Nitric oxide selectively releases metals from the<i>N</i>‐terminal domain of metallothioneins: potential role at inflammatory sites

Zangger, Klaus; Öz, Gülin; Haslinger, Ernst; Kunert, Olaf; Armitage, Ian M.

doi:10.1096/fj.00-0641fje

Cited by 110 publications

(98 citation statements)

References 48 publications

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“…Rather high concentrations of NO are needed to observe significantly reduced cadmium levels in MT2, which corroborates the role of MTs in heavy metal detoxification as a result of rather tight binding of cadmium to MTs [18,19]. The maximum number of metals released from Cd 5 Zn 2 -MT2 at the highest NO concentrations used in these ICPMS studies amount to 1.5 Zn and 3.25 Cd per MT2 molecule, which shows that in contrast to mouse MT1, [31] significant amounts of metal are also set free from the a-domain.…”

Section: Sec-icpmssupporting

confidence: 75%

“…2) clearly show that the release of both cadmium and zinc by NO is suppressed completely by GSH, but not GSSG. As already suggested in our previous paper [31], zinc is more readily released than cadmium. Rather high concentrations of NO are needed to observe significantly reduced cadmium levels in MT2, which corroborates the role of MTs in heavy metal detoxification as a result of rather tight binding of cadmium to MTs [18,19].…”

Section: Sec-icpmssupporting

confidence: 71%

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Modulation of nitric oxide‐mediated metal release from metallothionein by the redox state of glutathione in vitro

Khatai

Goessler

Lorencova

et al. 2004

European Journal of Biochemistry

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Metallothioneins (MTs) release bound metals when exposed to nitric oxide. At inflammatory sites, both metallothionein and inducible nitric oxide synthase (iNOS) are induced by the same factors and the zinc released from metallothionein by NO suppresses both the induction and activity of iNOS. In a search for a possible modulatory mechanism of this coexpression of counteracting proteins, we investigated the role of the glutathione redox state in vitro because the oxidation state of thiols is involved in the metal binding in Cd-S or Zn-S clusters found in metallothioneins, and NO also binds to reduced glutathione via S-nitrosation. Using a variety of techniques, we found that NO and also ONOO --mediated metal release from purified MTs is suppressed by reduced glutathione (GSH), but not by oxidized glutathione. Considering the millimolar concentrations of GSH present in mammalian cells, the metal release from MTs by NO should play no role in living systems. Therefore, the fact that it has been observed in vivo points to a hitherto unknown mechanism or additional compound(s) being involved in this physiologically relevant reaction and as long as this additional factor is not found experimental results on the MT-NO interaction should be treated with caution. Contrary to the peroxynitrite-induced activation of guanylyl cyclase, where GSH is needed, we found that the metal release from metallothionein by peroxynitrite is not enhanced, but also suppressed by reduced glutathione. In addition, we show that zinc, the major natural metal ligand in mammalian MTs and suppressor of iNOS, is released more readily under the influence of NO than cadmium, but in contrast to the MT isoform 1, the amount of metal released from the b-domain of MT-2 is comparable to that from the a-domain.Keywords: glutathione; metallothionein; nitric oxide; NMR spectroscopy; SEC-ICPMS.Metallothioneins (MTs) are a family of small (6-7 kDa) metal-binding proteins [1][2][3] with the highest known metal content after ferritins. The high amount of cysteine residues in MTs (30% of all amino acids are cysteine) allows these proteins to coordinate multiple mono (Cu + , Ag + ) or divalent metals (Zn 2+ , Cd 2+ ). Mammalian MTs bind seven divalent metals in two separate domains [4]. Three metals are bound in an M 3 Cys 9 cluster in the N-terminal b-domain, while an M 4 Cys 11 four metal cluster is formed in the C-terminal a-domain [4]. Of the four known mammalian MT isoforms [2], the two best studied and most widely occurring isoforms (1 and 2) are most abundant in parenchymatous tissues, i.e. liver, kidney, pancreas and intestines [5][6][7] . The naturally bound metal zinc can be displaced by cadmium up to about 5 mol per mol protein by simple addition of Cd 2+ [13] in vitro. Living animals fed a cadmium-rich diet produce a mixed-metal MT with zinc bound preferentially in the b-and cadmium in the a-domain [11,13,14]. The artificial Cd 7 -MT can only be obtained after complete zinc removal by lowering the pH [15] in vitro.Although the biological function(s) o...

