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

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

The three-dimensional structure of the enzyme myeloperoxidase has been determined by X-ray crystallography to 3 A resolution. Two heavy atom derivatives were used to phase an initial multiple isomorphous replacement map that was subsequently improved by solvent flattening and non-crystallographic symmetry averaging. Crystallographic refinement gave a final model with an R-factor of 0.257. The root-mean-square deviations from ideality for bond lengths and angles were 0.011 A and 3.8 degrees. Two, apparently identical, halves of the molecule are related by local dyad and covalently linked by a single disulfide bridge. Each half-molecule consists of two polypeptide chains of 108 and 466 amino acid residues, a heme prosthetic group, a bound calcium ion and at least three sites of asparagine-linked glycosylation. There are six additional intra-chain disulfide bonds, five in the large polypeptide and one in the small. A central core region that includes the heme binding site is composed of five alpha-helices. Regions of the larger polypeptide surrounding this core are organized into locally folded domains in which the secondary structure is predominantly alpha-helical with very little organized beta-sheet. A proximal ligand to the heme iron atom has been identified as histidine 336, which is in turn hydrogen-bonded to asparagine 421. On the distal side of the heme, histidine 95 and arginine 239 are likely to participate directly in the catalytic mechanism, in a manner analogous to the distal histidine and arginine of the non-homologous enzyme cytochrome c peroxidase. The site of the covalent linkage to the heme has been tentatively identified as glutamate 242, although the chemical nature of the link remains uncertain. The calcium binding site has been located in a loop comprising residues 168 to 174 together with aspartate 96. Myeloperoxidase is a member of a family of homologous mammalian peroxidases that includes thyroid peroxidase, eosinophil peroxidase and lactoperoxidase. The heme environment, defined by our model for myeloperoxidase, appears to be highly conserved in these four mammalian peroxidases. Furthermore, the conservation of all 12 cysteine residues involved in the six intra-chain disulfide bonds and the calcium binding loop suggests that the three-dimensional structures of members of this gene family are likely to be quite similar.
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PMID:X-ray crystal structure of canine myeloperoxidase at 3 A resolution. 132 Jan 28

Myeloperoxidase (MPO) is a heme-containing glycoprotein found in the primary granules (or azurophilic granules) of human polymorphonuclear leukocytes. In the present study, cultured myeloid leukemia HL-60 cells were exposed for 0-72 h to 250 microM 4,6-dioxoheptanoic acid (succinylacetone, SA), a specific inhibitor of heme biosynthesis, and the effects were evaluated using ultrastructural, immunochemical, and cytochemical methods. En bloc peroxidase staining of glutaraldehyde-fixed cells was accomplished with a 30-min exposure to 3,3'-diaminobenzidine (DAB) tetrahydrochloride. Ultrastructural examination revealed that peroxidase reactivity in the endoplasmic reticulum (ER) was relatively unchanged for 8 h and decreased between 12 and 24 h; however, ER lacked DAB-reactive peroxidase at 48-72 h. Peroxidase reactivity in the ER reappeared within 4 h after removal of SA. Seventy-two hours after exposure to SA the number of condensed cytoplasmic granules stained with DAB was significantly decreased, and many of the granules had a "target" appearance with a central DAB-reactive dense core. Staining of mitochondria was observed with overnight exposure to DAB and persisted in HL-60 cells treated 72 h with SA. Mitochondrial and nuclear morphology appeared unaltered. Immunostaining of MPO in thin sections of paraformaldehyde/glutaraldehyde-fixed unosmicated HL-60 cells, embedded in Lowicryl K4M, was accomplished with sequential exposure to an affinity-purified monospecific rabbit antibody to HL-60-MPO and protein A conjugated to 5- or 10-nm colloidal gold. Compared to untreated control HL-60 cells, cells exposed to SA for 48 h exhibited comparable to increased immunoreactive MPO in the ER, despite the absence of heme-dependent peroxidase reactivity. The data indicate that SA inhibits formation of enzymatically active MPO and that in the presence of SA, the ER contains a form(s) of MPO that lacks enzymatic reactivity.
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PMID:Ultrastructural, immunochemical, and cytochemical study of myeloperoxidase in myeloid leukemia HL-60 cells following treatment with succinylacetone, an inhibitor of heme biosynthesis. 132 Oct 53

