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 dependence from temperature and viscosity of the shifts of the internal and external wide extremums in the ESR spectra of spin labelled bovine serum albumin has been studied. 2,2,6,6-tetramethylpiperidine-NI-oxyl-4-iodacetamide was used as a spin label. The obtained dependences was shown to be a consequence of the label participation in two types of rotations: an anisotropic fast rotation with tau less than 10(-9) sec relatively to a macromolecule, and the isotropic one with tau greater than 10(-8) sec due to rotation of the macromolecule itself. These conclusions were done on the basis of a model for complex rotation of the spin label. Comparison of theoretical and experimental data makes it possible to determined the correlation time for the protein moiety, to evaluate quantitatively the polarity of surroundings of the iminoxyl and to introduce a numerical parameter for the degree of mobility of the spin label relatively to protein molecule.
Mol Biol (Mosk)
PMID:[Macromolecule rotative correlation time measurement by ESR for covalently bound spin label]. 22 33

The oxidation of NADH and accompanying reduction of oxygen to H2O2 stimulated by polyvanadate was markedly inhibited by SOD and cytochrome c. The presence of decavanadate, the polymeric form, is necessary for obtaining the microsomal enzyme-catalyzed activity. The accompanying activity of reduction of cytochrome c was found to be SOD-insensitive and therefore does not represent superoxide formation. The reduction of cytochrome c by vanadyl sulfate was also SOD-insensitive. In the presence of H2O2, all the forms of vanadate were able to oxidize reduced cytochrome c, which was sensitive to mannitol, tris and also catalase, indicating H2O2-dependent generation of hydroxyl radicals. Using ESR and spin trapping technique only hydroxyl radicals, but not superoxide anion radicals, were detected during polyvanadate-dependent NADH oxidation.
Mol Cell Biochem 1992 Apr
PMID:Characterization of oxygen free radicals generated during vanadate-stimulated NADH oxidation. 131 4

Copper has been suggested to facilitate oxidative tissue injury through a free radical-mediated pathway analogous to the Fenton reaction. By applying the ESR spin-trapping technique, evidence for hydroxyl radical formation in vivo was obtained in rats treated simultaneously with copper and ascorbic acid. A secondary radical spin-trapping technique was used in which the hydroxyl radical formed the methyl radical upon reaction with dimethylsulfoxide. The methyl radical was then detected by ESR spectroscopy as its adduct with the spin trap phenyl-N-t-butylnitrone (PBN). Because copper excreted into the bile from treated animals is expected to be maintained in the Cu(I) state (by ascorbic acid or glutathione), a chelating agent that would redox-stabilize it in the Cu(I) state was used to prevent ex vivo redox chemistry. Bile samples were collected directly into solutions of bathocuproinedisulfonic acid, a Cu(I)-stabilizing agent, and 2,2'-dipyridyl, a Fe(II)-stabilizing agent. If these precautions were not taken, radical adducts were generated ex vivo and could be mistaken for radical adducts generated in vivo and excreted into the bile. Besides the PBN/.CH3 adduct, three other radical adducts were produced in vivo and excreted in bile.
Mol Pharmacol 1992 Oct
PMID:In vivo evidence of hydroxyl radical formation after acute copper and ascorbic acid intake: electron spin resonance spin-trapping investigation. 133 58

The use of clozapine, a unique antipsychotic drug, has been restricted due to a 1-2% incidence of drug-induced agranulocytosis. Metabolic activation of clozapine in neutrophils or stem cells could be the molecular mechanism underlying this side effect. Clozapine oxidation by human myeloperoxidase and horseradish peroxidase was evident from the disappearance of the UV absorbance at 290 nm. High performance liquid chromatography analysis revealed the formation of at least four radioactive peaks as a result of clozapine metabolism, including radioactivity coeluting with the protein. The tight association of radioactivity with the enzymatic protein was metabolism-dependent. This protein binding, which correlates with the total metabolism of clozapine, was reduced in the presence of glutathione and was absent in the presence of ascorbate. Similarly, in the presence of both reducing agents, the metabolite peaks in the high performance liquid chromatography radiogram, which are not associated with protein, disappeared. In contrast, in the presence of glutathione, two additional metabolites were found that could be isolated and identified by NMR and mass spectroscopy as clozapine glutathionyl adducts. Evidence for one-electron transfer reactions or the intermediate formation of a clozapine radical during the peroxidase-mediated metabolism of clozapine stems from the observation of thiyl and ascorbyl radicals in the presence of glutathione and ascorbate, respectively. The ascorbyl radical was detected by direct ESR spectroscopy in a peroxidase system. Its steady state concentration was significantly increased in the presence of clozapine. Glutathionyl radical formation was demonstrated by radical trapping with 5,5-dimethyl-1-pyrroline N-oxide in a peroxidase system. Again, the radical adduct concentration was significantly increased in the presence of clozapine. Similarly, when oxygen consumption was measured in peroxidase systems in the presence of glutathione or NADPH, the rate of oxygen uptake was markedly enhanced upon addition of clozapine. Thus, the data support the possibility of clozapine activation to free radical metabolites, which may cause oxidative stress or lead to adduct formation. Further, it can be concluded from these data that radical scavengers such as ascorbic acid, when coadministered with clozapine to patients, may reduce oxidative stress and protein adduct formation.
Mol Pharmacol 1991 Nov
PMID:Possible role of free radical formation in clozapine (clozaril)-induced agranulocytosis. 165 15

