Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.7.1.4 (nitrite reductase)
 1,847 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitrite is present in red blood cells (RBCs) and is proposed to be the largest intravascular storage pool of vasoactive NO. The mechanism by which nitrite exerts NO vasoactivity remains unclear but deoxyHb exhibits nitrite reductase activity. NitrosylHb (HbFe(II)NO) is formed on nitrite reduction by excess deoxyHb, and S-nitrosated Hb (HbSNO) has also been detected in nitrite/deoxyHb incubations. We report data consistent with efficient HbSNO generation from a nitrosylHb intermediate on oxygenation of anaerobic deoxyHb incubations containing physiologically revelant levels of nitrite, whereas previously a labile nitrosylmetHb (HbFe(III)NO) transient was proposed. The HbSNO yield as a function of the initial nitrite concentration varies with the nitrite/deoxyHb ratio, the incubation time, the concentration of added metHb (a nitrite trap), and the concentration of added cyanide (a strong metHb ligand). Our results reveal that metHb strongly attenuates HbSNO formation, which suggests that the met protein may play a regulatory role by limiting the amount of free (or non-Hb-bound) nitrite within RBCs to prevent hypotension.
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PMID:Hemoglobin S-nitrosation on oxygenation of nitrite/deoxyhemoglobin incubations is attenuated by methemoglobin. 1788 68

Nitrite is now recognized as a storage pool of bioactive nitric oxide (NO). Hemoglobin (Hb) and myoglobin (Mb) convert, under certain conditions, nitrite to NO. This newly discovered nitrite reductase activity of Hb and Mb provides an attractive alternative to mammalian NO synthesis from the NO synthase pathway that requires dioxygen. We recently reported the X-ray crystal structure of the nitrite adduct of ferric horse heart Mb, and showed that the nitrite ligand binds in an unprecedented O-binding (nitrito) mode to the d(5) ferric center in Mb(III)(ONO) [D.M. Copeland, A. Soares, A.H. West, G.B. Richter-Addo, J. Inorg. Biochem. 100 (2006) 1413-1425]. We also showed that the distal pocket in Mb allows for different conformations of the NO ligand (120 degrees and 144 degrees ) in Mb(II)NO depending on the mode of preparation of the compound. In this article, we report the crystal structures of the nitrite and NO adducts of manganese-substituted hh Mb (a d(4) system) and of the nitrite adduct of cobalt-substituted hh Mb (a d(6) system). We show that the distal His64 residue directs the nitrite ligand towards the rare nitrito O-binding mode in Mn(III)Mb and Co(III)Mb. We also report that the distal pocket residues allow a stabilization of an unprecendented bent MnNO moiety in Mn(II)MbNO. These crystal structural data, when combined with the data for the aquo, methanol, and azide MnMb derivatives, provide information on the role of distal pocket residues in the observed binding modes of nitrite and NO ligands to wild-type and metal-substituted Mb.
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PMID:Crystal structures of manganese- and cobalt-substituted myoglobin in complex with NO and nitrite reveal unusual ligand conformations. 1790 36

Hemoglobin A (HbA) is an allosterically regulated nitrite reductase that reduces nitrite to NO under physiological hypoxia. The efficiency of this reaction is modulated by two intrinsic and opposing properties: availability of unliganded ferrous hemes and R-state character of the hemoglobin tetramer. Nitrite is reduced by deoxygenated ferrous hemes, such that heme deoxygenation increases the rate of NO generation. However, heme reactivity with nitrite, represented by its bimolecular rate constant, is greatest when the tetramer is in the R quaternary state. The mechanism underlying the higher reactivity of R-state hemes remains elusive. It can be due to the lower heme redox potential of R-state ferrous hemes or could reflect the high ligand affinity geometry of R-state tetramers that facilitates nitrite binding. We evaluated the nitrite reductase activity of unpolymerized sickle hemoglobin (HbS), whose oxygen affinity and cooperativity profile are equal to those of HbA, but whose heme iron has a lower redox potential. We now report that HbS exhibits allosteric nitrite reductase activity with competing proton and redox Bohr effects. In addition, we found that solution phase HbS reduces nitrite to NO significantly faster than HbA, supporting the thesis that heme electronics (i.e. redox potential) contributes to the high reactivity of R-state deoxy-hemes with nitrite. From a pathophysiological standpoint, under conditions where HbS polymers form, the rate of nitrite reduction is reduced compared with HbA and solution-phase HbS, indicating that HbS polymers reduce nitrite more slowly.
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PMID:Nitrite reductase activity of hemoglobin S (sickle) provides insight into contributions of heme redox potential versus ligand affinity. 1805 15

