ライフサイエンスコーパス: PGHS

1 PGHS peroxidase (POX) activity reduces PGG2 to PGH2.

2 PGHS POX catalyzes heterolytic cleavage of primary and s

3 PGHS-1 and PGHS-2 are conformational heterodimers, each

4 PGHS-1 and PGHS-2 protein levels did not reflect the cha

5 PGHS-1-dependent ( small middle dot)NO consumption also

6 PGHS-2 efficiently oxygenated 3-HPAA to prostaglandin an

7 PGHS-2 induction, but not IL-6 secretion, was impaired i

8 PGHS-2 is a sequence homodimer.

9 PGHS-2 was also found in lesions, but 3-nitrotyrosine in

10 PGHS-2 was selectively, dose-dependently, and irreversib

11 PGHS-mediated eicosanoid (PGE(2)) synthesis was more tha

12 PGHSs are homodimers that display half of sites COX acti

13 PGHSs are homodimers that exhibit half-of-sites COX acti

14 PGHSs are homodimers with each monomer having a POX site

15 hacin-pretreated prostaglandin H synthase 1 (PGHS-1) were examined by low-temperature electron parama

16 human prostaglandin endoperoxide synthase-1 (PGHS-1) and PGHS-2 and purified the recombinant enzymes

17 se activities of prostaglandin H synthase-1 (PGHS-1) both become irreversibly inactivated during reac

18 Prostaglandin H synthase-1 (PGHS-1) is a bifunctional heme protein catalyzing both a

19 ith prostaglandin-endoperoxide H synthase-1 (PGHS-1), the constitutive cyclooxygenase.

20 alysis by prostaglandin H synthase-1 and -2 (PGHS-1 and -2) requires activation of the normally laten

21 rostaglandin endoperoxide synthase-1 and -2 (PGHS-1 and -2, respectively).

22 Prostaglandin H synthase isoforms 1 and 2 (PGHS-1 and -2) catalyze the first two steps in the biosy

23 staglandin endoperoxide H synthases-1 and 2 (PGHS-1 and PGHS-2; also cyclooxygenases-1 and 2, COX-1 a

24 Prostaglandin endoperoxide H synthase 2 (PGHS-2) catalyzes the rate-limiting steps in the synthes

25 selective for prostaglandin G/H synthase-2 (PGHS-2) (known colloquially as COX-2) were designed to m

26 on of prostaglandin endoperoxide synthase-2 (PGHS-2) in ovine fetal brain regions.

27 he modulation of prostaglandin H synthase-2 (PGHS-2) in primary mouse cortical astrocytes and COS-7 c

28 Prostaglandin endoperoxide H synthase-2 (PGHS-2), also called cyclooxygenase-2 (COX-2), converts

29 Prostaglandin endoperoxide H synthase-2 (PGHS-2), also known as cyclooxygenase-2 (COX-2), is a se

30 as prostaglandin endoperoxide H synthase-2 (PGHS-2), catalyzes the committed step in prostaglandin b

31 inhibitors of prostaglandin G/H synthase-2 (PGHS-2; known colloquially as COX-2) increase the incide

32 taglandin endoperoxide H synthases-1 and -2 (PGHSs) can oxygenate 18-22 carbon polyunsaturated fatty

33 tes for the peroxidase activities of PGHS-2, PGHS-1, and glutathione peroxidase (GPx).

34 ent generation of a free radical at Tyr-385 (PGHS-1 numbering) in the cyclooxygenase active site; the

35 pathway in vivo, we engineered a del595-612 PGHS-2 (Delta 18 COX-2) knock-in mouse lacking this 18-a

36 and COX sites of monomers was detected in a PGHS-2 heterodimer comprised of a Q203R monomer having a

37 hese adducts is inhibited by indomethacin, a PGHS inhibitor, and is enhanced by an inhibitor of throm

38 acids (FAs) are bound at both COX sites of a PGHS-2 dimer.

