Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The superoxide scavenging activities of copper(II) complexes with the ligands, 6,6'-methylene- bis(5'-amino-3',4'-benzo-2'-thiapentyl)-1,11-diamino- 2,3:9,10-dibenzo-4,8-dithiaundecane (H4L), and 6,6'- bis(5'-amino-3'4'-benzo-2'-thiapentyl)-1,11-diamino- 2,3:9,10-dibenzo-4,8-dithiaundecane (H4L"), were investigated by xanthine-xanthine oxidase (X/XO) assays using nitroblue tetrazolium (NBT) as indicator molecule, and the results were compared with respect to the particular type of anion (ClO4, Cl, NO3) on the apical site of the copper(II) complexes. All of the complexes inhibited the reduction of NBT by superoxide radicals, with the [Cu2(L')](ClO4)2 complex exhibiting the highest scavenging activity against superoxide radicals among the complexes examined. The catalytic efficiency of the complexes for dismutation of superoxide radicals depends on the particular anion liganded to Cu(II) ion in the complexes, and the order of potency was observed to be ClO4 > Cl > NO3 in phosphate buffer at pH 7.40. The Cu(II)-H4L' complexes had the lowest IC50 and catalytic rate constant values indicating that the distorted geometry of the Cu(II)-H4L' complexes influence their catalytic activities for dismutation of superoxide radicals more efficiently. The difference in the activities of the complexes toward superoxide radicals can also be attributed to the nature of the anions on the apical site of the copper(II) complexes and the superoxide dismutase-like activity.
J Biochem Mol Toxicol 1998
PMID:Superoxide dismutase-mimicking activities of dinuclear Cu(II) complexes with ligands containing a tetrathioether-tetraamino moiety. 941 87

The structure of adenine nucleotide bound at the active site of yeast hexokinase PII (PII) was studied in the complexes PII x ADPMg(II), PII x ADPMg(II) x Glc and PII x ADPMg(II) x NO3- x Glc using two-dimensional transferred NOE spectroscopy. Binding of the nucleotide ligand to the enzyme resulted in downfield shift of several ligand resonances. Changes in the chemical shift as a function of ligand concentration indicate that various resonances in the bound and free form of the ligand appear to be in fast exchange. The largest chemical shift change between the bound and the free states (delta vM = 88 +/- 9 Hz) at an NMR frequency of 500 MHz was observed for the H2 resonance of the adenine ring. A lower limit for the rate of ligand dissociation from the complex derived from these results is k(off) >> 550 s(-1). Interproton NOEs for various ligand protons in PII x ADPMg(II), PII x ADPMg(II) x Glc and PII x ADPMg(II) x NO3- x Glc complexes were measured at 500 MHz at 10 degrees C. The NOE buildup curves constructed from such measurements made at various mixing times (40, 80, 120, 160 and 200 ms) were analyzed using complete relaxation matrix calculations and various interproton distances were determined. These distances were used in restrained molecular dynamics calculations to derive the conformation of the nucleotide bound at the active site of the enzyme. The results of these calculations indicate that the nucleotide binds in an anti conformation. The glycosidic torsion angle chi (O4'-C1'-N9-C8) determined for the nucleotide in PII x ADPMg(II), PII x ADPMg(II) x Glc and PII x ADPMg(II) x NO3- x Glc complexes are 68 +/- 4 degrees, 52 +/- 4 degrees and 49 +/- 4 degrees respectively. In all these complexes, the ribose pucker is best represented by the unsymmetrical O4'-endo-C1'-exo twist ((o)T1). The observed decrease in the glycosidic torsion angle of the bound nucleotide is attributed to the glucose-induced conformational changes in the enzyme. The structure of the nucleotide derived here is at variance from the one proposed on the basis of X-ray crystallography and model building [Shoham, M. & Steitz, T. A. (1980) J. Mol. Biol. 140, 1-14].
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PMID:Yeast hexokinase PII--bound nucleotide conformation at the active site. 942 8

