ライフサイエンスコーパス: BH4

1 pendent on the cofactor tetrahydrobiopterin (BH4).

2 tients can benefit from tetrahydrobiopterin (BH4).

3 nction, is the cofactor tetrahydrobiopterin (BH4).

4 e cofactor (6R)-5,6,7,8-tetrahydrobiopterin (BH4).

5 on of the NOS cofactor, tetrahydrobiopterin (BH4).

6 owing to systemic and vascular oxidation of BH4.

7 (cholest-4-en-3-one oxime) and TAT-Bcl-X(L)-BH4.

8 fects were recovered by supplementation with BH4.

9 activity, had reduced levels of GTPCH I and BH4.

10 fects were recovered by supplementation with BH4.

11 d knockdown of eNOS or by supplementing with BH4.

12 tion and increased the levels of GTPCH I and BH4.

13 lowered the levels of both GTPCH protein and BH4.

14 igh glucose-triggered reduction of GTPCH and BH4.

15 nclusion, intestinal Actinobacteria generate BH4.

16 for 2 hours, accompanied with restoration of BH4.

17 th the dependence of tyrosine hydroxylase on BH4.

18 he PEGylated ILs and BMPyrTFSI containing Mg(BH4)2 by study of Raman modes of the coordinated and fre

19 ction of a beta-amino ketone product with Zn(BH4)2 gives a 1,3-amino alcohol with modest diastereosel

20 mical deposition/dissolution of Mg from a Mg(BH4)2 source.

21 that clean hydrogen can be released from Mg(BH4)2 under mild conditions and (2) clarifying the origi

22 strategy toward the purification of gamma-Mg(BH4)2 using supercritical nitrogen drying techniques, (1

23 ex hydride materials, such as gamma-phase Mg(BH4)2, which exhibits high surface area and readily adso

24 [{U(BH4)}2(mu-BH4)(L(Me))] and [Na(THF)4][{U(BH4)}2(mu-BH4)(L(A))(THF)2].

25 lear [U(BH4)(L)] and dinuclear [Li(THF)4][{U(BH4)}2(mu-BH4)(L(Me))] and [Na(THF)4][{U(BH4)}2(mu-BH4)(

26 -ray diffraction and display two new U(III)2(BH4)3 motifs.

27 synthesis of the valuable U(III) synthon [U(BH4)3(THF)2] is reported.

28 ductase (DHFR), an enzyme-recycling oxidized BH4 (7,8-dihydrobiopterin (BH2)), and studied the effect

29 th a concomitant reduction in BH4 levels and BH4:7,8-dihydrobiopterin ratio.

30 PCH in HEK-293 cells elicited 3-fold greater BH4 accumulation than an equivalent of wt-GTPCH.

31 , and tryptophan hydroxylases catalyzing the BH4-activated conversion of phenylalanine into tyrosine,

32 Atrial content of BH4 after perfusion was reduced (by 32%, p=0.001), as wa

33 oneopterin 3'triphosfate from GTP, producing BH4 after two further steps catalyzed by 6-pyruvoyltetra

34 dependent coronary flow well above that with BH4 alone.

35 NOS recoupling by exogenous BH4 ameliorates preexisting advanced cardiac hypertrophy

36 regulate the amounts of tetrahydrobiopterin (BH4), an enzyme cofactor essential for the synthesis of

37 in the biosynthesis of tetrahydrobiopterin (BH4), an essential cofactor of nitric oxide synthase, an

38 yme for biosynthesis of tetrahydrobiopterin (BH4), an obligate cofactor for NO synthases and aromatic

39 iens and Microbacterium schleiferi, generate BH4 and are present in hph-1 fecal material.