39 SC58125, a PGHS-2-selective inhibitor, could attenuate the inductio

40 evuglandinyl-lysine adducts are formed via a PGHS-dependent pathway in whole cells, even in the prese

41 are reportedly formed via aspirin-acetylated PGHS-2 from eicosapentaenoic acid and docosahexaenoic ac

42 Although PGHSs function as homodimers and each monomer has its ow

43 PGHS-1 and PGHS-2 are conformational heterodimers, each composed of

44 However, Q203V PGHS-1 and PGHS-2 mutants catalyzed heterolytic cleavage of peroxid

45 PGHS-1 and PGHS-2 protein levels did not reflect the changes in the

46 y of prostaglandin H(2) isoforms (PGHS-1 and PGHS-2).

47 endoperoxide H synthases-1 and 2 (PGHS-1 and PGHS-2; also cyclooxygenases-1 and 2, COX-1 and COX-2) c

48 Two forms of PGHS exist, PGHS-1 (COX-1) and PGHS-2 (COX-2).

49 glandin endoperoxide synthase-1 (PGHS-1) and PGHS-2 and purified the recombinant enzymes using buffer

50 sed in fetal brainstem and hypothalamus, and PGHS-2 mRNA was increased in fetal brainstem.

51 e show that inducible NO synthase (iNOS) and PGHS-1 co-localize in atherosclerotic lesions of ApoE(-/

52 Here we demonstrate that mPGES and PGHS-2 are expressed at very low levels in untreated hum

53 Induction of both mPGES and PGHS-2 was susceptible to either chemical inhibition or

54 iption was eliminated in the COS-7 system as PGHS-2 was maximally expressed, in primary astrocytes wh

55 In contrast, aspirin-treated PGHS-2 (ASA-PGHS-2) no longer forms prostaglandins but retains oxyge

56 yl radicals in lipoxygenase catalysis by ASA-PGHS-2 and also indicate that the AA radical in ASA-PGHS

57 and also indicate that the AA radical in ASA-PGHS-2 is more constrained than the corresponding radica

58 onal role of the wide singlet radical in ASA-PGHS-2, we have examined the ability of this radical to

59 Anaerobic addition of AA to ASA-PGHS-2 immediately after formation of the wide singlet r

60 ter the beginning of a 10 min period of BCO, PGHS-1 mRNA was increased in fetal brainstem and hypotha

61 In both PGHS isoforms the tyrosyl radical undergoes a time-depen

62 An S121P substitution in both PGHS-2 monomers yields a variant (S121P/S121P PGHS-2) th

63 Our data demonstrated that induction of both PGHS-2 mRNA and protein reached peak levels ( approximat

64 roduction of 2-series prostanoids from AA by PGHS-2 would be expected to decrease in proportion to th

65 enation of arachidonic acid (AA) and 2-AG by PGHS-2 are very similar, but the sensitivities of the tw

66 3-HPAA appeared to be converted by PGHS-1 in a similar manner; however, conversion was less

67 minants for efficient oxygenation of DHLA by PGHS-1, play similar roles in the oxygenation of EPA and

68 EPA significantly inhibits AA oxygenation by PGHS-1.

69 ising observation was that AA oxygenation by PGHS-2 is only modestly inhibited by EPA (i.e. PGHS-2 ex

70 the extent of endocannabinoid oxygenation by PGHS-2.

71 , conversion was less efficient than that by PGHS-2.

72 elm the ability of acetaminophen to decrease PGHS activation.

73 ion resulted in increased IL-1beta-dependent PGHS-2 and microsomal PGE(2) synthase levels.

74 HS-2 is only modestly inhibited by EPA (i.e. PGHS-2 exhibits a marked preference for AA when EPA and

75 curring between the monomers comprising each PGHS-1 dimer, we analyzed structures of PGHS-1 crystalli

76 Two forms of PGHS exist, PGHS-1 (COX-1) and PGHS-2 (COX-2).

77 The rates of reactions for PGHS-1 reconstituted with MnPPIX were approximately an o

78 n of PGHS-2, or deletion of the receptor for PGHS-2-derived PGI(2), was shown to accelerate thromboge

79 Native/G533A PGHS-2, a heterodimer with a COX-inactive subunit, had t

80 ity and decreased affinity for heme of H386A PGHS-1 imply that His386 helps optimize heme binding.