Soluble guanylyl cyclase (sGC) is the major physiological target of sydnonimine-based vasodilators such as molsidomine. Decomposition of sydnonimines results in the stoichiometric formation of nitric oxide (NO) and superoxide (O2-), which rapidly react to form peroxynitrite. Inasmuch as sGC is activated by NO but not by peroxynitrite, we investigated the mechanisms underlying sGC activation by 3-morpholinosydnonimine (SIN-1). Stimulation of purified bovine lung sGC by SIN-1 was found to be strongly dependent on glutathione (GSH). By contrast, GSH did not affect sGC activation by NO released from 2,2-diethyl-1-nitroso-oxyhydrazine, indicating that NO/O2- released from SIN-1 converted GSH to an activator of sGC. High performance liquid chromatography identified this product as the thionitrite S-nitrosoglutathione. Further, the reaction product decomposed to release NO upon addition of Cu(NO3)2 in the presence of GSH. Activation of sGC was antagonized by the Cu(I)-specific chelator neocuproine, whereas the Cu(II)-selective drug cuprizone was less potent. Carbon dioxide (delivered as NaHCO3) antagonized S-nitrosation by peroxynitrite but not by SIN-1. Thus, NO/O2- released from SIN-1 mediates a CO2-insensitive conversion of GSH to S-nitrosoglutathione, a thionitrite that activates sGC via trace metal-catalyzed release of NO. These results may provide novel insights into the molecular mechanism underlying the nitrovasodilator action of SIN-1.
Mol Pharmacol 1998 Jul
PMID:Activation of soluble guanylyl cyclase by the nitrovasodilator 3-morpholinosydnonimine involves formation of S-nitrosoglutathione. 965 7

Nitric oxide radical (.NO) and peroxynitrite anion (ONOO-) have been implicated in lung inflammation and may be important in pleural injury. The present study was undertaken to determine the effects of asbestos exposure and cytokine stimulation on .NO and ONOO- production by rat pleural mesothelial cells. Accordingly, rat parietal pleural mesothelial cells were cultured for 2 to 72 h with or without 50 ng/ml of recombinant interleukin-1beta (IL-1beta) in the presence (1.05 to 8.4 microg/cm2) or absence of crocidolite or chrysotile asbestos fibers. The effects of asbestos were compared with those of carbonyl iron, a nonfibrogenic particulate. Mesothelial cell messenger RNA (mRNA) expression of the inducible form of .NO synthase (iNOS), assessed with the reverse transcription-polymerase chain reaction (RT-PCR), increased progressively from 2 to 12 h in IL-1beta-containing cultures. Nitrite (NO2-), the stable oxidation product of .NO in mesothelial cell conditioned medium, was assayed through the Griess reaction. Both types of asbestos fibers (chrysotile > crocidolite) upregulated the formation of NO2- in mesothelial cells costimulated with IL-1beta in a concentration-dependent and time-dependent fashion. In contrast, carbonyl iron did not upregulate NO2- formation in IL-1beta-stimulated cells. Both types of asbestos fibers also induced iNOS protein expression and the formation of nitrotyrosine in mesothelial cells and greatly induced the formation of nitrate (NO3-), a surrogate marker of ONOO- formation, in IL-1beta-stimulated cells. However, the effects of chrysotile were notably greater than those of crocidolite. These findings may have significance for the induction of pleural injury by asbestos fibers.
Am J Respir Cell Mol Biol 1998 Aug
PMID:Asbestos fibers and interleukin-1 upregulate the formation of reactive nitrogen species in rat pleural mesothelial cells. 969 94

The toxicity of NO3- and NO2- to mammals has been widely publicized. However, the kinetic mechanism of inhibition of human muscle creatine kinase by NO3- and NO2- has not been explored. The kinetic theory of the substrate reaction during the modification of enzyme activity previously described by Tsou (Adv. Enzymol. Related Areas Mol. Biol. 1988, 61, 381-436) has been applied to a study of the kinetics of slow reversible inhibition of human muscle creatine kinase by planar anions (NO3- and NO2-). The kinetic equation of the substrate reaction was derived from theoretical analysis and experimental data, then simplified. The microscopic rate constants for the reaction of the inhibitors with the enzyme were obtained from the simplified equation for the substrate reaction in the presence of the inhibitors. The results show that the apparent forward rate constant A is dependent on ATP concentration, indicating competition between the inhibitor (NO3- or NO2-) and ATP. The results also suggest that binding of creatine-MgADP and the anion with the enzyme is very tight, since their binding constants are much higher than those for normal substrates.
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PMID:Kinetics of slow reversible inhibition of human muscle creatine kinase by planar anions. 975 13

