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1.
Oxidation of glutathione disulfide by a mixture of performic and hydrochloric acids leads to the formation of several compounds that are stronger inhibitors than glutathione disulfide of the placental enzyme that posses both NADP-linked 15-hydroxypyrostaglandin dehydrogenase and 9-ketoprostaglandin reductase activities. The only one of these inhibitors that has been identified is glutathione thiosulfonate. The others are unstble and may include glutathione sulfinyl sulfone and glutathione disulfone. Since the enzyme appears to have a glutathione binding site in close proximity to its active site and glutathione thiosulfonate reacts with free sulfhydryl groups, the effects of this thiosulfonate on the enzyme were examined in more detail. Glutahione thiosulfonate and methyl methanethiosulfonate cause a time-dependent irreversible inhibition of both the hydroxyprostaglandin dehydrogenase and the ketoprostaglandin reductase activities, presumably by reacting with a free sulfhydryl at the prostaglandin binding site. Experiments with PGA-glutathione show that this sulfhydryl is not necessary for the catalytic activity of the enzyme as long as the substrate can bind at the glutahione site. 相似文献
2.
Two proteins containing 9-ketoprostaglandin reductase and NADP-linked 15-hydroxyprostaglandin dehydrogenase activities have been isolated. Both of these activities are inhibited by a low molecular weight placental protein and by indomethacin, ethacrynic acid, and furosemide. 相似文献
3.
Six glutathione-containing inhibitors of the human NADP-linked 15-hydroxyprostaglandin dehydrogenase have been isolated from placental homogenates. Glutathione disulfide is one of these inhibitors. Although the structures of the other five have not been fully elucidated, all are disulfides. Studies with these compounds and with other mixed disulfides have shown that the glutathione mixed disulfides of beta-mercaptopyruvate, mercaptoacetate, and beta-mercaptolactate are more effective inhibitors of the enzyme than are the glutathione-containing mixed disulfides isolated from placental homogenates. beta-Mercaptolactate is particularly noteworthy because of its low Ki (0.13 microM). The results reported here suggest that the activity of the prostaglandin dehydrogenase may be influenced in vivo by various glutathione mixed disulfides. 相似文献
4.
Hyangsook Chung Josef Fried Elisabeth Williams-Ashman Joseph Jarabak 《Prostaglandins & other lipid mediators》1987,33(3)
Six glutathione-containing inhibitors of the human NADP-linked 15-hydroxyprostaglandin dehydrogenase have been isolated from placental homogenates. Glutathione disulfide is one of these inhibitors. Although the structures of the other five have not been fully elucidated, all are disulfides. Studies with these compounds and with other mixed disulfides have shown that the glutathione mixed disulfides of β-mercaptopyruvate, mercaptoacetate, and β-mercaptolactate are more effective inhibitors of the enzyme than are the glutathione-containing mixed disulfides isolated from placental homogenates. β-Mercaptolactate is particularly noteworthy because of its low Kj (0.13 μM). The results reported here suggest that the activity of the prostaglandin dehydrogenase may be influenced
by various glutathione mixed disulfides. 相似文献
5.
H S Chung R G Harvey R N Armstrong J Jarabak 《The Journal of biological chemistry》1987,262(26):12448-12451
The human placental NADP-linked 15-hydroxyprostaglandin dehydrogenase catalyzes oxidoreduction at the 9- and 15-positions of many prostaglandins, but its catalytic efficiency (i.e. kcat/Km) for these reactions is low (Jarabak, J., Luncsford, A., and Berkowitz, D. (1983) Prostaglandins 26, 849-868). In the present study, we demonstrate that both K-region and non-K-region o-quinones of polycyclic aromatic hydrocarbons are excellent substrates for this enzyme. These compounds are reduced with kcat/Km values ranging from 3 to 20 X 10(6) S-1 M-1. The glutathione thioethers of menadione and toluquinone are reduced with similar catalytic efficiencies. Furthermore, these substances and certain other glutathione thioethers are potent inhibitors of prostaglandin B1 oxidation ([I50] = 7 X 10(-8) to 5 X 10(-6) M); while several glutathione thioethers also inhibit polycyclic aromatic hydrocarbon quinone reduction ([I50] = 1.7-6.5 microM). These findings raise the possibility that the potential toxicity of quinones of polycyclic aromatic hyrocarbons and other xenobiotic substances may be altered in the placenta by an oxidoreductase for which prostaglandins are relatively poor substrates. They also suggest that the presence in placental tissue of certain glutathione thioethers could influence the reduction of these quinones and other xenobiotic substances by this enzyme. 相似文献
6.