81 AA to the cyclooxygenase site of ovine H386A PGHS-1 reopens the constriction in the cyclooxygenase si

82 Heme titrations indicated that H386A PGHS-1 binds heme less tightly than does native PGHS-1.

83 could be restored (10-30%) by treating H386A PGHS-1 with cyclooxygenase inhibitors or AA, but not wit

84 erized in mammals; a functionally homologous PGHS isoform pair has been cloned from an evolutionarily

85 d bind Eallo of PGHSs stimulating human (hu) PGHS-2 but inhibiting huPGHS-1.

86 ximally acetylates one monomer of human (hu) PGHS-2.

87 e residue Ser-529 to be active against human PGHS-1; the S529A mutant is resistant to inactivation by

88 erodimers in which a native subunit of human PGHS-2 has been coupled to a subunit having a defect wit

89 tic acid, an efficacious stimulator of human PGHS-2, binds only E(allo) in palmitic acid/murine PGHS-

90 te-directed mutagenesis of recombinant human PGHS-2 to focus on one heme-vicinity residue that diverg

91 e radical to Tyr385 in the recombinant human PGHS-2 Y504F mutant was exploited in examining the effec

92 We find that human PGHS-2 functions as a conformational heterodimer having

93 We examined this concept using human PGHS-2 dimers composed of combinations of Y385F, R120Q,

94 In PGHS-2, this transition results from radical migration f

95 e chain structures of Asn-382 and Thr-383 in PGHS-2 thus selectively influence two important aspects

96 When His386 was substituted with alanine in PGHS-1, the mutant retained <2.5% of the native peroxida

97 removal of Tyr348-Tyr385 hydrogen bonding in PGHS-2 allows greater conformational flexibility in the

98 e can also induce a conformational change in PGHS-2 was unexpected, and the magnitude of changes sugg

99 the heme iron and the proximal histidine in PGHS-1.

100 Whereas OGD stimulated robust increases in PGHS-2 mRNA abundance, neither oxygen nor glucose depriv

101 munohistochemistry revealed Tyr nitration in PGHS-1 in aortic lesions but markedly less in adjacent n

102 ssion by cytosolic glutathione peroxidase in PGHS-2 than in PGHS-1.

103 ortions and stability of the two radicals in PGHS-2 pretreated with peroxide.

104 lic glutathione peroxidase in PGHS-2 than in PGHS-1.

105 Attenuating Jak2 increases PGHS-2 steady-state mRNA levels, a consequence of increa

106 Thus, KAT-50 cells express the inefficient PGHS-2/cPGES pair, and this results in modest PGE(2) pro

107 utyl phenols such as darbufelone may inhibit PGHS-2 by exploiting a previously unrecognized binding s

108 ain the efficacy of acetaminophen to inhibit PGHS in cell types with moderate oxidant formation.

109 ation of AA oxygenation by cyanide-inhibited PGHS-2.

110 peroxynitrite (OONO(-)) generator inhibited, PGHS-2-dependent prostaglandin production.

111 at a cellular level; acetaminophen inhibits PGHS activity with an IC(50) of 4.3 microM in interleuki

112 ith inhibitor, darbufelone potently inhibits PGHS-2 (IC(50) = 0.19 microM) but is much less potent wi

113 0 approximately 11 microM) and thus inhibits PGHS by eliminating the peroxide tone.

114 the activity of prostaglandin H(2) isoforms (PGHS-1 and PGHS-2).

115 xynitrite increased the activity of isolated PGHS and prostacyclin formation by aortic endothelial ce

116 Two major PGHS isoforms, with distinct pathophysiological function

117 racteristics between the trout and mammalian PGHS proteins may reflect accomodations to differences a

118 NO(*) synergistically enhanced LPS-mediated PGHS-2 protein synthesis.

119 All donors lost their ability to modulate PGHS-2 expression and function when decayed.

120 Moreover, PGHS-1 protein cannot be detected in KAT-50.

121 Substitutions of Thr-383 (histidine in most PGHS-1) with histidine or aspartate decreased cyclooxyge

122 , binds only E(allo) in palmitic acid/murine PGHS-2 co-crystals.

123 rbiprofen to about the same extent as native PGHS-2.

124 f the rates of formation of PGH(2) by native PGHS-2.

125 This is unlike the corresponding native PGHS-2 variant and suggests that S121P substitutions als

126 S-1 binds heme less tightly than does native PGHS-1.

127 m a wide doublet to a wide singlet in native PGHS-2 and for formation of a narrow singlet in complexe

128 he pentadienyl AA radical obtained in native PGHS-2 or a 26-28-G singlet radical.