40 2, as well as the relative concentrations of BH4 and BH2, together play a determining role in the red

41 etes mellitus-induced reduction of GTPCH and BH4 and endothelial dysfunction in streptozotocin-induce

42 linking upstream redox-sensitive effects of BH4 and glutathione with redox-dependent targets and pat

43 XX patients were unable to increase plasma BH4 and had a greater reduction of flow-mediated dilatio

44 three AAAH genes and one AGMO gene, contains BH4 and has genes that function in BH4 synthesis and reg

45 Vaccination increased circulating BH4 and interleukin 6 and induced endothelial dysfunctio

46 The ratio between BH4 and its oxidized products was lower in mGCH1-Tg, ind

47 (2) nNOSox (with BH4 and l-Arg) yields a typical BH4 radical in a manner

48 The effects of BH4 and l-arginine on the oxygen-induced radical interme

49 lthough the functional relationships between BH4 and S-glutathionylation remain unknown.

50 Carriers of this haplotype produce less BH4 and therefore feel less pain, especially following n

51 H4 synthesis, to determine the importance of BH4 and Trp-447 in eNOS uncoupling.

52 (3) nNOSox (with BH4 and without l-Arg) yields a new radical.

53 OS oxygenase domain (eNOSox) with or without BH4 and/or l-arginine.

54 Early treatment with BH4 and/or neurotransmitter precursors had dramatic bene

55 In contrast, BH4(-) and BF4(-) are shown to be chemically stable in a

56 (Arg), NADPH, FAD, FMN, tetrahydrobiopterin (BH4), and calmodulin, indicating that H2S does not inter

57 AMPK (Thr172), GTPCH I, tetrahydrobiopterin (BH4), and endothelial functions.

58 redicted enzymatic activities, synthesize no BH4, and have indistinguishable behavioral and neurotran

59 egulated GCH1 expression, increased vascular BH4, and improved vasorelaxation in response to acetylch

60 Reactions of the BH4(-) anion with equimolar amounts of HN(NO2 )2 or of B

61 Development of this Bcl2-BH4 antagonist may provide a strategy to improve lung ca

62 Myocardial GCH1 activity and intracellular BH4 are a limiting factor for constitutive NOS1 and SERC

63 ng in hypertrophic heart disease and support BH4 as a potential new approach to treat this disorder.

64 These novel findings identify BH4 as a vascular defense mechanism against inflammation

65 When BH4 availability is limiting, eNOS becomes "uncoupled,"

66 P cyclohydrolase I to regulate intracellular BH4 availability.

67 key role of the NF-E2-related factor 2/GCH1/BH4 axis during radiation-induced skin damage.

68 ntly, VDAC1-NP did not affect the ability of BH4-Bcl-2 to suppress agonist-induced Ca(2+) release in

69 In intact cells, delivery of the BH4-Bcl-XL peptide via electroporation limits agonist-in

70 peptide (VDAC1-NP) abolishes the ability of BH4-Bcl-XL to suppress mitochondrial Ca(2+) uptake and t

71 ble NOS oxygenase domain reveal a homologous BH4-binding site located in the dimer interface and a co

72 )] to investigate the impact of hyperoxia on BH4 bioavailability and retinal vascular pathology in th

73 human atherosclerosis and the importance of BH4 bioavailability in determining endothelial function

74 on of the kynurenine pathway could attenuate BH4 biosynthesis and BH4-dependent enzymatic reactions,

75 yclohydrolase 1, the rate-limiting enzyme in BH4 biosynthesis which catalyses the formation of dihydr

76 clohydrolase 1 (the rate-limiting enzyme for BH4 biosynthesis) in ECs by gene trasfer enhanced endoth

77 lase-1 (GTPCH1), the rate-limiting enzyme in BH4 biosynthesis, and dihydrofolate reductase (DHFR), an

78 The results also show a decrease in NOS and BH4 biosynthetic enzyme in submandibular glands.

79 changes in NO cofactor tetrahydrobiopterin (BH4) biosynthetic enzymes (guanosine triphosphate cycloh

80 tely 1.9.10(-5) m in the presence of Arg and BH4 but exhibited much higher IC50 values ( approximatel

81 ol/l) reduction of GTPCH I, biopeterins, and BH4 but had no effect on GTPCH I mRNA.

82 esence of only l-arginine in nNOSox (without BH4 but with l-Arg) caused conversion of approximately 7

83 of superoxide production in nNOSox (without BH4 but with l-Arg).