Myeloperoxidase was solubilized with hexadecyltrimethylammonium bromide and myeloperoxidase activity was measured with a dianisidine-H2O2 assay in the ischemic area after middle cerebral artery occlusion in rats. This enzyme could be measured 6 hours after the occlusion of the middle cerebral artery, then showed two peaks, one after 8 hours and another after 18 to 24 hours in 2 phase fashion as could be measured as far as 7 days, which was the termination of this experiments. These findings suggest that leukocyte infiltration into the ischemic area play an important role for the extension of the ischemic area. Further study should undertake whether leukocyte depletion decrease the ischemic area or not.
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PMID:[Myeloperoxidase activity as an indicator of leukocyte infiltration into the ischemic area in the middle cerebral artery occlusion model of the rats]. 132 20

The role of neutrophils in the pathogenesis of acute colitis was investigated using a rabbit model. Colitis was induced by intracolonic administration of trinitrobenzene sulfonic acid in 30% ethanol. Myeloperoxidase activity was measured at various times after induction of colitis as an index of neutrophil infiltration, and this was confirmed by histology. The permeability of the colonic epithelium to [51Cr]EDTA was also measured at various times after induction of colitis. The most marked increase in neutrophil infiltration of the colon occurred during the period 3-6 h after induction of colitis. This was also the period in which the greatest increase in colonic permeability was observed. Pretreatment with a monoclonal antibody (IB-4) directed against the leukocyte adhesion molecule, CD18, markedly suppressed neutrophil infiltration into the colonic tissue after induction of colitis. This pretreatment also significantly reduced the extent of epithelial injury. Administration of IB-4 to rabbits 12 h after induction of colitis resulted in a rapid decline in tissue myeloperoxidase activity. When measured 12 h after IB-4 administration (3 mg/kg), colonic myeloperoxidase activity was reduced by about 80% compared to the control group treated with the vehicle. These results are consistent with the hypothesis that neutrophils contribute significantly to the epithelial dysfunction that characterizes colitis and suggest that antibodies directed against adhesion molecules may represent a novel approach to the treatment of intestinal inflammatory disorders.
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PMID:Prevention and reversal of experimental colitis by a monoclonal antibody which inhibits leukocyte adherence. 132 82

Myeloperoxidase and defensin interaction with lipid mixtures of phosphatidylcholine and cholesterol or rat eye lens lipids were studied. The solubility of myeloperoxidase in 1-octanol and octanol was determined. It was shown that myeloperoxidase can be concentrated at the interface and is readily soluble in the membrane lipid phase. Defensins exhibit similar properties and increase, in addition, the cholesterol-rich monolayer tension. Possible consequences of highly cationic proteins adsorption on cholesterol-rich membranes are discussed.
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PMID:[Interaction of myeloperoxidase and defensins with lipid monolayers]. 132 87

Myeloperoxidase (MPO)- and Sudan Black B-not more than 3%-positive, esterase staining-negative, lymphoid, megakaryocyte lineage and erythroid surface marker-negative and electron microscopic platelet peroxidase-negative acute leukemia (AL) was diagnosed as acute undifferentiated leukemia (AUL), and myeloid marker (CD13, CD33), electron microscopic MPO (EMMPO), and DNA analysis of immunoglobulin heavy chain and T cell receptor as well as chemotherapy and its reactivity were examined. Of 239 cases of AL, 10 (4.2%) were AUL, and of these 10 cases, 9 were CD13 or CD33-positive AML-MO (MO) cases. Of 9 cases examined for EMMPO, 4 (44%) were positive, and of 3 cases of MO subjected to DNA analysis, 1 and 1 showed rearrangements of immunoglobulin heavy chain and T cell receptor beta chain, respectively. Of 6 cases of MO on myeloid induction therapy, 1 and 1 showed complete remission (CR) and partial remission (PR), respectively, each having lymphoid genotype, and 4 showed no remission (NR), being 3 of them EMMPO-positive. Of 2 cases on lymphoid induction therapy, 1 and 1 showed CR and NR, respectively, the former being EMMPO-positive MO. BHAC-EM therapy with behenoyl cytosine arabinoside, VP-16 and mitoxantrone performed on 2 cases refractory to any one of both these myeloid and lymphoid induction therapies led to CR in all these 2 cases.
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PMID:[Acute undifferentiated leukemia from the viewpoints of diagnosis and therapy]. 133 62

