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)

A study of the enzymes of the arachidonic acid cascade revealed a high sensitivity of prostacyclin synthetase and a complete resistance of thromboxane A2 synthetase to time-dependent destruction by an oxidant [Ox] released during the peroxidase-catalyzed reduction of hydroperoxy fatty acids. The destructive action of [Ox] derived from prostaglandin G1 (PGG1), 15-hydroperoxy-PGE1, 15-hydroperoxy-5,8,11,13-eicosatetraenoic acid, and 12-hydroperoxy-5,8,10,14-eicosatetraenoic acid upon prostacyclin synthetase was prevented by 2-aminomethyl-4-t-butyl-6-iodophenol. On the other hand, deactivation resulting from PGG2 metabolism was neither time-dependent nor sensitive to 2-aminomethyl-4-t-butyl-6-iodophenol. The possibility that the action of [Ox] may alter the arachidonic acid cascade in favor of thromboxane A2 is discussed in view of its possible implications in inflammatory and other pathological processes.
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PMID:Peroxidase-dependent deactivation of prostacyclin synthetase. 37 78

We describe the enzymological regulation of the formation of prostaglandin (PG) D2, PGE2, PGF2 alpha, 9 alpha, 11 beta-PGF2, PGI2 (prostacyclin), and thromboxane (Tx) A2 from arachidonic acid. We discuss the three major steps in prostanoid formation: (a) arachidonate mobilization from monophosphatidylinositol involving phospholipase C, diglyceride lipase, and monoglyceride lipase and from phosphatidylcholine involving phospholipase A2; (b) formation of prostaglandin endoperoxides (PGG2 and PGH2) catalyzed by the cyclooxygenase and peroxidase activities of PGH synthase; and (c) synthesis of PGD2, PGE2, PGF2 alpha, 9 alpha, 11 beta-PGF2, PGI2, and TxA2 from PGH2. We also include information on the roles of aspirin and other nonsteroidal anti-inflammatory drugs, dexamethasone and other anti-inflammatory steroids, platelet-derived growth factor (PDGF), and interleukin-1 in prostaglandin metabolism.
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PMID:Prostaglandin and thromboxane biosynthesis. 190 23

The peroxidase activity of prostaglandin (PGH) synthase catalyzes the reduction of PGG2 and other natural and synthetic hydroperoxides by reducing substrates. Sulfides serve as reductants by incorporating the oxo ligand from the ferryl-oxo complex which represents the higher oxidation state of the peroxidase (Compound I). A series of alkylaryl sulfides and substituted dihydrobenzo[b]thiophenes were synthesized to determine the electronic and steric requirements of PGH synthase for sulfide reducing substrates. Kinetic parameters were determined for most of the molecules by determining their ability to support reduction of 5-phenyl-4-pentenyl-1-hydroperoxide in the presence of PGH synthase purified from ram seminal vesicle microsomes. Electron-donating groups on the aryl moiety para to the sulfide enhanced reducing substrate activity (p = -0.8). As expected from previous results, the major oxidation product of p-methylthioanisole was the corresponding sulfoxide. The presence of a para-amino group increased binding to the enzyme and changed the reduction mechanism from oxygen transfer to electron transfer. The major oxidation product of p-(dimethylamino)thioanisole was identified as p-(methylamino)thioanisole; an equivalent amount of formaldehyde was produced. Increasing the size of the alkyl group attached to sulfur decreased the ability of the sulfide to act as a peroxidase reductant. The maximal turnover for reduction by p-methoxyphenylalkyl sulfides decreased 10-fold on substitution of isopropyl for ethyl. Chiral derivatives of benzo[b]thiophenes demonstrated differences in the ability of the two enantiomers to support reduction. Introduction of a carboxylic acid moiety anywhere in the molecule decreased the maximal turnover for reduction. Esterification of the carboxylate doubled the extent of reduction relative to the free acid. The results are used to develop models for the interaction of sulfides with Compound I of PGH synthase.
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PMID:Alkylaryl sulfides as peroxidase reducing substrates for prostaglandin H synthase. Probes for the reactivity and environment of the ferryl-oxo complex. 250 8

Prostaglandin-H-synthase (PHS) is a key enzyme in the biosynthesis of prostaglandins (PGs) from arachidonic acid and can oxidatively metabolize synthetic and steroidal estrogens. To investigate the relationship between estrogen cooxidation and PG synthesis, purified PHS-holoenzyme was incubated with radiolabeled arachidonic acid and various estrogens, namely diethylstilbestrol (DES), estradiol (E2), 2-hydroxyestradiol (2-OHE2), and 2-methoxyestradiol (2-MeOE2). The amount and pattern of PGs synthesized were analyzed by TLC and HPLC, estrogen metabolism was studied by HPLC. All tested compounds increased conversion of arachidonic acid to PG H2-derived prostanoids. A stoichiometric ratio between net estrogen oxidation and net PG H2 formation of approximately 2:1 for monophenolic compounds (2-MeOE2, E2) and of 1:1 for diphenolic estrogens (DES, 2-OHE2) was found, indicating that estrogens are apparently acting as electron donors for the PHS-peroxidase. In contrast, glutathione was not found to provide electrons for the reduction of PGG2 to PGH2, and rather decreased the conversion of arachidonic acid. The results of this in vitro study are discussed with respect to its implications for the in vivo situation.
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PMID:Studies on the stoichiometry of estrogen oxidation catalyzed by purified prostaglandin-H-synthase holoenzyme. 250 95