Podophyllotoxin (PD) and its derivative etoposide (VP-16), a clinically useful anticancer drug, exhibit different mechanisms of action. PD binds specifically to tubulin to prevent its polymerization, whereas VP-16 lacks this action. The DNA strand breakage caused by VP-16 is thought to be due to its interaction with topoisomerase II or to free radical formation by oxidation of its 4'-phenolic hydroxyl group to a semiquinone free radical. We have demonstrated that PD, VP-16, 4'-demethylepipodophyllotoxin (DEPD), and syringic acid (SA) exhibit no DNA-cleaving activity but, in the presence of metal ions such as Cu2+ and Fe3+, DEPD and SA form metal complexes, which in turn show high activity for DNA strand scission at pH 7.8 under air. Furthermore, it was found that DNA cleavage was greatly promoted by irradiation with UV light. The PD-Fe3+ system at pH 7.8 showed very low DNA-cleaving activity, but irradiation with UV light in the system induced almost complete DNA breakage. DNA cleavages were significantly inhibited in the presence of hydroxyl radical scavengers, such as sodium benzoate and dimethylurea, in the Cu(2+)-SA and Fe(3+)-PD systems, with or without UV irradiation. These reactions were investigated by optical and ESR spectra, coupled with ESR spin-trapping techniques, by which the formation of hydroxy radicals was clearly detected in all systems. These findings have led us to a new proposal of the metal- and photo-induced mechanism for understanding the antitumor action of PD, VP-16, and their related compounds.
Mol Pharmacol 1991 Dec
PMID:Metal- and photo-induced cleavage of DNA by podophyllotoxin, etoposide, and their related compounds. 175 45

We have employed the ESR spin trapping technique in vivo to detect the formation of the 5,5-dimethyl-1-pyrroline-N-oxide (DMPO)/hemoglobin thiyl free radical adduct in the blood of rats following administration of either aniline, phenylhydroxylamine, nitrosobenzene, or nitrobenzene. This DMPO adduct was a six-line, strongly immobilized, radical adduct. Using rat red blood cells, both phenylhydroxylamine and nitrosobenzene were able to induce the formation of the DMPO/glutathiyl free radical adduct and the same DMPO/hemoglobin thiyl free radical adduct was detected in in vivo samples. In experiments using purified rat oxyhemoglobin, a four-line, weakly immobilized, DMPO/hemoglobin thiyl free radical adduct was detected, in addition to the six-line strongly immobilized adduct. When this study was repeated using human red blood cells, we detected only the DMPO/glutathiyl free radical adduct and, when purified human oxyhemoglobin was employed, only the four-line, weakly immobilized, DMPO/hemoglobin thiyl radical adduct could be detected. In a study using reduced glutathione, we found that phenylhydronitroxide free radicals were reduced by glutathione and that glutathione was concomitantly oxidized to its thiyl free radical. We propose that the species responsible for the oxidation of the thiols to yield the thiyl free radicals in vivo and in vitro was the phenylhydronitroxide radical produced from the reaction of phenylhydroxylamine with oxyhemoglobin.
Mol Pharmacol 1990 Feb
PMID:Aniline-, phenylhydroxylamine-, nitrosobenzene-, and nitrobenzene-induced hemoglobin thiyl free radical formation in vivo and in vitro. 215 77