Purification of the human placental NAD-linked 15-hydroxyprostaglandin dehydrogenase 总被引:1,自引:0,他引:1
An NAD-linked 15-hydroxyprostaglandin dehydrogenase has been purified 13,100-fold from human placental tissue. The specific activity of the purified enzyme ranges from 6900 to 8300 mU/mg protein depending on the method used to determine the protein concentration. On discontinuous electrophoresis in sodium dodecyl sulfate more than 95% of the protein migrates as a single band; its estimated molecular weight is 25.5-26.0 kDa. This is half the value obtained when the molecular weight is estimated under non-denaturing conditions and suggests that the enzyme is composed of two identical or nearly identical subunits. 相似文献
7.
An NAD-linked 15-hydroxyprostaglandin dehydrogenase has been purified 13, 100-fold from human placental tissue. The specific activity of the purified enzyme ranges from 6900 to 8300 mU/mg protein depending on the method used to determine the protein concentration. On discontinous electrophoresis in sodium dodecyl sulfate more than 95% of the protein migrates as a single band; its estimated molecular weight is 25.5–26.0 kDa. This is half the value obtained when the molecular weight is estimated under non-denaturing conditions and suggests that the enzyme is composed of two identical or nearly identical subunits. 相似文献
8.
A number of nonsteroidal anti-inflammatory drugs are non-competitive or mixed inhibitors of human placental dehydrogenases.
- and
-sulindac sulfide and
- and
-sulindac inhibit the NAD-linked enzyme as well or better than they inhibit various cyclooxygenases
. The remainder of the compounds tested are at least one order of magnitude less effective as inhibitors of the 15-hydroxyprostaglandin dehydrogenases than they are as inhibitors of cyclooxygenases.
- and
-sulindac sulfide are sufficiently strong inhibitors of the NAD-linked enzyme (Kis of 7.8 μM and 6.8 μM respectively) to raise the possibility that they might also inhibit this enzyme
. 相似文献
9.
Inhibition of the human placental NAD- and NADP-linked 15-hydroxyprostaglandin dehydrogenases by nonsteroidal anti-inflammatory drugs 总被引:1,自引:0,他引:1
J Jarabak 《Prostaglandins》1988,35(3):403-411
A number of nonsteroidal anti-inflammatory drugs are non-competitive or mixed inhibitors of human placental NAD- and NADP-linked 15-hydroxyprostaglandin dehydrogenases. Cis- and trans-sulindac sulfide and cis- and trans-sulindac inhibit the NAD-linked enzyme as well or better than they inhibit various cyclooxygenases in vitro. The remainder of the compounds tested are at least one order of magnitude less effective as inhibitors of the 15-hydroxyprostaglandin dehydrogenases than they are as inhibitors of cyclooxygenases. Cis- and trans-sulindac sulfide are sufficiently strong inhibitors of the NAD-linked enzyme (Kis of 7.8 microM and 6.8 microM respectively) to raise the possibility that they might also inhibit this enzyme in vivo. 相似文献
10.
A study of the relative activity of the purified placental NAD- and NADP-linked 15-hydroxyprostaglandin dehydrogenases with various prostaglandins and thromboxane B2(TxB2) suggests that most, if not all, oxidation in the placenta of the 15-hydroxyl group of prostaglandins of the A, E, and F series as well as PGI2 (prostacyclin) and 6-keto PGF1α is catalyzed by the NAD-linked enzyme. Prostaglandin B1 is an excellent substrate for the NADP-linked enzyme. Despite the conformational similarities between PGB1 and PGI2, the latter molecule is a poor substrate for the NADP-linked enzyme. Thromboxane B2 is not oxidized by the NAD-linked enzyme and is oxidized slowly by the NADP-linked enzyme. 相似文献
11.
