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)

Histidyl dipeptides such as carnosine (beta-alanyl-L-histidine) and homocarnosine (gamma-amino-butyryl-L-histidine) are reported at millimolar concentrations in several mammalian tissues (O'Dowd et al., 1988; House et al., 1989), but their precise physiological function, or functions, is uncertain. These compounds are known to be potent buffers at physiological pH (Davey, 1960). They are also able to restore functional capacity to fatigued muscle preparations, stimulate some glycolytic enzymes and maintain coupling between mitochondrial oxidation and phosphorylation (Severin, 1964). Histidyl dipeptides may also have antioxidant activity, though this finding is controversial. For example, Aruoma et al. have argued that these compounds, individually, are unable to scavenge superoxide (O2-.), hydrogen peroxide (H2O2) or hypochlorous acid (HOCl) at rates which could offer antioxidant protection in vivo. Since there is a range of these histidyl dipeptides within mammalian tissue we have investigated possible synergism between them in respect of antioxidant activity. Our results show that combining histidine-containing compounds at near physiological concentrations results in synergistic antioxidant activity.
J Mol Cell Cardiol 1991 Nov
PMID:Synergism of histidyl dipeptides as antioxidants. 180 15

Experiments were performed to investigate the hypothesis that exposure of vascular endothelial cells to low levels of reduced oxygen products results in DNA strand breakage as an early event and to determine if endothelial cells derived from bovine pulmonary artery demonstrate a susceptibility to oxidant injury that is different from that of cells derived from bovine aorta. Endothelial cells grown in culture were exposed to H2O2 (either added directly or generated from glucose oxidase) or superoxide radical (generated from xanthine oxidase), and DNA strand breakage was determined using fluorescent analysis of DNA unwinding. Cell injury was also assessed by measuring the release of lactate dehydrogenase (LDH) or the release of 51Cr from prelabeled cells. Whereas LDH or 51Cr release detected injury resulting from exposure of endothelial cells to greater than or equal to 100 microM H2O2 and was apparent only 2 or more h after exposure, DNA strand breakage was detectable after 15 min of exposure of endothelial cells to 50 microM H2O2. Approximately equivalent DNA strand breakage resulted from exposure to 50 microM H2O2, to 25 mU glucose oxidase, or to 10 mU xanthine oxidase; this injury is similar to that seen following exposure to 10 gray X-radiation. DNA strand breakage following exposure of cells to xanthine oxidase was preventable by catalase but not by superoxide dismutase or hydroxyl radical scavengers, suggesting that H2O2 is the active extracellular oxidant mediating DNA strand breaks. No differences were seen in the susceptibility of pulmonary artery or aortic endothelial cells to oxidant injury.
Am J Respir Cell Mol Biol 1991 Jan
PMID:DNA strand break formation following exposure of bovine pulmonary artery and aortic endothelial cells to reactive oxygen products. 189 51

During carbon-starvation-induced entry into stationary phase, Escherichia coli cells exhibit a variety of physiological and morphological changes that ensure survival during periods of prolonged starvation. Induction of 30-50 proteins of mostly unknown function has been shown under these conditions. In an attempt to identify C-starvation-regulated genes we isolated and characterized chromosomal C-starvation-induced csi::lacZ fusions using the lambda placMu system. One operon fusion (csi2::lacZ) has been studied in detail. csi2::lacZ was induced during transition from exponential to stationary phase and was negatively regulated by cAMP. It was mapped at 59 min on the E. coli chromosome and conferred a pleiotropic phenotype. As demonstrated by two-dimensional gel electrophoresis, cells carrying csi2::lacZ did not synthesize at least 16 proteins present in an isogenic csi2+ strain. Cells containing csi2::lacZ or csi2::Tn10 did not produce glycogen, did not develop thermotolerance and H2O2 resistance, and did not induce a stationary-phase-specific acidic phosphatase (AppA) as well as another csi fusion (csi5::lacZ). Moreover, they died off much more rapidly than wild-type cells during prolonged starvation. We conclude that csi2::lacZ defines a regulatory gene of central importanc e for stationary phase E. coli cells. These results and the cloning of the wild-type gene corresponding to csi2 demonstrated that the csi2 locus is allelic with the previously identified regulatory genes katF and appR. The katF sequence indicated that its gene product is a novel sigma factor supposed to regulate expression of catalase HPII and exonuclease III (Mulvey and Loewen, 1989). We suggest that this novel sigma subunit of RNA polymerase defined by csi2/katF/appR is a central early regulator of a large starvation/stationary phase regulon in E. coli and propose 'rpoS' ('sigma S') as appropriate designations.
Mol Microbiol 1991 Jan
PMID:Identification of a central regulator of stationary-phase gene expression in Escherichia coli. 184 9