Hemoglobin (Hb) potently inactivates the nitric oxide (NO) radical via a dioxygenation reaction forming nitrate (NO(3)(-)). This inactivation produces endothelial dysfunction during hemolytic conditions and may contribute to the vascular complications of Hb-based blood substitutes. Hb also functions as a nitrite (NO(2)(-)) reductase, converting nitrite into NO as it deoxygenates. We hypothesized that during intravascular hemolysis, nitrite infusions would limit the vasoconstrictive properties of plasma Hb. In a canine model of low- and high-intensity hypotonic intravascular hemolysis, we characterized hemodynamic responses to nitrite infusions. Hemolysis increased systemic and pulmonary arterial pressures and systemic vascular resistance. Hemolysis also inhibited NO-dependent pulmonary and systemic vasodilation by the NO donor sodium nitroprusside. Compared with nitroprusside, nitrite demonstrated unique effects by not only inhibiting hemolysis-associated vasoconstriction but also by potentiating vasodilation at plasma Hb concentrations of <25 muM. We also observed an interaction between plasma Hb levels and nitrite to augment nitroprusside-induced vasodilation of the pulmonary and systemic circulation. This nitrite reductase activity of Hb in vivo was recapitulated in vitro using a mitochondrial NO sensor system. Nitrite infusions may promote NO generation from Hb while maintaining oxygen delivery; this effect could be harnessed to treat hemolytic conditions and to detoxify Hb-based blood substitutes.
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PMID:Nitrite reductase activity of hemoglobin as a systemic nitric oxide generator mechanism to detoxify plasma hemoglobin produced during hemolysis. 1855 66

The nitrite anion is reduced to nitric oxide (NO*) as oxygen tension decreases. Whereas this pathway modulates hypoxic NO* signaling and mitochondrial respiration and limits myocardial infarction in mammalian species, the pathways to nitrite bioactivation remain uncertain. Studies suggest that hemoglobin and myoglobin may subserve a fundamental physiological function as hypoxia dependent nitrite reductases. Using myoglobin wild-type ((+/+)) and knockout ((-/-)) mice, we here test the central role of myoglobin as a functional nitrite reductase that regulates hypoxic NO* generation, controls cellular respiration, and therefore confirms a cytoprotective response to cardiac ischemia-reperfusion (I/R) injury. We find that myoglobin is responsible for nitrite-dependent NO* generation and cardiomyocyte protein iron-nitrosylation. Nitrite reduction to NO* by myoglobin dynamically inhibits cellular respiration and limits reactive oxygen species generation and mitochondrial enzyme oxidative inactivation after I/R injury. In isolated myoglobin(+/+) but not in myoglobin(-/-) hearts, nitrite treatment resulted in an improved recovery of postischemic left ventricular developed pressure of 29%. In vivo administration of nitrite reduced myocardial infarction by 61% in myoglobin(+/+) mice, whereas in myoglobin(-/-) mice nitrite had no protective effects. These data support an emerging paradigm that myoglobin and the heme globin family subserve a critical function as an intrinsic nitrite reductase that regulates responses to cellular hypoxia and reoxygenation [corrected]
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PMID:Nitrite reductase activity of myoglobin regulates respiration and cellular viability in myocardial ischemia-reperfusion injury. 1863 62

Small increases in physiological nitrite concentrations have now been shown to mediate a number of biological responses, including hypoxic vasodilation, cytoprotection after ischemia/reperfusion, and regulation of gene and protein expression. Thus, while nitrite was until recently believed to be biologically inert, it is now recognized as a potentially important hypoxic signaling molecule and therapeutic agent. Nitrite mediates signaling through its reduction to nitric oxide, via reactions with several heme-containing proteins. In this report, we show for the first time that the mitochondrial electron carrier cytochrome c can also effectively reduce nitrite to NO. This nitrite reductase activity is highly regulated as it is dependent on pentacoordination of the heme iron in the protein and occurs under anoxic and acidic conditions. Further, we demonstrate that in the presence of nitrite, pentacoordinate cytochrome c generates bioavailable NO that is able to inhibit mitochondrial respiration. These data suggest an additional role for cytochrome c as a nitrite reductase that may play an important role in regulating mitochondrial function and contributing to hypoxic, redox, and apoptotic signaling within the cell.
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PMID:Nitrite reductase activity of cytochrome c. 1882 Mar 38

Growing evidence indicates that nitrite, NO2-, serves as a circulating reservoir of nitric oxide (NO) bioactivity that is activated during physiological and pathological hypoxia. One of the intravascular mechanisms for nitrite conversion to NO is a chemical nitrite reductase activity of deoxyhemoglobin. The rate of NO production from this reaction is increased when hemoglobin is in the R conformation. Because the mammalian fetus exists in a low-oxygen environment compared with the adult and is exposed to episodes of severe ischemia during the normal birthing process, and because fetal hemoglobin assumes the R conformation more readily than adult hemoglobin, we hypothesized that nitrite reduction to NO may be enhanced in the fetal circulation. We found that the reaction was faster for fetal than maternal hemoglobin or blood and that the reactions were fastest at 50-80% oxygen saturation, consistent with an R-state catalysis that is predominant for fetal hemoglobin. Nitrite concentrations were similar in blood taken from chronically instrumented normoxic ewes and their fetuses but were elevated in response to chronic hypoxia. The findings suggest an augmented nitrite reductase activity of fetal hemoglobin and that the production of nitrite may participate in the regulation of vascular NO homeostasis in the fetus.
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PMID:Increased nitrite reductase activity of fetal versus adult ovine hemoglobin. 1902 97