84 Here, we demonstrate that diabetes reduced BH4 by increasing 26S proteasome-dependent degradation o

85 BH4 can limit its own synthesis by triggering decameric

86 We tested whether tetrahydrobiopterin (BH4) can recouple NOS and reverse preestablished advance

87 xide synthase activity (secondary to reduced BH4 content and/or increased arginase activity) and mito

88 How alterations in endothelial BH4 content impact myocardial ischemia/reperfusion injur

89 These results demonstrate that increased BH4 content in ECs by either pharmacological or genetic

90 with an emphasis on the role of endothelial BH4 content.

91 ency may allow for an increase in total body BH4 content.

92 Furthermore, BH4 deficiency alone is alone sufficient to reduce intra

93 We conclude that diabetes mellitus triggers BH4 deficiency by increasing proteasome-dependent degrad

94 To investigate the role of BH4 deficiency in disease phenotypes, 12-month-old Fabry

95 In conclusion, this study showed that BH4 deficiency occurs in Fabry disease and may contribut

96 echanism by which diabetes actually leads to BH4 deficiency remains elusive.

97 are abolished, whereas uncoupling induced by BH4 deficiency was preserved.

98 In the Fabry mice receiving SRT but not ERT, BH4 deficiency was restored, concomitant with ameliorate

99 In eNOS uncoupling induced by BH4 deficiency, BCNU exposure further exacerbates supero

100 These data provide the first evidence that BH4 deficiency- and S-glutathionylation-induced mechanis

101 Tetrahydrobiopterin (BH4) deficiency is reported to uncouple the enzymatic ac

102 proportion (2%) exhibit tetrahydrobiopterin (BH4) deficiency with additional neurotransmitter (dopami

103 d in W447A eNOS cells and further reduced in BH4-deficient cells, as demonstrated using a novel split

104 In uncoupled, BH4-deficient cells, the deleterious effects of W447A mu

105 BH4-deficient mutants also have a fragile cuticle and ar

106 BH4 deletion converts Bcl-2 into a proapoptotic protein,

107 superoxide production by eNOS, by effects on BH4-dependent catalysis, and by modulating eNOS dimer fo

108 lternative strategies are required to target BH4-dependent endothelial function in established vascul

109 pathway could attenuate BH4 biosynthesis and BH4-dependent enzymatic reactions, linking two major met

110 vely active RAS with which it interacts in a BH4-dependent manner.

111 upling of eNOS by S-glutathionylation- or by BH4-dependent mechanisms exemplifies eNOS as an integrat

112 st that NOS s-glutathionylation, rather than BH4 depletion, accounts for NOS dysfunction in patients

113 BH4 did not enhance net protein kinase G activity.

114 the cells with BH4, either by application of BH4 directly or of its precursors dihydrobiopterin or se

115 Removal of the BH1 or BH4 domain abrogates the inhibitory effect of Bcl2 on Ku

116 The BCL-2 BH4 domain also confers anti-apoptotic functionality, bu

117 We identified a small-molecule Bcl2-BH4 domain antagonist, BDA-366, that binds BH4 with high

118 We find that a synthetic alpha-helical BH4 domain binds to BAX with nanomolar affinity and inde

119 Although the presence of a BH4 domain distinguishes the antiapoptotic protein Bcl-2

120 Deletion of the BH4 domain from Bcl2 abrogates the ability of Bcl2 to in

121 Thus, the BH4 domain has antiapoptotic activity independent of ful

122 signals at their point of origin, the Bcl-2 BH4 domain has the facility to block diverse pathways th

123 a stapled peptide corresponding to the Bclw BH4 domain interact with axonal IP3R1 and prevent paclit

124 inhibition of BAX and suggest that the BCL-2 BH4 domain may participate in apoptosis blockade by a no

125 Here we report that the BH4 domain mediates interaction of Bcl-2 with the inosit

126 interacting site on the IP(3)R, binds to the BH4 domain of Bcl-2 and functions as a competitive inhib

127 Furthermore, the BH4 domain of Bcl-2 was found to be required for success

128 Here, we report that in contrast to the BH4 domain of Bcl-2, the BH4 domain of Bcl-XL binds and

129 in contrast to the BH4 domain of Bcl-2, the BH4 domain of Bcl-XL binds and inhibits VDAC1.