Superoxide dismutases (SOD) play a major role in the intracellular defense against oxygen radical damage to aerobic cells. In eucaryotes, the cytoplasmic form of the enzyme is a 32-kDa dimer containing two copper and two zinc atoms (CuZn SOD) that catalyzes the dismutation of the superoxide anion (O2-) to H2O2 and O2. Superoxide-mediated damage has been implicated in a number of biological processes, including aging and cancer; however, it is not certain whether endogenously elevated levels of SOD will reduce the pathological events resulting from such damage. To understand the in vivo relationship between an efficient dismutation of O2- and oxidative injury to biological structures, we generated transgenic strains of Drosophila melanogaster overproducing CuZn SOD. This was achieved by microinjecting Drosophila embryos with P-elements containing bovine CuZn SOD cDNA under the control of the Drosophila actin 5c gene promoter. Adult flies of the resulting transformed lines which expressed both mammalian and Drosophila CuZn SOD were then used as a novel model for evaluating the role of oxygen radicals in aging. Our data show that expression of enzymatically active bovine SOD in Drosophila flies confers resistance to paraquat, an O2(-)-generating compound. This is consistent with data on adult mortality, because there was a slight but significant increase in the mean lifespan of several of the transgenic lines. The highest level of expression of the active enzyme in adults was 1.60 times the normal value. Higher levels may have led to the formation of toxic levels of H2O2 during development, since flies that died during the process of eclosion showed an unusual accumulation of lipofuscin (age pigment) in some of their cells. In conclusion, our data show that free-radical detoxification has a minor by positive effect on mean longevity for several strains.
Mol Cell Biol 1991 Feb
PMID:Expression of bovine superoxide dismutase in Drosophila melanogaster augments resistance of oxidative stress. 189 85

This study tested whether adducts formed by covalent linkage of superoxide dismutase (SOD) or catalase to polyethylene glycol (PEG) could augment SOD and catalase activity in alveolar type II cells and document enhanced resistance to oxidant damage. Alveolar type II cells were isolated from adult, pathogen-free rats. Antioxidant enzymes were added to the medium of cell cultures in various concentrations for periods up to 48 h. Incubation with 500 to 3,000 U of PEG-SOD or 10,000 to 40,000 U of PEG-catalase/10(6) cells produced a dose-response-related increase in intracellular enzyme activity in comparison with controls (untreated or treated with SOD or catalase, inactivated PEG-SOD or PEG-catalase, or PEG alone). Uptake was maximal during the first 4 h. Using fluorescent label (fluorescein isothiocyanate) bound to PEG-catalase, we found intracellular localization of the labeled enzyme. Exposure to H2O2 led to reduced cytotoxicity in cells pretreated with PEG-catalase than in controls. We conclude that supplementation with PEG-SOD or PEG-catalase enhanced the activity of these enzymes in alveolar type II cells and increased their resistance to oxidant stress.
Am J Respir Cell Mol Biol 1991 Apr
PMID:Augmentation of superoxide dismutase and catalase activity in alveolar type II cells. 190 19

