nitroxyl, heme proteins, transition metals and/or peroxidases can catalyze NTYR formation. Intense NTYR staining in the blood bolus may, therefore, reflect heme iron catalysis of tyrosine nitration in an environment of Hb digestion and high · NO flux [42]. Kumar et al [39] hypothesized that · NO synthesis following parasite infection in An.…”

Section: Ntyr Formation In the A Stephensi Midgutmentioning

confidence: 99%

Nitric oxide metabolites induced in Anopheles stephensi control malaria parasite infection

Peterson

Gow

Luckhart

2007

Free Radical Biology and Medicine

100

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Malaria parasite infection in anopheline mosquitoes is limited by inflammatory levels of nitric oxide metabolites. To assess the mechanisms of parasite stasis or toxicity, we investigated the biochemistry of these metabolites within the blood-filled mosquito midgut. Our data indicate that nitrates, but not nitrites, are elevated in the Plasmodium-infected midgut. Although levels of S-nitrosothiols do not change with infection, blood proteins are S-nitrosylated after ingestion by the mosquito. In addition, photolyzable nitric oxide, which can be attributed to metal nitrosyls, is elevated following infection and, based on the abundance of hemoglobin, likely includes heme iron nitrosyl. The persistance of oxyhemoglobin throughout blood digestion and changes in hemoglobin conformation in response to infection suggest that hemoglobin catalyzes the synthesis of nitric oxide metabolites in a reducing environment. Provision of urate, a potent reductant and scavenger of oxidants and nitrating agents, as a dietary supplement to mosquitoes increased parasite infection levels relative to allantoin-fed controls, suggesting that nitrosative and/or oxidative stresses negatively impact developing parasites. Collectively, our results reveal a unique role for nitric oxide in an oxyhemoglobin-rich environment. In contrast to facilitating oxygen delivery by hemoglobin in the mammalian vasculature, nitric oxide synthesis in the blood-filled mosquito midgut drives the formation of toxic metabolites that limit parasite development.

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“…Elevations of redox active metals systems such as iron (Fe), copper (Cu), and manganese (Mn) contribute to oxidative damage in disease states (12,14). Also, inflammatory conditions trigger the release of leukocyte peroxidases, including myeloperoxidase (MPO) and eosinophil peroxidase (EPO), which play central roles in tissue oxidant formation (13,15,41 …”

Section: The Transition Metal-dependent Formation Of Strong Oxidants mentioning

confidence: 99%

“…However, the role of peroxynitrite as a central species in biological nitration has been more recently questioned (11,12), and alternative pathways, most notably mechanisms that depend on the formation of • NO 2 by the action of hemeperoxidases and͞or transition metal complexes on a main product of • NO metabolism, nitrite (NO 2 Ϫ ), have been presented as contributors (12)(13)(14)(15).…”

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confidence: 99%