Prostaglandin H synthase has two distinct enzymatic activities: a cyclooxygenase that forms PGG2 from arachidonate and a peroxidase that can reduce hydroperoxides, such as PGG2, to the corresponding alcohols. The relative sensitivities of the two synthase activities to proteolytic attack have been examined, using trypsin, chymotrypsin, and proteinase K, all known to attack the native apoprotein in the arg 253 region. The relation between the specific activity of the synthase and the loss of the two activities and the cleavage of the synthase subunit during trypsin digestion was also examined. The cyclooxygenase and peroxidase activities declined in concert throughout room temperature digestions with each of the three proteases. There was no indication of a selective loss of either activity in any of the digestions. In separate digestions with the same preparation of synthase, 3.3% (w/w) proteinase K resulted in more extensive loss of activity (90% decrease after 90 min) than did 3% (w/w) trypsin (70% decrease after 120 min) or 5% (w/w) chymotrypsin (60% decrease after 135 min). In tryptic digestions of synthase preparations with cyclooxygenase specific activity between 16 and 125 k units/mg protein, the fractional loss of cyclooxygenase activity was, within experimental error, the same as that of peroxidase activity. The extent of cleavage of the 70 kDa synthase subunit was greater than the loss of enzymatic activity, with the discrepancy being larger for synthase preparations with lower specific activity. The presence of a variable amount of catalytically-inactive, protease-sensitive, synthase protein could account for the difference between surviving activity and intact subunit in six out of the seven synthase preparations examined. Thus, it is likely that the cyclooxygenase and peroxidase activities are destroyed together during proteolytic attack on the arg 253 region of the native synthase apoprotein.
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PMID:Concerted loss of cyclooxygenase and peroxidase activities from prostaglandin H synthase upon proteolytic attack. 250 12

Prostaglandin H synthase catalyzes the formation of prostaglandin (PG) G2 from arachidonic acid (cyclooxygenase activity), and also the reduction of PGG2 to PGH2 (peroxidase activity). The ability of the pure synthase to accumulate the hydroperoxide, PGG2, under conditions allowing the concurrent function of both catalytic activities was investigated. The peroxidase velocity was continuously determined from the absorbance increases at 611 nm that accompanied oxidation of a peroxidase cosubstrate, N,N,N',N'-tetramethylphenylenediamine, and PGG2 concentrations were calculated from the peroxidase velocities and the peroxidase Vmax and Km values. Cyclooxygenase velocities were then calculated from the changes in PGG2. Parallel reactions monitored by the use of radiolabelled arachidonate or with a polarographic oxygen electrode were used to confirm the calculated PGG2 levels and the cyclooxygenase velocities. The concentration of PGG2 was found to follow a transient course as the reaction of the synthase progressed, rapidly rising to a maximum of 0.7 microM in the first 10 s, and then declining slowly, reaching 0.1 microM after 60 s. The maximal level of PGG2 achieved during the reaction was constant at about 0.7 microM with higher amounts of added cyclooxygenase capacity (0.3-0.6 microM PGG2/s) but was only about 0.4 microM when the added cyclooxygenase capacity was 0.1 microM PGG2/s. The peroxidase was found to lose only 30% of its activity after 90 s, a point where the cyclooxygenase was almost completely inactive. These results support the concept of a burst of catalytic action from the cyclooxygenase and a reactive, more sustained, catalytic action from the peroxidase during the reaction of the synthase with arachidonic acid.
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PMID:Prostaglandin G2 levels during reaction of prostaglandin H synthase with arachidonic acid. 311 17