130 y binding and inhibiting IP3Rs, although the BH4 domain of Bcl-XL was protective independently of bin

131 In conclusion, our data indicate that the BH4 domain of Bcl-XL, but not that of Bcl-2, selectively

132 Removal of the BH4 domain of Bcl2 abrogates its inhibitory effects on R

133 PP2A directly interacts with the BH4 domain of Bcl2 as a docking site to potentially "bri

134 The BH4 domain of Bcl2 is required for its antiapoptotic fun

135 IP3Rs appears to be mediated by the putative BH4 domain of Bok and the docking site localizes to a sm

136 the cytoplasm and directly interacts via its BH4 domain with hRRM2 but not hRRM1.

137 Another region of Bcl-2, the BH4 domain, also contributes to the antiapoptotic activi

138 nd, that it is the helical nature of the Bok BH4 domain, rather than specific amino acids, that media

139 ylates Bcl-xL at Ser14, which resides in the BH4 domain, thereby antagonizing Bcl-xL-Bax binding.

140 g the functional hRRM1/hRRM2 complex via its BH4 domain.

141 h interacts with hMSH6 but not hMSH2 via its BH4 domain.

142 usly demonstrated that the Bcl-2 homology 4 (BH4) domain of Bcl-2 protects against Ca(2+)-dependent a

143 ociate following exposure of the BAK BH3 and BH4 domains before BAK homodimerization.

144 Bcl2 to interact with Mre11 via the BH1 and BH4 domains.

145 acts with both Ku70 and Ku86 via its BH1 and BH4 domains.

146 e effects, supplementation of the cells with BH4, either by application of BH4 directly or of its pre

147 plementation of human vessels and blood with BH4 ex vivo revealed rapid oxidation of BH4 to BH2 with

148 Although there are no known BH4 exogenous sources, the tissue content of this biopte

149 in, a synthetic form of tetrahydrobiopterin (BH4), for reduction of blood phenylalanine concentration

150 lyether chains can displace both TFSI(-) and BH4(-) from the coordination sphere of Mg(2+).

151 2 into a proapoptotic protein, whereas a TAT-BH4 fusion peptide inhibits apoptosis and improves survi

152 synthase (PTPS-2) an enzyme only present in BH4-generating bacteria.

153 ed PTPS-2 mRNA indicative of the presence of BH4-generating bacteria.

154 g BIM BH3 helix were suppressed by the BCL-2 BH4 helix.

155 DTT prevents oxidation of BH4 in both isoforms, but in nNOS, DTT also inhibits oxi

156 ontribute to the known beneficial effects of BH4 in cardiovascular disorders associated with oxidativ

157 pecies, nitric oxide synthase uncoupling, or BH4 in patients with permanent AF.

158 Hyperoxia decreased BH4 in retinas, lungs, and aortas in all experimental gr

159 To address a possible role for BH4 in S-glutathionylation-induced eNOS uncoupling, we e

160 , a rate-limiting enzyme in the synthesis of BH4, in parallel with increased formation of both supero

161 When 3 is reduced by tetrahydrobiopterin (BH4), instead of an externally supplied electron, the re

162 Structural analyses localized the BH4 interaction site to a groove formed by residues of a

163 Bioavailability of BH4 is a critical factor in regulating the balance betwe

164 BH4 is an essential co-factor in the production of serot

165 Vascular but not plasma BH4 is an important determinant of eNOS coupling, endoth

166 We hypothesized that endothelial BH4 is an important regulator of inflammation and vascul

167 Therefore, administration of BH4 is considered a promising therapy for cardiovascular

168 Maintaining sufficient endothelial BH4 is crucial for cardioprotection against hypoxia/reox

169 Our findings suggest that the depletion of BH4 is not sufficient to perturb NO signaling, but rathe

170 We now show that excessive BH4 is produced in mice by both axotomized sensory neuro

171 BH4 is regulated by GTP cyclohydrolase 1, the rate-limit

172 mpounds where the complex borohydride anion, BH4(-), is replaced by another anion, i.e. a halide or a