Carbon tetrachloride and bromotrichloromethane are both metabolized by cytochrome P-450 in the presence of phenyl-N-t-butyl nitrone PBN) to the PBN/trichloromethyl (PBN/.CCl3) and the PBN carbon dioxide anion (PBN/.CO2-) radical adducts in the liver. The formation of the latter but not the former species in perfused liver was reduced markedly by prior depletion of hepatic glutathione with either diethyl maleate or buthionine sulfoximine treatments. In microsomal incubations, the PBN/.CO2- radical adduct was detected only upon the addition of cytosol. In microsomal incubations containing PBN, CCl4, and GSH, but no added cytosol, a novel radical adduct with distinctive coupling constants was detected. This radical adduct's ESR spectrum exhibited 13C isotope effects when it was formed in an incubation containing 13CCl4 or Br13CCl3. The presence of GSH in the radical adduct is postulated based on the radical adduct's hydrophilicity and slow rate of rotation in solution. The detection of this new radical adduct, PBN/[GSH-.CCl3], establishes the reaction of GSH with a CCl4-derived free radical as a significant event in the metabolism of CBrCl3 and CCl4. The cytosolic conversion of PBN/[GSH-.CCl3] into PBN/.CO2- has been demonstrated and characterizes the PBN/.CO2- radical adduct as the product of metabolism of PBN/[GSH-.CCl3], a primary radical adduct. Thus, it is concluded that GSH rather than oxygen is obligatory for the formation of PBN/.CO2- from .CCl3 in intact cells.
Mol Pharmacol 1990 Mar
PMID:Reaction of glutathione with a free radical metabolite of carbon tetrachloride. 215 56

Segmental mobility dynamic peculiarities of poly(U), poly(A) and poly(C) synthetic polymers and their complexes were investigated by spin-label method. Imidazolide spin-label was introduced into 2'-oxi-groups of polymer ribose in correlation: one spin-label on 18-20 bases. Formation of complexes was observed by ESR spectra at two pH: 4.2 and 7.2. Segmental mobility of only single strand spin-labelled polymer segment and in the complex was evaluated by measuring rotational correlation time (tau) determined by dependence of distances between outer wide extrema in ESR spectra from solvent viscosity at different temperatures. It turned out that correlation time tau of single strand structures in a high degree depend on pH and temperature. For three strand structures abrupt increase of tau because of appearance of rigidity was observed. It is possible to evaluate part of triple complexes poly(U.A.A) and poly(U.U.A) existing in dynamic equilibrium depending on pH and temperature by the form of outer wide extrema. Adding of dye to complex of poly(U).poly(A) causes an increase of rigidity of the supermolecular structure. Quantitative characteristics of formed complexes were obtained by simulation of ESR spectra on computer.
Mol Biol (Mosk)
PMID:[Segmental flexibility of single-, double-, and triple-stranded polyribonucleotides from the data of spin label method. Formation of the triple-stranded poly(A.A.U) polynucleotide helix]. 216 92

The etiology of mercury-induced porphyrinuria was investigated by testing the hypothesis that mercuric ions (Hg2+) promote free radical-mediated oxidation of reduced porphyrins (porphyrinogens) by compromising the antioxidant potential of endogenous thiols, particularly GSH. Studies in vitro demonstrated that porphyrinogens (uroporphyrinogen and coproporphyrinogen) readily undergo H2O2-dependent oxidization in the presence of Fe3(+)-EDTA and that this action is attenuated by GSH at biologically relevant concentrations (0.5-10 mM). At low concentrations, Hg2+ complexes with GSH in a 1:2 molar ratio to decrease the antioxidant effect of GSH. However, at Hg2+ concentrations approaching saturation-complexation with available GSH, stimulation of porphyrinogen oxidation to 2 to 3 times that mediated by the H2O2/Fe3(+)-dependent system alone is observed. Stimulation of porphyrinogen oxidation by Hg2+ plus GSH increases in a dose-related manner with the concentration of H2O2 in the reaction mixture but is independent of the presence of iron. No porphyrinogen oxidation is observed in reaction mixtures containing H2O2 and either Hg2+ or GSH alone or when Hg+ is substituted for Hg2+. Studies with reactive oxidant scavengers and ESR spectroscopy suggest the participation of free radical species in Hg:GSH-mediated porphyrinogen oxidation. A mechanism involving ligand exchange between Hg2+ and GSH, which leads to formation of GS radicals and subsequent propagation of reactive oxygen-based radical species, is proposed. These studies support the view that Hg2+ both compromises the antioxidant potential of GSH and promotes formation of reactive species via thiol complexation. These findings suggest a mechanistic basis underlying the porphyrinogenic as well as tissue-damaging properties of mercuric ions.
Mol Pharmacol 1990 Aug
PMID:Stimulation of porphyrinogen oxidation by mercuric ion. I. Evidence of free radical formation in the presence of thiols and hydrogen peroxide. 216 5

Structure of the RecA x ADP(ATP) and recA x ADP x cation(+2) complexes was studied by methods of ESR, NMR and near-ultraviolet spectroscopy. The strong hypochromism in the adenine absorption band occurs. The complexes of nucleotide with cation and with protein were independently involved in the triple recA x ADP x cation(+2) complex. The triple complex can be treated as a three-link chain with the ADP localized in the middle.
Mol Biol (Mosk)
PMID:[Interaction of protein RecA with ADP (ATP): the mechanism of the ATPase reaction]. 216 82


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