129 ned than the corresponding radical in native PGHS-2.

130 nit and a native subunit (i.e. Mutant/Native PGHS-2) have COX activities similar to native PGHS-2.

131 cupancy of the cyclooxygenase site of native PGHS-1 had no effect on peroxidase activity.

132 2) that has 1.7-1.8 times the Vmax of native PGHS-2 and is relatively insensitive to activation by FA

133 singlet EPR signal similar to that of native PGHS-2.

134 one-quarter of the monomers of S530A/Native PGHS-2 with or without heme.

135 With other heterodimers (e.g. S530A/Native PGHS-2), heme binds with similar affinities to both subu

136 These results suggest that native PGHS-2 assumes a reasonably stable, asymmetric Eallo/Eca

137 These results imply that native PGHS-2 exhibits half-of-sites reactivity.

138 lates one-half of the subunits of the native PGHS-2 dimer, the Ecat subunits.

139 ablished that only one monomer of the native PGHS-2 homodimer binds flurbiprofen tightly.

140 GHS-2) have COX activities similar to native PGHS-2.

141 With some heterodimers (e.g. Y385F/Native PGHS-2), heme binds with significantly higher affinity t

142 ay account for the ability of PGHS-2 but not PGHS-1 to efficiently oxygenate AA in intact cells when

143 Acetylation of Ser-530 of PGHS-1 by aspirin abolishes all oxygenase activity and t

144 iors of PGHSs may account for the ability of PGHS-2 but not PGHS-1 to efficiently oxygenate AA in int

145 c regulation likely underlies the ability of PGHS-2 to operate at low AA concentrations, when PGHS-1

146 ad no significant effect on the abundance of PGHS-1 mRNA in any brain region.

147 adiol, by itself, increased the abundance of PGHS-2 mRNA in brainstem and cerebellum, and augmented t

148 tex in response to BCO, and the abundance of PGHS-2 protein was increased by both oestradiol and BCO

149 ough the preferential peroxide activation of PGHS-2 over PGHS-1 seen in mammals was conserved in the

150 substrates for the peroxidase activities of PGHS-2, PGHS-1, and glutathione peroxidase (GPx).

151 vo and blocks the cyclooxygenase activity of PGHS in vitro.

152 ma, elicited a 2- to 3-fold amplification of PGHS-2 induction, delayed-phase PGD(2) generation, and I

153 PATHWAYS analysis of PGHS crystal structures identified four tyrosine residue

154 Analysis of PGHS inactivation by AcSHA, coupled with the X-ray cryst

155 e markedly the kinetics and the chemistry of PGHS-1 peroxidase inactivation.

156 ormation of a narrow singlet in complexes of PGHS-2 with cyclooxygenase inhibitors.

157 The results suggest a new concept of PGHS inactivation: that distinct damage can occur at the

158 between oestradiol and BCO in the control of PGHS-2 expression in the fetal brainstem.

159 that oestradiol increases the expression of PGHS isoforms, and that oestradiol augments the PGHS res

160 that oestradiol increases the expression of PGHS-2 in specific fetal brain regions, and that there i

161 Darbufelone quenches the fluorescence of PGHS-2 at 325 nm (lambda(ex) = 280 nm) with K(d) = 0.98

162 Two forms of PGHS exist, PGHS-1 (COX-1) and PGHS-2 (COX-2).

163 His386 of PGHS-1 is not formally part of either active site, but l

164 However, there was no impairment of PGHS-2 induction in BMMC deficient in hematopoietic PGD

165 for substrate metabolism and inactivation of PGHS and report the first metabolism-dependent, selectiv

166 Inactivation of PGHS peroxidase activity has been found to begin with In

167 Complete inactivation of PGHS-2 was achieved with 10 muM 3-HPAA.

168 tabolism-dependent, selective inactivator of PGHS-2.

169 These results indicate that the induction of PGHS-2 and mPGES by IL-1beta underlies robust PGE(2) pro

170 this study, we report that the induction of PGHS-2 by IL-1beta is dramatically enhanced and prolonge

171 Inhibition of PGHS activity by acetaminophen in human umbilical vein e

172 f acetaminophen is mediated by inhibition of PGHS activity, and that hydroperoxide concentration cont

173 he structural requirements for inhibition of PGHS, we discovered that the meta isomer of AM404, N-(3-

174 Inhibition of PGHS-2 with darbufelone is time dependent: with no prein

175 darbufelone is a noncompetitive inhibitor of PGHS-2 (K(i) = 10 +/- 5 microM).