Labile oligomeric structure of human placental 15-hydroxyprostaglandin dehydrogenase 总被引:1,自引:0,他引:1
T Tanaka T Kotani S Ohtaki K Nagai K Tsuruta N Mori 《Biochemical and biophysical research communications》1986,135(3):1058-1063
NAD-dependent 15-hydroxyprostaglandin dehydrogenase has been isolated from human term placenta. About 9,000-fold enrichment was achieved with a yield of 7.6%. Electrophoretic analyses suggested that glycerol stabilized an active structure of the enzyme, and sodium dodecyl sulfate might dissociate it. The instability of the enzyme activity may relate to its labile oligomeric structure which is easily dissociated into subunits. 相似文献
12.
Tsuyoshi Watanabe Takao Shimizu Shuh Narumiya Osamu Hayaishi 《Archives of biochemistry and biophysics》1982,216(1):372-379
Two forms of NADP-linked 15-hydroxyprostaglandin dehydrogenase for prostaglandin D2 were found in the cytosol fraction of human blood platelets. These enzymes were purified by ammonium sulfate fractionation, Blue Sepharose, and Sephadex G-100 column chromatography. The two enzymes differed in molecular weights (65,000 for peak I enzyme and 31,000 for peak II as estimated by gel filtration) and their substrate specificities. The relative rates for reaction with peak I enzyme were: prostaglandin D2, 100(%); E2, 14; F2α, 2; I2, 29; and B2, 0; whereas for peak II enzyme, D2, 100; E2, 23; F2α, 61; I2, 29; and B2, 131. Prostaglandin D2 was converted to 15-ketoprostaglandin D2 and then 13,14-dihydro-15-ketoprostaglandin D2, which were identified by spectrophotometry and gas chromatography/mass spectrometry, respectively. These metabolites were three orders of magnitude less potent in inhibiting human platelet aggregation than prostaglandin D2. The results indicated that NADP-linked dehydrogenases participated in the metabolic inactivation of prostaglandin D2 in the platelets. Furthermore, the dehydrogenase activity for prostaglandin D2 was high in monkey (0.128 nmol/min · mg at 24 °C) and human platelets (0.066), but was not detectable (less than 0.007) in the rabbit, rat, and chicken. Because prostaglandin D2, which was demonstrated by several authors to be synthesized in platelet-rich plasma during platelet aggregation, exhibited significant antiaggregatory activity only in human and monkey platelets, these prostaglandin dehydrogenases appear to play a physiological role in the circulatory system. 相似文献
13.
A study of the relative activity of the purified placental NAD- and NADP-linked 15-hydroxyprostaglandin dehydrogenases with various prostaglandins and thromboxane B2 (TxB2) suggests that most, if not all, oxidation in the placenta of the 15-hydroxyl group of prostaglandins of the A, E, and F series as well as PGI2 (prostacyclin) and 6-keto PGF1 alpha is catalyzed by the NAD-linked enzyme. Prostaglandin B1 is an excellent substrate for the NADP-linked enzyme. Despite the conformational similarities between PGB1 and PGI2, the latter molecule is a poor substrate for the NADP-linked enzyme. Thromboxane B2 is not oxidized by the NAD-linked enzyme and is oxidized slowly by the NADP-linked enzyme. 相似文献
14.
W. Schlegel Laurence M. Demers Helga E. Hilldebrandt-Stark Harold R. Behrman Roy O. Greep 《Prostaglandins & other lipid mediators》1974,5(5)
The enzyme system, 15-hydroxyprostaglandin dehydrogenase, which catalyzes the first inactivation step in the catabolism of the prostaglandins has been isolated and purified 107-fold from human placenta. Kinetic studies reveal different Michaelis-Menten constants for most of the naturally occurring prostaglandins. The Km for PGE2 was found to be 10 μM, for PGE1, 27 μM; for PGA2, 32 μM; for PGA1, 33 μM; and for PGF2α 59 μM. The enzyme has a sharp pH-optimum between 7.5 and 8.8. Prostaglandin dehydrogenase appears to be isoenzymic as judged by separation on polyacrylamide disc gel electrophoresis. Inhibition studies with the partially purified enzyme indicate that progesterone and estrogen may influence the conversion of biologically active prostaglandins into the biologically inactive 15-ketoprostaglandins. These findings offer evidence for the control of prostaglandin metabolism in the human placenta. 相似文献
15.
