Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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At physiological pH values, Cu(II)-tetraglycine and Cu(II) complexes with peptides containing a histidyl residue at the N-terminal caused DNA strand breakage in the presence of H2O2, whereas Cu(II) complexes with peptides containing histidyl residue in the second or third position did not. Because of the correlation between the generation of hydroxyl radical and DNA strand scission, a mechanism for the reaction is proposed.
Biochem Mol Biol Int 1994 Oct
PMID:Oxidative DNA damage induced by Cu(II)-oligopeptide complexes and hydrogen peroxide. 786 7

The kinetic parameters of almond beta-glucosidase (beta-D-glucoside glucohydrolase; EC 3.2.1.21), using pNGP as substrate were kM = 2.24 +/- 0.11 mM and Vmax 588 +/- 25.1 U/mg protein. Only Hg(II) and Cu(II) showed irreversible inactivation of the enzyme. However, when these metals were present in the reaction system the inhibition effects were consistent with a mixed-type inhibition pattern (Cu(II) ki: 5.08 mM and Hg(II) ki: 0.07 mM). The glucose kinetic effect was also consistent with a mixed-type inhibition (ki = 406 mM) pattern with pNGP as varied substrate. Ethanol displayed the kinetic pattern of competitive inhibition (ki = 640 mM).
Biochem Mol Biol Int 1994 Aug
PMID:Effects of glucose, ethanol, Hg(II) and Cu(II) on almond beta-glucosidase. 798 62

Repair of quercetin-induced single-strand breaks of DNA was studied in vitro using cell free extract from GM 00637D cells, a human cell line. Single-strand breaks were introduced into DNA by the treatment of closed circular, superhelical form of pBR322 plasmid DNA with quercetin and Cu(II). Repair of these breaks was demonstrated by agarose gel electrophoresis after incubating damaged DNA with cell extract, DNA polymerase I (klenow fragment of DNA polymerase), four deoxynucleotide triphosphates, ATP and T4 DNA ligase. The present results suggested that 1) the exonuclease is involved in the initiation of repair of quercetin-induced single-strand breaks by removing the 3' ends of quercetin damaged DNA and 2) oxygen free radicals are involved in quercetin-induced DNA strand scission.
Biochem Mol Biol Int 1994 Feb
PMID:Repair of quercetin-induced single-strand breaks by a cell free system. 801 39

The conversion of the closed circular double stranded supercoiled DNA (pBR322) to the nicked circular form and linear form was used to investigate DNA nicking induced by the reactions of Cu(II) complexes with hydrogen peroxide (H2O2). As a result, the dose-response curve for the CuII(en) (en:ethylenediamine) mediated H2O2 dependent DNA nicking was observed. For a fixed concentration of CuII(en)2 (1 mM), the concentration of H2O2 producing a maximum extent of DNA nicking was 100 mM. On the other hand, for a fixed concentration of H2O2 (100 mM), the concentration of CuII(en)2 was 1 mM. That is, when the concentration ratio of H2O2 to CuII(en)2 was 100, a maximum extent of DNA nicking was observed. This result is a good accordance with that observed by thiobarbituric acid (TBA) and ESR-spin trapping methods. This result gives first experimental evidence that Cu(II) complex did cause the DNA damage in the presence of H2O2. On the other hand, CuII(edta) (edta: ethylenediaminetetraacetic acid) did not cause the DNA strand breaks with the reaction of H2O2, but it was activated by addition of the biological reductant such as ascorbic acid in the presence of H2O2 to cause the DNA strand breaks.
Biochem Mol Biol Int 1993 Nov
PMID:DNA single strand breakage by copper(II) complexes and hydrogen peroxide at physiological conditions. 811 20

The transcription factor ALCR of the ethanol utilisation pathway in Aspergillus nidulans contains a zinc binuclear motif (CysX2CysX6CysX16CysX2CysX6Cys), within the DNA-binding domain located in the N-terminal region of the ALCR protein. Specific targets have been localised in the promoter of the alcR gene, involved in the autoregulation process, and in the promoter of the structural gene alcA (encoding alcohol dehydrogenase I), which is also under the control of ALCR. The DNA-binding domain has been expressed in-Escherichia coli as a GST-ALCR (7-58*) fusion protein and also obtained as an ALCR (7-58*) peptide. Both the ALCR fusion protein and the ALCR peptide are able to bind 65Zn(II) in vitro, if reduction of cysteines occurs prior to the addition of zinc. Competition experiments showed that Cd(II), Co(II) and Cu(II) are efficient competitors for the zinc binding sites. The ALCR DNA-binding domain was shown to contain 2 mol of tightly bound Zn(II) per mole of fusion protein. Removal of the intrinsic Zn(II) requires treatment with Chelex. This treatment abolishes the ability of the protein to bind to the targets of ALCR located in the alcA and alcR promoters. The apo-ALCR DNA-binding motif could be reconstituted with Zn(II) or Cd(II), restoring specific DNA binding to both types of targets. Thus a direct relationship was shown to exist between the zinc content of ALCR and its DNA-binding activity.
Mol Gen Genet 1994 Jan
PMID:Relationship between zinc content and DNA-binding activity of the DNA-binding motif of the transcription factor ALCR in Aspergillus nidulans. 827 45