Platelets are suggested to exacerbate ischemia-induced myocardial injury, which has led to the study of various antiplatelet therapies including thromboxane synthetase inhibitors (TXSI). Two such agents, benzylimidazole and OKY-046, reduce infarct size commensurate with a diminution in serum thromboxane B2 formation in anesthetized dogs subjected to 90 minutes of coronary artery occlusion followed by 5 hours of reperfusion. In contrast, platelet depletion with specific antiserum does not reduce infarct size but prevents the cardioprotection afforded by the TXSI. Platelet-derived prostaglandin endoperoxides (PGG2 and PGH2), which cannot be converted to thromboxane A2 in the inhibited platelet, can be transformed to PGE2 and PGD2 in plasma and to PGI2 by the blood vessel wall. These prostaglandins are considered "cardioprotective." Consequently, a low dose of aspirin (3-5 mg/kg) given 24 hours before coronary occlusion was used to selectively block the platelet cyclooxygenase enzyme. Aspirin, by itself, does not reduce infarct size, but it suppresses the myocardial salvage induced by OKY-046. Thus, TXSI reduce infarct size by platelet-dependent, aspirin-sensitive mechanism that depends on the redirection of platelet-derived PGG2 and PGH2 to protective metabolites, rather than inhibition of thromboxane A2 per se. Moreover, myocardial salvage induced by the TXSI is accompanied by a reduction in neutrophil accumulation in the myocardium, as indicated by the levels of the neutrophil-specific myeloperoxidase enzyme. Platelet depletion or pretreatment with aspirin prevents the TXSI-induced suppression of neutrophil accumulation. Consequently, it is proposed that the prostaglandin-mediated protective effects of TXSI can be resolved, at least in part, in terms of a braking action on neutrophil activation to prevent leukocyte-dependent tissue injury.
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PMID:Thromboxane synthetase inhibitors reduce infarct size by a platelet-dependent, aspirin-sensitive mechanism. 312 73

There is increasing evidence that prostaglandins (PG) and thromboxane (Tx) play a major role in the pathogenesis of coronary artery disease. The regulation of arachidonic acid (AA) metabolism through cyclooxygenase (COx) pathway and the AA-dependent Ca2+ influx were investigated in platelets from 10 patients with unstable angina and 10 controls. The activation of the hexose monophosphate shunt (HMS), a sensitive index of the flux through the PGG2 to PGH2 step of the COx pathway, in response to AA was significantly enhanced in platelets from patients. AA-induced malonyldialdehyde (MDA) production as well as AA-evoked Ca2+ flux and glutathione-dependent peroxidase activity resulted significantly increased. Moreover, platelet sensitivity to prostacyclin (PGI2), measured as inhibition of Ca2+ flux, was highly decreased. Thus far, evidence is presented for intrinsic platelet hyperactivity (at the PG-peroxidase reaction of the COx pathway) in patients with unstable angina: the resulting increase in PGH2 and TxA2 synthesis, alone or in combination with decreased PGI2 sensitivity, may account for a facilitated thrombus formation.
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PMID:Platelet arachidonic acid metabolism in patients with cardiovascular disorders. 324 16

Glutathione S-transferases (GSTs) purified from both rat liver cytosol and microsomes catalyzed the direct reduction of PGH2 to PGF2 alpha. As much as 40% of the substrate was transformed into a prostanoid whose Rf value corresponded to that of PGF2 alpha. The identification of the reaction product as PGF2 alpha was confirmed by TLC and reverse-phase HPLC as well as by mass spectral analysis. In the absence of GSTs, PGH2 was found to be primarily converted to PGE2 and PGD2. Also, PGF2 alpha formation was completely abolished by decylglutathione, a potent inhibitor of both peroxidase and transferase activity associated with GSTs. These results indicate that the direct reduction of endoperoxide moiety of PGH2 to form PGF2 alpha is an enzymatic process. Interestingly, selenium-dependent glutathione peroxidase (Se-GSH-Px) showed very little PGF2 alpha formation from PGH2. However, this enzyme was very active in the reduction of PGG2 to PGH2. In contrast, GSTs were very poor in the conversion of PGG2 to PGH2. Therefore, it is possible that the relative tissue distribution of Se-GSH-Px and GSTs might play an important role in the tissue specific synthesis of PGF2 alpha.
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PMID:Enzymatic transformation of PGH2 to PGF2 alpha catalyzed by glutathione S-transferases. 346 49

Two types of mechanisms have been proposed to account for the combination of peroxidase and cyclooxygenase activities in prostaglandin H synthase (PGHS). One, a branched-chain mechanism [Dietz, R., et al. (1988) Eur. J. Biochem. 171, 321-328], postulates that the cyclooxygenase reaction propagates essentially independently of peroxidase catalysis. The second, a tightly coupled mechanism [Bakovic, M., & Dunford, H. B. (1994) Biochemistry 33, 6475-6482], postulates that peroxidase catalysis is an integral part of cyclooxygenase propagation. Qualitative and quantitative predictions from the two mechanisms have been compared with several observed characteristics of the PGHS reaction with arachidonate, including the ability to accumulate PGG2 and oxidized enzyme intermediates, the stoichiometry between cosubstrate and fatty acid consumption, and the hydroperoxide activator requirement. The observed characteristics, particularly the accumulation of micromolar levels of PGG2 even in the presence of cosubstrate and the stoichiometry between cosubstrate oxidation and fatty acid oxygenation of less than 1.3 (compared to a theoretical maximum of 2.0), were largely consistent with predictions from the branched-chain mechanism, but contradicted important predictions of the tightly coupled mechanism. These results indicate that PGHS catalysis is more accurately described by the branched-chain mechanism than by the tightly coupled mechanism.
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PMID:Comparison of branched-chain and tightly coupled reaction mechanisms for prostaglandin H synthase. 759 39


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