C Westbrook Y M Lin J Jarabak 《Biochemical and biophysical research communications》1977,76(3):943-949
An NADP-linked 15-hydroxyprostaglandin dehydrogenase has been identified in human placental tissue and partially purified. Prostaglandins of the A and B series are good substrates for this enzyme while those of the E and F series are not. This enzymic preparation also catalyzes oxido-reductions at the 9 position of the prostaglandin molecule; these are slow compared to those occurring at the 15 position of the prostaglandins in the A and B series. Disc gel electrophoresis of the purified enzyme reveals the presence of three protein bands which contain dehydrogenase activity. Boiled placental homogenates contain an inhibitor which appears to be specific for the NADP-linked 15-hydroxyprostaglandin dehydrogenase. The inhibitor is heat stable and has a molecular weight of 6,000 – 7,000. 相似文献
16.
17.
Three types of 15-hydroxyprostaglandin dehydrogenase were identified in rabbit whole kidney homogenate when the centrifuged homogenate was sequentially fractionated by ammonium sulfate precipitation, DEAE-cellulose and Mātrex Gel Blue A chromatographies, and Sephadex gel filtration. The first type is not adsorbed to DEAE-cellulose (peak 1). It catalyzes oxidoreduction of prostaglandins at both the C-15 and C-9 positions, is more active with NADP than NAD, is inhibited by indomethacin and ethacrynic acid, and migrates as three bands on disc gel electrophoresis. The second type is adsorbed to DEAE-cellulose (peak 2). It also migrates as multiple electrophoretic bands, has similar catalytic actions and co-factor requirements as the peak 1 enzyme and is inhibited by indomethacin and ethacrynic acid. A third type of 15-hydroxyprostaglandin dehydrogenase is also adsorbed to DEAE-cellulose but is partially separable from the other peak 2 enzymes on Mātrex Gel Blue A and differs from those enzymes in preferentially oxidizing PGI2. It migrates as a single electrophoretic band and is also inhibited by indomethacin and ethacrynic acid. 相似文献
18.
C L Hsin-Hsiung-TaiTai C S Hollander 《Biochemical and biophysical research communications》1974,57(2):457-462
15-Hydroxyprostaglandin dehydrogenase has been purified from swine kidney to a specific activity of near 100 miliunits per mg of protein. The purified enzyme was found to be inhibited by thyroid hormone analogues of which triiodothyroacetic acid was the most potent inhibitor. The concentration required for 50% inhibition was 5 μM for triiodothyroacetic acid. The inhibition by thyroid hormones was uncompetitive and non-competitive with regard to NAD+ and prostaglandin E1, respectively. The sensitivity of this enzyme to thyroid hormones suggests that these hormones may regulate the metabolism of prostaglandins . 相似文献
19.
Cloning and sequence analysis of the cDNA for human placental NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase. 总被引:7,自引:0,他引:7
NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase catalyzes the oxidation of many prostaglandins at C-15, resulting in a subsequent reduction in their biological activity. We report the isolation of the cDNA for this enzyme. A human placental lambda gt11 cDNA library was screened using polyclonal antibodies prepared against the human placental enzyme. A 2.5-kilobase cDNA containing the entire coding region for the enzyme was isolated. The cDNA encodes for a protein of 266 amino acids with a calculated Mr of 28,975. Identification of the cDNA as that coding for 15-hydroxyprostaglandin dehydrogenase was based on the comparison of the deduced amino acid sequence with the amino acid sequence of two peptides, one from the rabbit lung enzyme and the other from the human placental enzyme. This cDNA hybridizes with two species of poly(A+) RNA isolated from human placenta: one of 3.4 kilobases and the other of 2.0 kilobases. Isolation of the cDNA for 15-hydroxyprostaglandin dehydrogenase should facilitate studies on the structure, function, and regulation of this enzyme. 相似文献
20.
Niesen FH Schultz L Jadhav A Bhatia C Guo K Maloney DJ Pilka ES Wang M Oppermann U Heightman TD Simeonov A 《PloS one》2010,5(11):e13719