176 fusion on the expression of both isoforms of PGHS.

177 (IL)-1beta treatment elicits high levels of PGHS-2 and mPGES expression.

178 ithelial cell line, expresses high levels of PGHS-2 but surprisingly low levels of PGE(2) when compar

179 lls expressed significantly higher levels of PGHS-2 mRNA and protein, and generated more PGE2.

180 ssential for 3-nitrotyrosine modification of PGHS-1 was confirmed by the absence of 3-nitrotyrosine i

181 did not result from covalent modification of PGHS-2 or damage to the heme moiety.

182 lective inhibition, knockout, or mutation of PGHS-2, or deletion of the receptor for PGHS-2-derived P

183 Plots of PGHS-2 activity vs preincubation time at various darbufe

184 ng cells can express a suboptimal profile of PGHS and PGES isoforms, resulting in diminished levels o

185 ons with the wide singlet tyrosyl radical of PGHS-2 to generate a radical intermediate that was analy

186 ermediate II, which forms during reaction of PGHS with peroxide and which contains two oxidants, a fe

187 e peroxidase activity during the reaction of PGHS-1 with EtOOH or 15-HPETE correlated with oxyferryl

188 Reaction of PGHS-1 with peroxide forms Intermediate I, which has an

189 n of reducing cosubstrate during reaction of PGHS-1 with peroxide protected the peroxidase activity t

190 f peroxidase inactivation during reaction of PGHS-1 with peroxide.

191 clooxygenase inactivation during reaction of PGHS-1 with several hydroperoxides.

192 e inactivation were examined in reactions of PGHS-1 reconstituted with heme or mangano protoporphyrin

193 a mechanism for regulating the reactivity of PGHS tyrosyl radicals with cellular antioxidants.

194 that cyclooxygenase active site residues of PGHS-1 fall into five functional categories as follows:

195 The distinctive binding specificities of PGHS subunits permit different combinations of non-ester

196 also influences the substrate specificity of PGHS-1; an S530T substitution causes 40- and 750-fold de

197 each PGHS-1 dimer, we analyzed structures of PGHS-1 crystallized under five different conditions incl

198 and their adverse effects by suppression of PGHS-2-derived prostacyclin (PGI(2)) and PGE(2).

199 These different kinetic behaviors of PGHSs may account for the ability of PGHS-2 but not PGHS

200 bstrate FAs like palmitic acid bind Eallo of PGHSs stimulating human (hu) PGHS-2 but inhibiting huPGH

201 r affinities for Ecat than Eallo subunits of PGHSs.

202 ological examination of bone from 5-week-old PGHS-2(-/-) mice revealed no abnormalities.

203 tely reverses the action of acetaminophen on PGHS-1.

204 signaling with the largest effects being on PGHS-1 pathways involving PGD, PGE, and PGF.

205 S, suggesting a dependence of this enzyme on PGHS-2 activity.

206 s indicate that the ultimate effect of NO on PGHS-2 enzyme activity and expression is dictated by the

207 C deficient in hematopoietic PGD synthase or PGHS-1 in the presence or absence of the PGHS-2 inhibito

208 one in this way, in place of Tween 20 in our PGHS buffers.

209 ferential peroxide activation of PGHS-2 over PGHS-1 seen in mammals was conserved in the fish enzymes

210 es and COS-7 cells engineered to overexpress PGHS-2 was assessed.

211 ling: residues 148, 348, 404, and 504 (ovine PGHS-1 numbering).

212 In ovine PGHS-1 crystallized in the absence of an NSAID, there is

213 ay crystal structure of the complex of ovine PGHS-1 with AcSHA, confirms that the inhibitor elicits i

214 ecause acetaminophen inhibits purified ovine PGHS-1 and murine recombinant PGHS-2 equally.

