Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:1.11.1.7 (peroxidase)
65,474 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The highly purified prostaglandin endoperoxide synthetase from bovine vesicular gland microsomes had two still unresolved enzyme activities; the oxygenative cyclization of 8,11,14-eicosatrienoic acid to produce prostaglandin G1 and the conversion of the 15-hydro-peroxide of prostaglandin G1 to a 15-hydroxyl group, producing prostaglandin H1. The latter enzymatic reaction required heme and was stimulated by a variety of compounds, including tryptophan, epinephrine, and guaiacol, but not by glutathione. A peroxidatic dehydrogenation was demonstrated with epinephrine or guaiacol in the presence of various hydroperoxides, including hydrogen peroxide and prostaglandin G1. Higher activity and affinity were observed with the 15-hydroperoxide of eicosapolyenoic acid, especially those with the prostaglandin structure. Both the dehydrogenation of epinephrine or guaiacol and the 15-hydroperoxide reduction of prostaglandin G1 were demonstrated in nearly stoichiometric quantities. With tryptophan, however, such a stoichiometric transformation was not observed. The peroxidase activity as followed with guaiacol and hydrogen peroxide and the tryptophan-stimulated conversion of prostaglandin G1 to H1 were not dissociable as examined by isoelectric focusing, heat treatment, pH profile, and heme specificity. The results suggest that the peroxidase with a broad substrate specificity is an integral part of prostaglandin endoperoxide synthetase which is responsible for the conversion of prostaglandin G1 to H1.
...
PMID:Prostaglandin hydroperoxidase, an integral part of prostaglandin endoperoxide synthetase from bovine vesicular gland microsomes. 10 98

The membrane-bound prostaglandin endoperoxide synthetase was purified until homogeneity, starting from sheep vesicular glands. The enzyme was obtained as a complex with Tween-20, containing 0.69 mg detergent per mg protein. No residual phospholipid could be detected. Prostaglandin endoperoxide synthetase appeared to be a glycoprotein, containing mannose and N-acetyl-glucosamine. No haemin or metal atoms were present. A molecular weight of 126 000 was found for the apoprotein by ultracentrifugation in 0.1% Tween solutions. The polypeptide chain without carbohydrate had a molecular weight of 69 000 as determined by sodium dodecyl sulphate-polyacrylamide gel electrophoresis. The pure enzyme displays both cyclooxygenase and peroxidase activity, thus converting arachidonic acid into prostaglandin H2. The isolated synthetase requires haemin, which possibly acts as an easily dissociable prosthetic group, and a suitable hydrogen donor to protect the enzyme from peroxide inactivation and which is consumed in stoichiometric amounts to reduce the intermediate hydroperoxy group.
...
PMID:Purification and characterisation of prostaglandin endoperoxide synthetase from sheep vesicular glands. 40 45

Peroxidase activity in the uterine luminal fluid of mice treated with diethylstilbestrol was measured by the guaiacol assay and also by the formation of 3H2O from [2-3H]estradiol. In the radiometric assay, the generation of 3H2O and 3H-labeled water-soluble products was dependent on H2O2 (25 to 100 microM), with higher concentrations being inhibitory. Tyrosine or 2,4-dichlorophenol strongly enhanced the reaction catalyzed either by the luminal fluid peroxidase or the enzyme in the CaCl2 extract of the uterus, but decreased the formation of 3H2O from [2-3H]estradiol by lactoperoxidase in the presence of H2O2 (80 microM). NADPH, ascorbate, and cytochrome c inhibited both luminal fluid and uterine tissue peroxidase activity to the same extent, while superoxide dismutase showed a marginal activating effect. Lactoferrin, a major protein component of uterine luminal fluid, was shown not to contribute to its peroxidative activity, and such an effect by prostaglandin synthase was also ruled out. However, it was not possible to exclude eosinophil peroxidase, brought to the uterus after estrogen stimulation, as being the source of peroxidase activity in uterine luminal fluid.
...
PMID:Characteristics of estrogen-induced peroxidase in mouse uterine luminal fluid. 165 74