173 Tetrahydrobiopterin (BH4) is a cofactor of a number of regulatory enzymes.

174 Tetrahydrobiopterin (BH4) is a key redox-active cofactor in endothelial isofo

175 Tetrahydrobiopterin (BH4) is a key regulator of endothelial nitric oxide synt

176 Tetrahydrobiopterin (BH4) is a major endogenous vasoprotective agent that imp

177 Tetrahydrobiopterin (BH4) is a required cofactor for nitric oxide (NO) produc

178 Tetrahydrobiopterin (BH4) is a required cofactor for the synthesis of NO by N

179 Tetrahydrobiopterin (BH4) is an absolute requirement for eNOS activity.

180 5,6,7,8-Tetrahydrobiopterin (BH4) is an essential cofactor for all nitric oxide synth

181 Tetrahydrobiopterin (BH4) is an essential cofactor for endothelial nitric oxi

182 Tetrahydrobiopterin (BH4) is an essential cofactor of endothelial nitric oxid

183 Tetrahydrobiopterin (BH4) is an essential cofactor of nitric oxide synthases

184 hough the eNOS cofactor tetrahydrobiopterin (BH4) is depleted, its repletion only partially restores

185 oxide synthase cofactor tetrahydrobiopterin (BH4) is essential for maintenance of enzymatic function.

186 Tetrahydrobiopterin (BH4) is the natural cofactor of several enzymes widely d

187 ontrol of the co-factor tetrahydrobiopterin (BH4) is tight in normal circumstances but levels increas

188 (mu-BH4)(L(Me))] and [Na(THF)4][{U(BH4)}2(mu-BH4)(L(A))(THF)2].

189 4)(L)] and dinuclear [Li(THF)4][{U(BH4)}2(mu-BH4)(L(Me))] and [Na(THF)4][{U(BH4)}2(mu-BH4)(L(A))(THF)

190 c U(III) complexes, including mononuclear [U(BH4)(L)] and dinuclear [Li(THF)4][{U(BH4)}2(mu-BH4)(L(Me

191 Inadequate availability of BH4 leads to uncoupling of nitric oxide synthases and pr

192 coronary artery disease and to determine how BH4 levels affect endothelial function, eNOS coupling, a

193 ction, along with a concomitant reduction in BH4 levels and BH4:7,8-dihydrobiopterin ratio.

194 enzyme for BH4 synthesis, restored cellular BH4 levels and nitric oxide production and decreased rad

195 Inhibiting SPR will reduce BH4 levels and therefore should act as an analgesic.

196 the extent to which vascular and/or systemic BH4 levels are altered in human atherosclerosis and the

197 When BH4 levels are decreased, eNOS becomes uncoupled to prod

198 Augmentation of endogenous BH4 levels by oral BH4 treatment has been proposed as a

199 Excess BH4 levels cause pain, likely through excess production

200 Gb3 levels were inversely correlated with BH4 levels in animal tissues and cultured patient cells.

201 Oral BH4 treatment significantly augmented BH4 levels in plasma and in saphenous vein (but not inte

202 y effectively with a concomitant decrease in BH4 levels in target tissues, acting both on sensory neu

203 Reduction of cellular BH4 levels resulted in a switch from an eNOS dimer to an

204 Renal BH4 levels were closely correlated with glutathione leve

205 Arterial GTPCH I activity and BH4 levels were decreased significantly in wild-type DOC

206 scular superoxide, endothelial function, and BH4 levels were determined in segments of saphenous vein

207 in ECs by gene trasfer enhanced endothelial BH4 levels, the ratio of eNOS dimer/monomer, eNOS phosph

208 shed in cells expressing W447F, despite high BH4 levels.

209 efore and after treatment, along with plasma BH4 levels.

210 rphisms, which decrease tetrahydrobiopterin (BH4) levels, and reduced pain in patients.

211 g, reflected in reduced tetrahydrobiopterin (BH4) levels, increased BH2 levels, decreased dihydrofola

212 cl-2-IP3 receptor interaction prevents these BH4-mediated effects.