215 Co(3+) protoporphyrin IX-reconstituted ovine PGHS-1 (Co(3+)-oPGHS-1) and compare the effects of activ

216 2 (COX-2), converts arachidonic acid to PGH2 PGHS-2 is a conformational heterodimer composed of allos

217 isoform of prostaglandin H synthase (PGHS), PGHS-2.

218 Under optimal conditions purified PGHS-1 oxygenates EPA with only 10% of the efficiency of

219 lamide (3-HPAA), is a substrate for purified PGHS.

220 -nitrotyrosine modification site in purified PGHS-1 exposed to peroxynitrite.

221 ndinyl-lysine adducts are formed on purified PGHSs following the oxygenation of arachidonic acid.

222 However, Q203V PGHS-1 and PGHS-2 mutants catalyzed heterolytic cleavage

223 Native/R120Q PGHS-2, a heterodimer in which both subunits can oxygena

224 We expressed recombinant PGHS-2 proteins containing single Tyr --> Phe mutations

225 purified ovine PGHS-1 and murine recombinant PGHS-2 equally.

226 e not COX substrates differentially regulate PGHS-1 versus PGHS-2.

227 acting in an autocrine fashion, to regulate PGHS-2 induction and IL-6 secretion in mouse BMMC.

228 lls, the FA tone, is a key factor regulating PGHS-2 activity and its responses to COX inhibitors.

229 s of helical residues 119-122 of S121P/S121P PGHS-2 are displaced from their normal positions.

230 Additionally, the S121P/S121P PGHS-2 variants in which Pro-127 and Ser-541 are replace

231 GHS-2 monomers yields a variant (S121P/S121P PGHS-2) that has 1.7-1.8 times the Vmax of native PGHS-2

232 ing that iNOS-derived NO markedly suppresses PGHS activity in vascular cells.

233 Whether NO activates or suppresses PGHS activity is determined by alternative protein modif

234 Prostaglandin endoperoxide synthase (PGHS)-2, the inducible isoform of this enzyme, is induce

235 uced expression of PG endoperoxide synthase (PGHS)-2.

236 Prostaglandin H synthase (PGHS) catalyzes the conversion of arachidonic acid to pr

237 ed at the level of prostaglandin H synthase (PGHS) cyclooxygenase catalysis by the availability and s

238 f the prostaglandin-endoperoxide H synthase (PGHS) family.

239 Reaction of prostaglandin H synthase (PGHS) isoforms 1 or 2 with peroxide forms a radical at T

240 Both prostaglandin H synthase (PGHS) isoforms utilize a radical at Tyr385 to abstract a

241 l radicals in both prostaglandin H synthase (PGHS) isozymes have been demonstrated to couple the pero

242 ducible isoform of prostaglandin H synthase (PGHS), PGHS-2.

243 ce was seen with PG endoperoxide H synthase (PGHS)-1.

244 and inhibitors of prostaglandin H synthase (PGHS)-2 by exhibiting little effect on platelets or infl

245 dical on Tyr385 in prostaglandin H synthase (PGHS).

246 anoid synthesis by prostaglandin H synthase (PGHS).

247 inactivates prostaglandin (PG) H2 synthase (PGHS) via acetylation of an active-site serine residue.

248 n is prostaglandin endoperoxide H2 synthase (PGHS).

249 The prostaglandin H synthases (PGHS) catalyze the conversion of arachidonic acid to pro

250 Prostaglandin G/H synthases (PGHS), commonly referred to as cyclooxygenases (COX-1 an

251 donic acid by the prostaglandin H synthases (PGHS), prostaglandin H(2) (PGH(2)), undergoes rearrangem

252 Prostaglandin endoperoxide H synthases (PGHS)-1 and -2, also called cyclooxygenases, convert ara

253 Prostaglandin endoperoxide H synthases (PGHSs) 1 and 2 convert arachidonic acid to prostaglandin

254 Prostaglandin endoperoxide H synthases (PGHSs) 1 and 2, also known as cyclooxygenases (COXs), ca

255 y of prostaglandin endoperoxide H synthases (PGHSs) converts arachidonic acid and O2 to prostaglandin

256 Prostaglandin-endoperoxide H synthases (PGHSs) have a cyclooxygenase that forms prostaglandin (P

257 Prostaglandin endoperoxide H synthases (PGHSs), also called cyclooxygenases (COXs), convert arac

258 Prostaglandin endoperoxide H synthases (PGHSs)-1 and -2 (also called cyclooxygenases (COXs)-1 an

259 ctive products of prostaglandin H-synthases (PGHSs) to the enzyme and to other molecules.