Exposure of mammalian cells to DNA-damaging agents leads to activation of a genetic response known as the UV response. Because several previously identified UV-inducible genes contain AP-1 binding sites within their promoters, we investigated the induction of AP-1 activity by DNA-damaging agents. We found that expression of both c-jun and c-fos, which encode proteins that participate in formation of the AP-1 complex, is rapidly induced by two different DNA-damaging agents: UV and H2O2. Interestingly, the c-jun gene is far more responsive to UV than any other immediate-early gene that was examined, including c-fos. Other jun and fos genes were only marginally affected by UV or H2O2. Furthermore, UV is a much more efficient inducer of c-jun than phorbol esters, the standard inducers of c-jun expression. This preferential response of the c-jun gene is mediated by its 5' control region and requires the TPA response element, suggesting that this element also serves as an early target for the signal transduction pathway elicited by DNA damage. Both UV and H2O2 lead to a long-lasting increase in AP-1 binding activity, suggesting that AP-1 may mediate the induction of other damage-inducible genes such as human collagenase.
Mol Cell Biol 1991 May
PMID:Rapid and preferential activation of the c-jun gene during the mammalian UV response. 190 48

The hydroxyl radical scavengers thiourea, ethanol, and dimethyl sulfoxide significantly reduced the killing of Escherichia coli elicited by low concentrations of H2O2 (resulting in mode 1 killing) when treatments with the oxidant and the scavengers were performed in a complete growth medium (K medium) but not in M9 salts. In addition, thiourea efficiently prevented the toxic response to high concentrations of H2O2 (resulting in mode 2 killing) under both exposure conditions. Sod A cells, which do not respond with a bimodal pattern of toxicity when challenged with increasing concentrations of H2O2, were markedly protected by thiourea against the lethal action of various levels of the oxidant (which in the wild-type strain result in either mode 1 or mode 2 killing) under conditions of treatments in both K medium and M9 salts. In some experiments, wild-type cells were challenged with a low concentration of H2O2 (in the absence or presence of hydroxyl radical scavengers) and then postincubated in fresh K medium for various time intervals. It was found that scavengers were able to inhibit the filamentous response generated by exposure to the oxidant in K medium. Both the length and the number of filaments were markedly reduced. Treatment in M9 salts resulted in a limited number of very short filaments, and this response was slightly reduced by the scavengers.
Environ Mol Mutagen 1991
PMID:Cytocidal and filamentous response of Escherichia coli cells exposed to low concentrations of hydrogen peroxide and hydroxyl radical scavengers. 190 40

The role of protein residues in activating the substrate in the reaction catalyzed by the flavoprotein p-hydroxybenzoate hydroxylase was studied. X-ray crystallography (Schreuder, H. A., Prick, P.A.J., Wieringa, R.K., Vriend, G., Wilson, K.S., Hol, W.G. J., and Drenth, J. (1989) J. Mol. Biol. 208, 679-696) indicates that Tyr-201 and Tyr-385 form a hydrogen bond network with the 4-OH of p-hydroxybenzoate. Therefore, site directed mutants were constructed, converting each of these tyrosines into phenylalanines. Spectral (visible and fluorescence) properties, reduction potentials, and binding constants are very similar to those of wild type, indicating that there are no major structural changes in the mutants. In the absence of substrate, the mutants and wild type exhibit similar pH-dependent changes in the FAD spectrum. However, the enzyme-substrate complex of Tyr-201----Phe lacks an ionization observed in both wild type and Tyr-385----Phe, which preferentially bind the phenolate form of substrates. Tyr-201----Phe shows no preference, indicating that Tyr-201 is required to ionize the substrate. The mutants have less than 6% the activity of the wild type enzyme. The effects on catalysis were studied by stopped flow techniques. Reduction of FAD by NADPH is slower by 10-fold in Tyr-201----Phe and 100-fold in Tyr-385----Phe. When the reduced Tyr-201----Phe-p-hydroxybenzoate complex reacts with oxygen, a long-lived flavin-C(4a)-hydroperoxide is observed, which slowly eliminates H2O2 with very little hydroxylation. Thus, the role of Tyr-201 is to activate the substrate by stabilizing the phenolate. Tyr-385----Phe reacts with oxygen to form 25% oxidized enzyme, and 75% flavin hydroperoxide, which successfully hydroxylates the substrate. This mutant also hydroxylates the product (3, 4-dihydroxybenzoate) to form gallic acid.
 ...
PMID:Catalytic function of tyrosine residues in para-hydroxybenzoate hydroxylase as determined by the study of site-directed mutants. 191 43