EPR spectroscopy was used to study the effects of various nonsteroidal anti-inflammatory agents on the peroxidase-related tyrosyl radical present in prostaglandin H synthase (prostaglandin endoperoxide synthase; EC 1.14.99.1). Two types of perturbation of the tyrosyl radical by these anticyclooxygenase agents were observed. In the first case, aspirin, indomethacin, ibuprofen, (S)-flurbiprofen, and (S)-naproxen converted the doublet tyrosyl EPR signal seen on reaction of the uninhibited enzyme with ethyl hydroperoxide to a singlet bearing additional partially resolved hyperfine splittings. These compounds also decreased the maximum amount of radical generated, but they did not change the kinetics of formation and decay of the tyrosyl radical. In the second case, acetaminophen and three fenamate analogs (meclofenamate, flufenamate, and mefenamate) did not perturb the EPR line shape observed after reaction with hydroperoxide but did cause a more rapid decay of the tyrosine radical species. It would appear that, despite considerable variation in structure, the nonsteroidal anti-inflammatory agents may inhibit the cyclooxygenase activity of the synthase by two basic mechanisms.
...
PMID:Prostaglandin H synthase: perturbation of the tyrosyl radical as a probe of anticyclooxygenase agents. 165 13

Prostaglandin endoperoxide synthase (PES, EC 1.14.99.1) catalyse the conversion of arachidonic acid into prostaglandin H2. The enzyme is a 140 kDa homodimer which contains both a cyclo-oxygenase activity (converting arachidonate into prostaglandin G2) and peroxidase activity (reducing prostaglandin G2 to H2). PES undergoes rapid self-inactivation during oxygenation of arachidonate to prostaglandin H2 in vitro. The previously reported cDNA-derived amino acid sequence indicates numerous sites for trypsin or thrombin cleavage. Most of these sites must be inaccessible, since these enzymes cleave only at Arg253. The enzyme appears to be a self-adherent and highly folded molecule, since after cleavage it retains its functional assembly and its homodimer size of 140 kDa, as well as its overall enzymic activity. Only under denaturing conditions (e.g. SDS/PAGE) can the proteolytic peptides be demonstrated: a 38 kDa C-terminal fragment containing the aspirin-derived-acetyl-binding ability, and a 33 kDa N-terminal fragment. In the present studies we investigated whether the two enzymic activities of PES can be differentially manipulated by proteolytic cleavage or by substrate (arachidonate) self-inactivation. The results indicated that, during arachidonate oxygenation by PES, the cyclooxygenase activity is selectively inactivated, whereas the peroxidase activity is essentially retained. By contrast, thrombin or trypsin cleavage of pure PES or microsomal PES (to yield the 38 and 33 kDa peptide fragments) inactivated the peroxidase, but not the cyclo-oxygenase. Taken together, these results suggest the presence of separate cyclo-oxygenase and peroxidase structural domains on the enzyme.
...
PMID:Differential modification of cyclo-oxygenase and peroxidase activities of prostaglandin endoperoxidase synthase by proteolytic digestion and hydroperoxides. 211 18