260 We conclude that PGHS monomers comprising a dimer, although identical in

261 These results indicate that PGHS-2 gene expression is induced by oxygen and glucose

262 The PGHS substrate, arachidonate, and various cyclooxygenase

263 brainstem and cerebellum, and augmented the PGHS-2 mRNA response to BCO in brainstem.

264 S isoforms, and that oestradiol augments the PGHS response to cerebral hypoperfusion.

265 To investigate the mechanism of the PGHS-2 gene expression in response to cerebral hypoperfu

266 arily dampens and limits the duration of the PGHS-2 induction by IL-1beta.

267 or PGHS-1 in the presence or absence of the PGHS-2 inhibitor, NS-398.

268 Increasing the peroxide product of the PGHS-cyclooxygenase, prostaglandin G(2) (PGG(2)), by ele

269 ct of oxygenation of arachidonic acid by the PGHSs, prostaglandin (PG) H2, undergoes rearrangement to

270 Inhibition of the PGHSs with NSAIDs acutely reduces inflammation, pain, an

271 the reductant action of acetaminophen on the PGHSs by cellular peroxides.

272 lysyl-levuglandin adducts are formed on the PGHSs following the oxygenation of arachidonic acid; aft

273 ay half of sites COX activity with AA; thus, PGHSs function as conformational heterodimers.

274 darbufelone competes directly for binding to PGHS-2.

275 ossible with H2O2, are major contributors to PGHS POX specificity.

276 In contrast, aspirin-treated PGHS-2 (ASA-PGHS-2) no longer forms prostaglandins but r

277 idase self-inactivation in inhibitor-treated PGHS-1 and MnPGHS-1 was characterized by stopped-flow sp

278 ion was about 0.3 s(-)1 in inhibitor-treated PGHS-1 and much slower in MnPGHS-1 (0.05 s(-)1); as with

279 tra during inactivation of inhibitor-treated PGHS-1 were similar to those observed with PGHS-1 but we

280 t the cyclooxygenase site (inhibitor-treated PGHS-1) thus can influence markedly the kinetics and the

281 red during inactivation of inhibitor-treated PGHS-1, producing iron chlorin and heme-protein adduct s

282 genase activities of recombinant brook trout PGHS-1 and -2 were characterized to test the generality

283 differential catalytic regulation of the two PGHS isoforms observed in vivo.

284 tivity observed in aspirin-treated wild-type PGHS-2.

285 trates differentially regulate PGHS-1 versus PGHS-2.

286 -2 to operate at low AA concentrations, when PGHS-1 is effectively latent.

287 mally expressed, in primary astrocytes where PGHS-2 expression was induced by lipopolysaccharide (LPS

288 ring the composition of the FA pool in which PGHS-1 functions.

289 the free FA pool in the environment in which PGHS-2 functions in cells, the FA tone, is a key factor

290 uch slower in MnPGHS-1 (0.05 s(-)1); as with PGHS-1 itself, the peroxidase inactivation rates were in

291 cardiovascular consequences associated with PGHS-2-mediated PGI(2) suppression.

292 is inducible and works more efficiently with PGHS-2, the inflammatory cyclooxygenase, while the cytop

293 smic isoform (cPGES) pairs functionally with PGHS-1, the cyclooxygenase that ordinarily exhibits cons

294 nation are typically 1.5-2 times higher with PGHS-2 than with PGHS-1.

295 (0.0001%), darbufelone appears inactive with PGHS-2 due to a detergent interaction that is detectable

296 d PGHS-1 were similar to those observed with PGHS-1 but were rather distinct in MnPGHS-1; the kinetic

297 than the wide doublet radical observed with PGHS-1 reconstituted with heme.

298 versus 3-series compounds were observed with PGHS-2, PGD synthases, microsomal PGE synthase-1 and EP1

299 = 0.19 microM) but is much less potent with PGHS-1 (IC(50) = 20 microM).

300 In contrast to the situation with PGHS-1 itself, significant amounts of heme degradation o

301 lly 1.5-2 times higher with PGHS-2 than with PGHS-1.