The potential role of oxidative stress conditions in the induction of heat shock proteins was studied in human umbilical vein endothelial cells. We compared the effects of temperature (43 to 45 degrees C), exposure to hydrogen peroxide (H2O2) and oxygen metabolites generated by the enzyme system hypoxanthine-xanthine oxidase (O2- plus H2O2), as well as exposure to 95% O2, on the expression of the major 70-kD heat shock proteins (hsp70). Northern blot analysis indicated that: (1) heat shock induced a rapid and marked increase in hsp70 mRNA levels that reached a maximum during recovery from a 30-min exposure to 45 degrees C; (2) treatment with a 5-mM H2O2 bolus or 50 mU/ml xanthine oxidase also increased hsp70 mRNA levels but to a lesser extent than heat shock (about 10 and 25 times less, respectively); (3) no change was detected after a 5-day exposure to 95% O2. Nuclear run on transcription data and kinetics of mRNA decay in the presence of actinomycin D indicated that the observed increase in hsp70 mRNA levels in both heat-shocked and H2O2-treated cells was mainly due to a transcriptional induction. The kinetics of hsp70 synthesis correlated with the accumulation of hsp70 mRNA. Two-dimensional gel electrophoresis and immunologic analysis of these heat shock proteins revealed a series of at least five distinct hsp70 isoforms induced in heat-shocked cells, whereas only a specific subset of these proteins, mainly one acidic isoform, was induced in very low amounts in response to H2O2 treatment. These results clearly indicate that the endothelial cell responses to oxidative stress and heat shock differ in both qualitative and quantitative terms in respect to hsp70 induction. They also suggest that the intensity of this response to oxidative stress conditions may vary depending on the nature of the oxidative challenge.
Am J Respir Cell Mol Biol 1991 Sep
PMID:Differential expression of hsp70 stress proteins in human endothelial cells exposed to heat shock and hydrogen peroxide. 191 Aug 12

A new visualization (Ce/Ce-H2O2-DAB-Ni) procedure for cerium (Ce III) phosphate in semithin and ultrathin plastic sections (Epon 812, Lowicryl K4M, glycol methacrylate) of rat kidney tissues that had been incubated before embedding for the demonstration of phosphatases (alkaline and acid phosphatase, 5(1)-nucleotidase, Mg-dependent ATPase) is described. For this purpose the hydrophobic Epon resin was removed in NaOH-ethanol solution, whereas the hydrophilic Lowicryl and methacrylate sections did not required any etching. The primary reaction product Ce III-phosphate was amplified in a Ce III-citrate solution, subsequently oxidized with H2O2 and then visualized in a H2O2 containing DAB-nickel medium (Ce IV-perhydroxy induced DAB polymerization principle). The method yielded a very clear localization of enzyme activity. The final reaction product (DAB-nickel polymers) in 0.5 - 2.0 microns semithin sections is blue-black; the background staining is completely prevented. An increase of the staining contrast was obtained by posttreatment with OsO4 (osmium black formation). Furthermore, the enzyme reaction product could be demonstrated in 40 nm thick ultrathin sections by silver intensification, which utilized the high argyrophilia of the polymerized DAB-nickel complexes. This procedure replaces the earlier published technique.
Cell Mol Biol 1991
PMID:Cerium as amplifying agent--an improved cerium-perhydroxide-DAB-nickel (Ce/Ce-H2O2-DAB-Ni) method for the visualization of cerium phosphate in resin sections. 193 7


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