The mechanism of activation of the bladder carcinogen 2-amino-4-(5-nitro-2-furyl)thiazole (ANFT) was investigated by comparison with benzidine. In comparison with benzidine, ANFT has a higher electrochemical potential (approximately 700 mV) and is less effective as a reducing co-substrate for either prostaglandin H synthase (PHS) or horseradish peroxidase. Activation was monitored by measuring binding to protein (BSA) and DNA. ANFT binding to protein was reduced by indomethacin, a fatty acid cyclooxygenase inhibitor; phenol and aminopyrine, competitive reducing co-substrates; ascorbic acid, an antioxidant; and glutathione, thioether conjugate formation. These results are consistent with those previously reported for benzidine and demonstrate a peroxide co-substrate requirement, interaction of peroxidase with amine, formation of reactive intermediates and inactivation of reactive intermediates. 5,5-Dimethyl-1-pyrroline N-oxide (DMPO), a radical trap, also reduced ANFT binding to protein. Similar results were observed whether activation by PHS or horseradish peroxidase was investigated. Peroxidative activation of ANFT and benzidine to bind DNA was inhibited by these test agents in a manner similar to that observed with protein except that DMPO did not reduce binding. In addition, 2-methyl-2-nitrosopropane and methyl viologen, which are radical traps, and methionine and p-nitrobenzyl-pyridine, which are strong nucleophiles, did not reduce ANFT or benzidine binding to DNA. These agents also did not prevent binding of benzidinediimine, the two-electron product of benzidine oxidation, to polydeoxyguanosine. Glutathione inhibited diimine binding by forming a conjugate. Results demonstrate that activation of ANFT to bind protein and DNA is similar to benzidine. Peroxidative activation of benzidine occurs by both one- and two-electron oxidation. A similar mechanism would explain ANFT binding to protein (one electron) and DNA (two electron).
...
PMID:Mechanism of peroxidative activation of the bladder carcinogen 2-amino-4-(5-nitro-2-furyl)-thiazole (ANFT): comparison with benzidine. 212 82

This review presents a unifying hypothesis that provides a connection between several types of hypersensitivity reactions associated with several types of drugs and explains some of the therapeutic effects (antiinflammatory activity and antithyroid effects) of these same drugs. This hypothesis centers on the oxidation of these drugs to chemically reactive metabolites by peroxidases. The drugs of interest have functional groups that are easily oxidized. The major peroxidase involved in this hypothesis is MPO because of its critical location in leukocytes which play a key role in the function of the immune system. However, thyroid peroxidase can probably also oxidize many of the same drugs to reactive metabolites, and this may be responsible for the thyroid autoimmunity observed in connection with some hypersensitivity reactions. Peroxidases have also been described in the skin and in platelets, and their presence may be responsible for the high incidence of skin reactions in the hypersensitivity response and the occurrence of immune-mediated thrombocytopenia, respectively. Involvement of other peroxidases, such as prostaglandin peroxidase, may also be important for antiinflammatory effects of drugs. In addition, leukocytes contain prostaglandin synthetase, and the activation of leukocytes leads to the release of arachidonic acid and the production of prostaglandins. This process may also lead to the metabolism of drugs to reactive metabolites. In studies of the metabolism of procainamide and dapsone, aspirin and indomethacin did not inhibit the formation of the hydroxylamine by neutrophils and mononuclear leukocytes. This is evidence against the involvement of prostaglandin synthetase in these oxidation; however, preliminary studies with other drugs suggest that prostaglandin synthetase may contribute to the metabolism of some drugs by leukocytes. Furthermore, the metabolism of phenylbutazone, phenytoin, and tenoxicam, as well as our preliminary work with other drugs such as carbamazepine, suggests that the range of drugs that are metabolized to reactive metabolites by peroxidases may be broader than initially suspected. There are several other drugs that do not fit into the functional group classes covered in this review but have similar properties. A good example is alpha-methyldopa, which is associated with drug-induced lupus, immune-mediated hemolytic anemia, and other hypersensitivity reactions. Such drugs may also be metabolized to reactive metabolites by peroxidases. Another aspect of the hypothesis is that an infection, or other inflammatory condition, may be an important risk factor for a hypersensitivity reaction because such a stimulus leads to activation of leukocytes which can lead to formation of reactive metabolites from certain drugs.(ABSTRACT TRUNCATED AT 400 WORDS)
...
PMID:Drug metabolism by leukocytes and its role in drug-induced lupus and other idiosyncratic drug reactions. 217 25

Peroxidases can metabolize a variety of xenobiotics to reactive intermediates capable of binding to protein or DNA. The potential role of these enzymes in fetotoxicity has not been explored. In this study, the presence of peroxidase activity was observed in human term and pre-term placenta. Human term placental peroxidase activity (HTPP) was partially purified by concanavalin A affinity chromatography from CaCl2 extracts of the particulate fraction. HTPP appears to be a membrane-bound glycoprotein. Arachidonic acid-dependent oxidation of guaiacol was not observed, suggesting that the peroxidase activity was not due to prostaglandin synthase. Moreover, HTPP preparations were devoid of catalase and spectrally dissimilar from human haemoglobin, cytochrome P-450, eosinophil peroxidase and myloperoxidase, suggesting an endogenous origin. An Mr of approx. 119,000 was determined for HTPP by gel filtration. Cathodic slab-PAGE of cetyltrialkylammonium bromide-solubilized HTPP yielded two peroxidase-staining bands.
...
PMID:Partial purification and characterization of a peroxidase activity from human placenta. 236 7