Apoptosis induced by peroxynitrite in cultured cerebellar granule cells was confirmed morphologically by chromatin condensation and biochemically by DNA laddering. A 30 min exposure to peroxynitrite (10 microM) initiated oxidative stress, which caused the formation of thiobarbituric acid-reactive substances (TBARS) and the alteration of cell membrane fluidity. Peroxynitrite treatment also caused ATP decrease and thus activated the apoptotic program. Pre-treating cells with antioxidant EPC-K1 (L-ascorbic acid 2-[3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H -1- benzopyran-6-yl-hydrogen phosphate] potasium salt), a new water-soluble derivative of vitamin C and vitamin E, attenuated oxidative injury and prevents cells from apoptosis. The results suggest that EPC-K1 might be used as a potential therapeutic agent for diseases associated with NO/ONOO(-)-mediated neuronal injury.
Biochem Mol Biol Int 1998 Sep
PMID:EPC-K1 attenuates peroxynitrite-induced apoptosis in cerebellar granule cells. 978 43

The cellular coenzymatic role of NAD, being a pleiotropic cofactor for diverse cellular reactions, is extended to poly(ADP-ribose) and to the highly abundant nuclear protein, poly(ADP-ribose) polymerase, with special focus on the pharmacological action of ligands on the latter. The polymer is defined to possess a helical configuration. From direct analyses of the polymer under physiological conditions, it is concluded that the polymerase is dormant in normal tissues, but is activated under certain pathological conditions: malignancy, retroviral integrate containing cells, and in a variety of inflammatory states. The interaction of poly(ADP-ribose) polymerase ligands with the DNA component of the active poly (ADP-ribose) polymerase - DNA complex is shown. A major cellular function of the poly(ADP-ribose) polymerase protein is its binding capacity to a large number of nuclear proteins and DNA sites, an effect which is induced by drugs that inhibit the polymerase activity. The malignancy-reverting effect of poly(ADP-ribose) polymerase ligand drugs is illustrated in chemically and oncovirally transformed cancer cells. The poly(ADP-ribose) polymerase ligand-induced cessation of HIV replication is analyzed. Peroxynitrite-induced DNA damage-initiated pathological responses are shown to be inhibited by a specific poly(ADP-ribose) polymerase ligand. The irreversibly acting C-NO drugs oxidize asymmetric zinc fingers [poly(ADP-ribose) polymerase, HIV gag-precursor protein] and act as anti-cancer and anti-HIV agents, an effect that is regulated by cellular concentration of GSH.
Int J Mol Med 1998 Aug
PMID:Poly(ADP-ribose) polymerase, a potential target for drugs: Cellular regulatory role of the polymer and the polymerase protein mediated by catalytic and macromolecular colligative actions (Review). 985 79

Macrophages play an important role against Trypanosoma cruzi infection, via superoxide, nitric oxide, and peroxynitrite production. Peroxynitrite has been shown to be highly cytotoxic against Trypanosoma cruzi epimastigotes. Calcium is involved in many vital functions of the parasites, being its intracellular concentration governed by several transport systems, involving mitochondrial and non-mitochondrial compartments. In this paper, we report the effect of peroxynitrite on the calcium uptake systems, as studied by digitonin-permeabilized trypanosomes in the presence of arsenazo III. Peroxynitrite, at biologically relevant concentrations produced within phagosomes (250-750 microM), inhibited calcium uptake in a dose-dependent manner. Peroxynitrite decreased the mitochondrial membrane potential obtained in the presence of tetramethyl-p-phenylenediamine (TMPD)/ascorbate. In addition, a decrease of the non-mitochondrial Ca(2+)-uptake, concomitant with the inactivation of a Ca(2+)-dependent ATPase activity, was observed. HPLC analyses of the cellular adenine nucleotide pool showed a time-dependent decrease of ATP content and energy charge of the parasite; however this drop in ATP levels was significantly delayed with respect to decrease of the ATP-dependent Ca(2+)-transport. We conclude that the disruption of calcium homeostasis by peroxynitrite may contribute to the observed cytotoxic effects of macrophages against T. cruzi.
Mol Biochem Parasitol 1999 Jan 05
PMID:Peroxynitrite affects Ca2+ transport in Trypanosoma cruzi. 1002 11