The dependence of the properties of the azurin blue copper site on the nature of the axial ligand at position 121 was tested by site-directed mutagenesis. This residue was substituted for a glutamine, the purported fourth copper ligand in the related protein stellacyanin. M121Q azurin was isolated and purified from Escherichia coli and characterized by spectroscopic methods. The mutant copper site has the ultra-violet-vis and electron paramagnetic resonance (EPR) characteristics of a type I site, but the spectroscopic details differ significantly from wild-type (wt) azurin. The X and S-band EPR spectra of M121Q azurin can be well stimulated with the parameters for stellacyanin, indicating that the copper sites of both proteins in the oxidized state are similar. The midpoint potential of M121Q is 263 mV, 25 mV lower than for wt azurin. The reactivity of the mutant was probed by measuring the electron self exchange rate by nuclear magnetic resonance spectroscopy. The rate was 8 x 10(3) mol-1 s-1, almost two orders of magnitude lower than the value for wt azurin (5 x 10(5) mol-1 s-1). Detailed structural information on the M121Q Cu(II)-site was obtained by X-ray analysis of M121Q azurin crystals at 1.9 A resolution. The histidine and cysteine copper ligand distances and angles in the equatorial plane around the copper are very similar to the wt protein. Gln121 is co-ordinated in a monodentate fashion via its side-chain oxygen atom at a distance of 2.26 A. The distance between copper and the carbonyl group of Gly45 is increased from 3.13 A (wt) to 3.37 A resulting in a distorted tetrahedral N2SO copper co-ordination. The possible significance of these results for the structure of the copper site of stellacyanin, the only small blue copper protein lacking a methionine ligand, is discussed. Conformational changes with respect to the wt azurin are seen in some of the connecting loops between secondary structure elements, in the mutation site and in the beta-strand 2a. The side-chains involved in the hydrophobic patch surrounding His117 are subject to large changes in their conformations. In contrast to wt azurin, the copper site in M121Q azurin undergoes significant structural changes on reduction.(ABSTRACT TRUNCATED AT 400 WORDS)
J Mol Biol 1993 Feb 20
PMID:X-ray analysis and spectroscopic characterization of M121Q azurin. A copper site model for stellacyanin. 838 7

Copper(II)-albumin complex did not directly react with hydrogen peroxide (H2O2). However, Cu(II)-albumin complex was easily reduced to Cu(I) complex by some biological reductants such as L-cysteine and L-ascorbic acid. Cu(I) complex thus formed could react with H2O2 to give hydroxyl radical (.OH) which was detected by electron spin resonance (ESR) spectroscopy using some water-soluble spin-traps. This result gives the first ESR evidence for the formation of OH radical by the reaction of Cu(II)-albumin with H2O2 in the presence of biological reductants.
Biochem Mol Biol Int 1993 Feb
PMID:Copper(II)-albumin complex can activate hydrogen peroxide in the presence of biological reductants: first ESR evidence for the formation of hydroxyl radical. 838 92

A mutagenic steroidal derivative (3 beta-Acetoxy-5 alpha-Cholestano[6 alpha,5-d']1'-3'oxathiolane-2' thione) structurally related to cholesterol caused strand scission and induced nicks in calf thymus, supercoiled pBR322 and single stranded M13 mp8 phage DNAs. S1 nuclease hydrolysis, reaction with pBR322 and M13 phage DNA as well as treatment of E. coil mutant strains and phage was used to evaluate the effect of test steroid on the DNA molecule. The strand scission/nicking of DNA by the test steroid was enhanced by some metal ions, especially the Cu(II). Scavengers of active oxygen radical species significantly inhibited the S1 nuclease hydrolysis by the test steroid indicating the major role of active oxygen species in DNA strand scission and nicking. The steroid brought about the DNA degradation even in the absence of S1 nuclease. There was an appreciable reduction in the survival of steroid treated polA and lig mutants of E. coli K12 compared to the wild type strain. Phage on steroid treatment also lost its plaque forming units (P.F.U.) which was more pronounced in the polA and rec A background.
Biochem Mol Biol Int 1993 Mar
PMID:Steroid induced single strand breaks in DNA mediated by active oxygen species and its biological consequences. 848 66