Nitrite reductase, which reduces nitrite to ammonium in a six-electron reaction, was characterized through kinetic analysis of an electron transfer cascade involving photoexcited Photosystem I and ferredoxin. This cascade was studied at physiological pH by flash-absorption spectroscopy. Two different forms of the enzyme were studied: one isolated from spinach leaf and one histidine-tagged recombinant form. When the enzyme is oxidized in the absence of nitrite, single-enzyme reduction leads mostly to siroheme reduction with the leaf enzyme, whereas the siroheme and the [4Fe-4S] cluster are both reduced in equivalent amounts in the recombinant enzyme. When combined with the results of deazaflavin/EDTA photoreduction experiments, these data support a 50 mV negative shift of the siroheme midpoint potential in the recombinant enzyme. Despite this difference, the two forms of the enzyme exhibit similar values for the rate constant of single reduction by reduced ferredoxin (1200 s(-1)) and for k(cat) (420-450 electrons per second and per nitrite reductase). When nitrite reductase is initially pre-reduced to the state ferrous siroheme-NO(*), the fast kinetics of reduction by ferredoxin and the thermodynamics of ferredoxin binding are equivalent to those observed with oxidized nitrite reductase without nitrite. Spectral and kinetic analyses of single reduction of the recombinant enzyme in the ferrous siroheme-NO(*) state by photoreduced ferredoxin reveal that this process leads to reduction of the [4Fe-4S] cluster with little, if any, NO(*) reduction. These data show that the enzyme must wait for the next reduction step before NO(*) undergoes substantial reduction.
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PMID:New insights into the catalytic cycle of plant nitrite reductase. Electron transfer kinetics and charge storage. 1922 4

Nitrite is endogenously produced as an oxidative metabolite of nitric oxide, but it also functions as a NO donor that can be activated by a number of cellular proteins under hypoxic conditions. This article discusses the physiological role of nitrite and nitrite-derived NO in blood flow regulation and cytoprotection from a comparative viewpoint, with focus on mammals and fish. Constitutive nitric oxide synthase activity results in similar plasma nitrite levels in mammals and fish, but nitrite can also be taken up across the gills in freshwater fish, which has implications for nitrite/NO levels and nitrite utilization in hypoxia. The nitrite reductase activity of deoxyhemoglobin is a major mechanism of NO generation from nitrite and may be involved in hypoxic vasodilation. Nitrite is readily transported across the erythrocyte membrane, and the transport is enhanced at low O(2) saturation in some species. Also, nitrite preferentially reacts with deoxyhemoglobin rather than oxyhemoglobin at intermediate O(2) saturations. The hemoglobin nitrite reductase activity depends on heme O(2) affinity and redox potential and shows species differences within mammals and fish. The NO forming capacity is elevated in hypoxia-tolerant species. Nitrite-induced vasodilation is well documented, and many studies support a role of erythrocyte/hemoglobin-derived NO. Vasodilation can, however, also originate from nitrite reduction within the vessel wall, and at present there is no consensus regarding the relative importance of competing mechanisms. Nitrite reduction to NO provides cytoprotection in tissues during ischemia-reperfusion events by inhibiting mitochondrial respiration and limiting reactive oxygen species. It is argued that the study of hypoxia-tolerant lower vertebrates and diving mammals may help evaluate mechanisms and a full understanding of the physiological role of nitrite.
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PMID:The role of nitrite in nitric oxide homeostasis: a comparative perspective. 1924 57

Abstract Diversity of the functional genes encoding dissimilatory nitrite reductase was investigated for the first time in denitrifying halobenzoate degrading bacteria and in two 4-chlorobenzoate degrading denitrifying consortia. Nitrite reductase genes were PCR-amplified with degenerate primers (specific to the two different types of respiratory nitrite reductase, nirS and nirK), cloned and sequenced to determine which type of nitrite reductase was present in each isolate and consortium. Halobenzoate degrading isolates belonging to the genera Ochrobactrum, Ensifer and Mesorhizobium, as well as Pseudomonas mendocina CH91 were found to have nirK genes, which were closely related to the previously published nirK genes of Ochrobactrum anthropi, Achromobacter cycloclastes, Alcaligenes faecalis and Pseudomonas aureofaciens, respectively. The isolates assigned to the genera Acidovorax, Azoarcus and Thauera as well as all other species in the genera Thauera and Azoarcus contained nirS genes, which were closely related to the nirS genes from Pseudomonas stutzeri with some exceptions. In addition, only nirS genes were found in 4-chlorobenzoate degrading denitrifying consortia. Three different major terminal restriction fragments from the nirS genes were detected by terminal restriction fragment length polymorphism analysis of the consortia, and five different nirS genes were cloned from one consortium. Three nirS gene clones were closely related to nirS genes from Thauera chlorobenzoica, Azoarcus tolulyticus and Pseudomonas aeruginosa, respectively. The phylogeny of nir genes was not entirely congruent with the 16S rRNA phylogeny of the genera nor was it correlated with the ecological and geographical origins or isolation substrates used for isolation and enrichment of consortia.
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PMID:Nitrite reductase genes in halobenzoate degrading denitrifying bacteria. 1971 66


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