Peroxynitrite and hydroxyl radical are reactive oxidants produced during myocardial reperfusion injury. They have been shown to induce dysfunction in cardiac myocytes, in part, via the activation of the nuclear enzyme poly (ADP-ribose) synthetase (PARS). These oxidants can trigger DNA single strand breakage, which triggers PARS activation, resulting in cellular NAD+ and ATP depletion and cytotoxicity. Recent work has demonstrated that hypoxia-reoxygenation of cardiac myocytes in vitro also causes peroxynitrite formation, PARS activation and cytotoxicity. In the present study, using hearts from genetically engineered mice lacking PARS, we have investigated whether the absence of PARS alters the functional response to hypoxia reoxygenation. Isolated work-performing mouse hearts were stabilized under the same loading condition (cardiac minute work of 250 mmHg x ml/min, an afterload of 50 mmHg aortic pressure and similar venous return of 5 ml/min, resulting in the same preload). After 30 min equilibration the hearts were subjected to 30 min hypoxia followed by 30 min of reoxygenation. At the end of the reoxygenation, in hearts from wild-type animals, there was a significant suppression in the rate of intraventricular pressure development (+dP/dt) from 3523 to 2907 mmHg. There was also a significant suppression in the rate of relaxation (-dP/dt) in the wild-type hearts from 3123 to 2168 mmHg. The time to peak pressure (TPP) increased from 0.48 to 0.59 ms/mmHg and the half-time of relaxation (RT1/2) increased from 0.59 to 0.74 ms/mmHg. In contrast, in the hearts from the PARS knockout animals, no significant suppression of +dP/dt (from 3654 to 3419 mmHg), and no significant increase in the TPP (from 0.462 to 0.448 ms/mmHg) were found, and the decrease in -dP/dt was partially ameliorated (from 3399 to 2687 mmHg) as well as the half-time of relaxation (from 0.507 to 0.55 ms/mmHg) when compared to the response to the wild-type hearts. The current data demonstrate that the reoxygenation induced suppression of the myocardial contractility is dependent on the functional integrity of PARS.
J Mol Cell Cardiol 1999 Jan
PMID:Protection against hypoxia-reoxygenation in the absence of poly (ADP-ribose) synthetase in isolated working hearts. 1007 36

1. We recently developed a new technique for measuring serum NO2 and NO3 levels precisely, and we examined these parameters in severely brain-injured ICU patients who could not take nutrition intestinally. 2. Our results demonstrated that NO increased rapidly after stroke, trauma, and the occurrence of infection in all ICU patients. Elevation of NO2/NO3 was most pronounced 24 to 48 hr after trauma or ischemic stroke. This dysregulation of free radical elimination closely correlated with hemoglobin levels. 3. In most ICU patients, with the exception of those with complications of infection, the free radical potentials were maximal at 24 to 48 hr and continued to remain high for 4 to 5 days after trauma or stroke. The level of free radical potentials was closely correlated with the severity and prognosis of critically injured patients. None with radical potential values higher than 0.4 microM survived. 4. Clinically, the maintenance of hemoglobin at > 12 g/dl and lower body temperature were demonstrated to be successful in the management of these free radical reactions.
Cell Mol Neurobiol 1999 Feb
PMID:Application of a novel technique for clinical evaluation of nitric oxide-induced free radical reactions in ICU patients. 1007 61


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