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Section: Sec-icpmssupporting

confidence: 75%

Section: Sec-icpmssupporting

confidence: 71%

Modulation of nitric oxide‐mediated metal release from metallothionein by the redox state of glutathione in vitro

Khatai

Goessler

Lorencova

et al. 2004

European Journal of Biochemistry

Self Cite

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“…7 and 23). Evidence is available suggesting that the binding sites of MT, particularly those that comprise the N-terminal (␤-cluster) metal-binding domain of the protein (24), may be the ultimate recipients of zinc ions lost from the plasma pool during stress and inflammation. Although IL-6 has been shown to enhance the induction of MT in hepatocytes (8,9,25), our data presented here suggest that both Zip14 and MT are components of the IL-6-mediated hypozincemia.…”

Section: Discussionmentioning

confidence: 99%

“…Zinc is needed for microbial pathogenicity (5,35), and a hypozincemia may limit zinc availability. Zn 2ϩ mobilization induced by nitric oxide may also be an explanation for the up-regulation of Zip14 during inflammation and infection (24). Zinc influences cytokine production by leukocytic populations in vivo and in vitro (36,37) and may be of therapeutic value during sepsis (38).…”

Section: Discussionmentioning

confidence: 99%

Interleukin-6 regulates the zinc transporter Zip14 in liver and contributes to the hypozincemia of the acute-phase response

Liuzzi

Lichten²,

Rivera³

et al. 2005

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

503

395

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Infection and inflammation produce systemic responses that include hypozincemia and hypoferremia. The latter involves regulation of the iron transporter ferroportin 1 by hepcidin. The mechanism of reduced plasma zinc is not known. Transcripts of the two zinc transporter gene families (ZnT and Zip) were screened for regulation in mouse liver after turpentine-induced inflammation and LPS administration. Zip14 mRNA was the transporter transcript most up-regulated by inflammation and LPS. IL-6 knockout (IL-6 ؊/؊ ) mice did not exhibit either hypozincemia or the induction of Zip14 with turpentine inflammation. However, in IL-6 ؊/؊ mice, LPS produced a milder hypozincemic response but no Zip14 induction. Northern analysis showed Zip14 up-regulation was specific for the liver, with one major transcript. Immunohistochemistry, using an antibody to an extracellular Zip14 epitope, showed both LPS and turpentine increased abundance of Zip14 at the plasma membrane of hepatocytes. IL-6 produced increased expression of Zip14 in primary hepatocytes cultures and localization of the protein to the plasma membrane. Transfection of mZip14 cDNA into human embryonic kidney cells increased zinc uptake as measured by both a fluorescent probe for free Zn 2؉ and 65 Zn accumulation, as well as by metallothionein mRNA induction, all indicating that Zip14 functions as a zinc importer. Zip14 was localized in plasma membrane of the transfected cells. These in vivo and in vitro experiments demonstrate that Zip14 expression is up-regulated through IL-6, and that this zinc transporter most likely plays a major role in the mechanism responsible for hypozincemia that accompanies the acute-phase response to inflammation and infection.endotoxemia ͉ inflammation ͉ hepatic ͉ Slc39a14 ͉ knockout mice

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“…2 The free radical nitric oxide (NO) can form stable complexes with MT, inducing conformational changes in the protein and the selective release of metals (e.g., zinc). 3 S-nitrosation of the MT sulphydryl groups, the mechanism responsible for the loss of metal from the binding centers of the protein, 4 is also a key event of NO signaling. 5 Stitt et al demonstrated that the metal responsive transcription factor MTF-1 required for the activation of genes, including the MT genes involved in the cell response to various stresses, is one of the cellular target of the zinc released from metallothionein and it has been hypothesized that the release of zinc caused by NO might act as a novel signal transduction pathway participating in the cell response to oxidative stress.…”

Section: Metallothionein and Nitric Oxide Signalingmentioning

confidence: 99%

Unraveling the response of plant cells to cytotoxic saponins

Balestrazz

Macovei

Tava

et al. 2011

Plant Signaling & Behavior

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Nitric oxide selectively releases metals from theN‐terminal domain of metallothioneins: potential role at inflammatory sites

Cited by 110 publications

References 48 publications

Modulation of nitric oxide‐mediated metal release from metallothionein by the redox state of glutathione in vitro

Modulation of nitric oxide‐mediated metal release from metallothionein by the redox state of glutathione in vitro

Interleukin-6 regulates the zinc transporter Zip14 in liver and contributes to the hypozincemia of the acute-phase response

Unraveling the response of plant cells to cytotoxic saponins

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