Watanabe and colleagues (Biochem. Biophys. Res. Commun. 147: 974-979, 1987) have constructed plasmid-containing derivatives of Salmonella typhimurium Ames tester strain TA1538 with high levels of acetyltransferase activities. In this paper, we describe the mutagenic response of one of these strains, TA1538/1,8-DNP6 (pYG 121), to the bladder carcinogen benzidine and other arylamines. Strain TA1538/1,8-DNP6 (pYG 121) was far more sensitive to benzidine than any previous tester strain, following metabolism of the aromatic amine by hamster hepatic S9, ram seminal vesicle microsomal preparation (RSVM), or purified prostaglandin synthase. Therefore, bacterial acetyltransferase-dependent metabolism of a proximate mutagen is implicated in each of these systems. The mechanism of RSVM-dependent activation of benzidine was examined further. The arachidonic acid-independence and indomethacin insensitivity previously noted with strain TA98 were also observed with the new tester strain. We confirmed that prostaglandin H synthase is the enzyme activity responsible for activation of benzidine by RSVM. Purified prostaglandin H synthase holoenzyme, or apoenzyme reconstituted with heme, supported benzidine activation. However, apoenzyme reconstituted with manganese protoporphyrin IX, which yields enzyme having cyclooxygenase activity but not peroxidase activity, was inactive. Addition of catalase inhibited, and addition of exogenous hydrogen peroxide increased, RSVM-mediated benzidine mutagenicity. We propose that hydrogen peroxide released by the tester strain bacteria (rather than arachidonic acid-derived peroxide) is the oxidizing agent which supports prostaglandin H synthase peroxidase activity in Ames test systems.
...
PMID:Prostaglandin H synthase-dependent mutagenic activation of benzidine in a Salmonella typhimurium Ames tester strain possessing elevated N-acetyltransferase levels. 249 7

The food antioxidants butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) are shown to be metabolized to covalent binding intermediates and various other metabolites by prostaglandin H synthase and horseradish peroxidase. BHA was extensively metabolized by horseradish peroxidase (80% conversion of parent BHA into metabolites) resulting in the formation of three dimeric products. Only two of these dimers were observed in prostaglandin H synthase-catalyzed reactions. In contrast to BHA, BHT proved to be a relatively poor substrate for prostaglandin synthase and horseradish peroxidase, resulting in the formation of a small amount of polar and aqueous metabolites (23% conversion of parent BHT into metabolites). With arachidonic acid as the substrate, prostaglandin H synthase catalyzed the covalent binding of [14C]BHA and [14C]BHT to microsomal protein which was significantly inhibited by indomethacin and glutathione. The covalent binding of BHA and its metabolism to dimeric products were also inhibited by BHT. In contrast, the addition of BHA enhanced the covalent binding of BHT by 400%. Moreover, in the presence of BHA, the formation of the polar and aqueous metabolites of BHT was increased and two additional metabolites, BHT-quinone methide and stilbenequinone, were detected. The increased peroxidase-dependent oxidation of BHT in the presence of BHA is proposed to occur via the direct chemical interaction of BHA phenoxyl radical with BHT or BHT phenoxyl radical. These results suggest a potential role for phenoxyl radicals in the activation of xenobiotic chemicals to toxic metabolites.
...
PMID:The peroxidase-dependent activation of butylated hydroxyanisole and butylated hydroxytoluene (BHT) to reactive intermediates. Formation of BHT-quinone methide via a chemical-chemical interaction. 249 93


1 2 3 4 5 6 7 8 Next >>

---