The tuberculostatic agent isoniazid has been implicated in inducing various idiosyncratic reactions including drug-induced lupus. The mechanism is unknown but may involve a reactive metabolite of the drug. Isoniazid was oxidized by activated leukocytes to isonicotinic acid. Myeloperoxidase is likely the enzyme in the leukocyte involved, since the oxidation was inhibited by azide, which inhibits myeloperoxidase, and by catalase, which catalyzes the breakdown of hydrogen peroxide. The same metabolic profile was observed when isoniazid was incubated with purified myeloperoxidase and hydrogen peroxide. The rate of the reaction was increased in the presence of chloride. Hypochlorous acid was also able to oxidize isoniazid to isonicotinic acid. Isoniazid, or an oxidative product, inhibited the reaction when high initial substrate concentrations were used. Isoniazid is oxidized by activated leukocytes, possibly to a reactive intermediate, which may have implications for isoniazid-induced lupus.
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PMID:Metabolism of isoniazid by activated leukocytes. Possible role in drug-induced lupus. 135 11

Myeloperoxidase (MyPo) is an enzyme found in neutrophils and monocytes that plays an important role in the microbicidal and cytocidal activities of these cells. The present studies show that this enzyme can also affect both capacities and functions of macrophages. When resident peritoneal macrophages from C57BL/6 mice were exposed to preparations of either human or canine enzyme in vitro, tumor necrosis factor (TNF) was released. The amount of TNF produced was dose dependent and could be neutralized with polyclonal anti-TNF. Low levels of interferon were also produced by these cells. In addition, exposure of murine macrophages in vitro to this enzyme resulted in increased ability to destroy 3T12 target cells. Intravenous injection of mice with myeloperoxidase induced the production of both TNF and interferon, which could be detected in the sera. Possible mechanisms of TNF induction include radical production by myeloperoxidase or ligand-receptor interaction by the binding of this enzyme to the mannosyl-fucosyl receptor. These results, when taken in their entirety, suggest that this enzyme can modulate the immune response through effects on macrophage function.
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PMID:Macrophage activation and immunomodulation by myeloperoxidase. 137 60

Oxygen-derived free radicals and leukocytes have been implicated in the pathogenesis of ischemia-reperfusion injury. This study aimed at determining, by using biochemical and histochemical techniques, whether an accumulation of neutrophils occurs in the ischemic reperfused rat liver and whether superoxide free radicals play a role in mediating this neutrophil accumulation. Hepatic ischemia was induced by occluding blood supply to the left and median lobes, and reperfusion was reinstituted by releasing the occlusion. Myeloperoxidase activity of the liver was measured with a tetramethylbenzidine-H2O2 assay after removal of glutathione (by dialysis) and in the presence of 3-aminotriazole (catalase inhibitor). A modification of Graham and Karnovsky's method was used to stain neutrophils in liver frozen sections, and the number of neutrophils was counted. Results showed that ischemia-reperfusion of the liver produced a 4.4-fold increase in myeloperoxidase activity (from 0.073 +/- 0.009 to 0.320 +/- 0.017 units/mg liver, means +/- SE), which was proportional to the number of neutrophils (3.1-fold increase from 18 +/- 7 to 57 +/- 4 cells/mm2) in the liver tissue. Pretreatment with long-acting superoxide dismutase significantly attenuated the elevated myeloperoxidase activity and the number of neutrophils. These results indicate that reperfusion after a period of ischemia induces an accumulation of neutrophils in the liver, and superoxide anion free radicals are important mediators in the mechanism of this neutrophil accumulation.
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PMID:Neutrophil accumulation in ischemic reperfused rat liver: evidence for a role for superoxide free radicals. 137 65

The effects of ketotifen, a 'mast cell stabiliser,' on two models of experimental colitis were examined. The inflammatory response elicited by either trinitrobenzene sulphonic acid or acetic acid resulted in increased colonic synthesis of platelet activating factor, prostaglandin E2, thromboxane B2, leukotrienes B4 and C4, and myeloperoxidase activity. Intragastric administration of ketotifen 100 micrograms/100 grams twice daily significantly decreased mucosal damage when given prophylactically 48 hours before the induction of colitis and then throughout the experiment. This effect was consistent in both models and was accompanied by a significant reduction in mucosal generation of platelet activating factor, prostaglandin E2, thromboxane B2, and leukotrienes C4 and B4. Myeloperoxidase activity was reduced as well, reaching significance only in the acetic acid model. This study shows that both trinitrobenzene sulphonic acid and acetic acid colitis can be pharmacologically manipulated by ketotifen. The mechanism of action of ketotifen has not yet been determined. Ketotifen's potential in the treatment of active inflammatory bowel disease or in the prevention of exacertations, or both, remains to be elucidated.
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PMID:Ketotifen effectively prevents mucosal damage in experimental colitis. 145 75


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