We examined the effects of various metal ions on the DNA-binding activity of the glucocorticoid receptor. Electrophoretic mobility shift assays demonstrated that the sequence-specific DNA binding activity of the receptor was decreased by metal ions in a dose-dependent fashion. The most potent inhibitor was Au(I). Cu(II), Cd(II), and Zn(II) were, in that order, less potent as inhibitors, whereas Fe(III), Al(III), and Mg(II) had no apparent effect. The inhibitory actions of metal ions were efficiently counteracted by the sulfhydryl reducing reagents 2-mercaptoethanol and N-acetyl-L-cysteine, indicating that metal ions interfere with the DNA binding activity of the glucocorticoid receptor through modification of sulfhydryl groups in the receptor molecule. Modification of sulfhydryls by metals seems to involve neither disulfide bond formation nor permanent destruction of the GR protein and is reversible. We also show that metal ions inhibit glucocorticoid-inducible gene transcription in vivo, presumably by interfering with the interaction between the glucocorticoid receptor and cognate DNA target sequences. In summary, these data demonstrates that metal ions are capable of modulating glucocorticoid receptor mediated intracellular signalling pathways.
Mol Pharmacol 1996 Apr
PMID:Modulation of glucocorticoid-inducible gene expression by metal ions. 860 88

Cu/Zn-superoxide dismutase (Cu/Zn-SOD) has been shown to modulate the autoxidation of a variety of phenoic compounds, including 1,4-hydroquinone (HQ), a benzene-derived metabolite. The acceleration of autoxidation of HQ by Cu/Zn-SOD results in the production of 1,4-benzoquinone (BQ). It has been proposed that the chemical mechanism involved in the Cu/Zn-SOD-catalyzed autoxidation of HQ may be occur through either its conventional activity as a superoxide:superoxide oxidoreductase or as a semiquinone:superoxide oxidoreductase. However, Cu/Zn-SOD-accelerated oxidation of HQ has not been resolved experimentally. In this study, with ESR spectroscopy we investigated further the chemical reactions involved in the SOD-accelerated oxidation of HQ. In phosphate-buffered saline (PSB), HQ underwent a slow autoxidation to BQ, which was accelerated by Cu/Zn-SOD, Mn-SOD, or Fe-SOD with similar efficiency. In contrast, among free metals, only Cu(II) strongly mediated the oxidation of HQ to BQ. Mn(II) exhibited a slight capacity to oxidize HQ, whereas neither FE(II) nor FE(III) was capable of modulating the autoxidation of HG. The presence of either form of SOD also dramatically enhanced the formation of semiquinone anion radicals SQ-. from HQ. The SOD-accelerated oxidation of HQ was also accompanied by the generation of H202. In PBS containing bovine serum albumin (BSA) (PBS/BSA), HQ did not undergo autoxidation to SQ-., and as such the presence of SOD was unable to induce the formation of either SQ-. or BQ or the consumption of O2. The addition of 10 microM BQ to HQ (100 or 1000 microM) in PBS/BSA resulted in the formation of SQ-. and initiated a slow rate of oxidation of HQ to BQ. In this case, the presence of Cu/Zn-SOD strongly accelerated the oxidation of HQ to SQ-. and BQ and the utilization of O2. Furthermore, the enhancement by Cu/Zn-SOD of the generation of SQ-. or BQ from HQ in PBS/BSA was extensively inhibited under anaerobic conditions. The enhancement of SQ-. generation from HQ by all three forms of SOD does not support the possibility that Cu/Zn-SOD can oxidize SQ-. to BQ. Taken together, this study demonstrates that unlike free copper, Cu/Zn-SOD does not directly interact with HQ to cause its oxidation to BQ. Rather, the autoxidation of HQ to SQ-. is a prerequisite for the enhancing capacity of Cu/Zn-SOD, and the dismutation of superoxide anion radicals generated from the SQ-. in the presence of O2 appears to be the underlying mechanism responsible for the enhancement by Cu/Zn-SOD of the oxidation of HQ.
Mol Pharmacol 1996 Mar
PMID:Role of Cu/Zn-superoxide dismutase in xenobiotic activation. I. Chemical reactions involved in the Cu/Zn-superoxide dismutase-accelerated oxidation of the benzene metabolite 1,4-hydroquinone. 864 79


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