213 ter deficiencies without mutations in PAH or BH4 metabolism disorder-related genes.

214 the pro- and antiapoptotic regions (BH3 and BH4) of Bcl-2, as demonstrated by a nested protein fragm

215 (1) nNOSox (without BH4 or l-Arg) produces superoxide in the presence or abs

216 low-dose (400 mg/d) or high-dose (700 mg/d) BH4 or placebo for 2 to 6 weeks before coronary artery b

217 Constitutive BH4 overproduction in sensory neurons increases pain sen

218 n of C908S, BCNU-induced eNOS uncoupling and BH4 oxidation are abolished, whereas uncoupling induced

219 BH4 oxidation is observed in vascular cells in the setti

220 e further exacerbates superoxide production, BH4 oxidation, and eNOS activity.

221 BH4, oxidised biopterins, GTP-cyclohydrolase 1 (GTPCH-1,

222 urthermore, understanding the role of the NO-BH4 pathway may give insight into possible treatment opt

223 BH4 peptide binds to the regulatory and coupling domain

224 uman vascular function and to determine oral BH4 pharmacokinetics in both plasma and vascular tissue

225 oxide synthase cofactor tetrahydrobiopterin (BH4) plays a pivotal role in maintaining endothelial fun

226 thesized that decreased tetrahydrobiopterin (BH4) plays a role in the pathogenesis of Fabry disease.

227 The addition of 100 microM sepiapterin (a BH4 precursor) or overexpression of GTP cyclohydrolase 1

228 Bl/6 controls for the presence of intestinal BH4-producing bacteria.

229 The rate limiting step for BH4 production is GTP Cyclohydrolase 1 (GCH1).

230 ain, especially following nerve injury where BH4 production is pathologically augmented.

231 increases pain sensitivity, whereas blocking BH4 production only in these cells reduces nerve injury-

232 ductase (SPR), whose blockade allows minimal BH4 production through the BH4 salvage pathways.

233 indicate that a decrease in submandibular NO-BH4 protein expression may provide insight pertaining to

234 nNOSox (with BH4 and l-Arg) yields a typical BH4 radical in a manner independent of DTT.

235 externally supplied electron, the resulting BH4(+) radical oxidizes HNO/NO(-) to NO.

236 relative roles of de novo BH4 synthesis and BH4 redox recycling in the regulation of eNOS bioactivit

237 is, increased levels of tetrahydrobiopterin (BH4), reduced endothelial superoxide, improved eNOS coup

238 Increased endothelial BH4 reduces vein graft neointimal hyperplasia and athero

239 The BH4 regeneration enzymes are not required for steady-sta

240 imilarly, a loss-of-function mutation in the BH4 region of Bcl-2 that forms part of the second interf

241 terface that includes helix 6 of Bax and the BH4 region of Bcl-2.

242 sidue segment (EWD) of Bcl-2 adjacent to the BH4 region, which is anchored to one of the two hydropho

243 in eNOS uncoupling; however, how endogenous BH4 regulates blood pressure is unknown.

244 With combined NADPH and BH4 repletion, full restoration of NOS-dependent coronar

245 iggering impaired eNOS function and limiting BH4 rescue through NADPH-dependent salvage pathways.

246 Without reducing loading, BH4 reversed hypertrophy and fibrosis, recoupled endothe

247 g or aromatic stacking interactions with the BH4 ring.

248 de allows minimal BH4 production through the BH4 salvage pathways.

249 gulation seen by the selective modulation of BH4 salvage/reduction versus de novo BH4 synthetic pathw

250 s with phenylketonuria who are responsive to BH4, sapropterin treatment to reduce blood phenylalanine

251 However, BH4 stopped subsequent remodeling when NOS activity was

252 0005) and this reduction was not affected by BH4 supplementation (10 muM) or NOX2 inhibition ex vivo.

253 Oral BH4 supplementation preserves cardiac function in animal

254 roduction; this effect of BH2 was blocked by BH4 supplementation.

255 Loss of AGMO or BH4 synthesis also specifically alters the sensitivity o

256 However, the relative roles of de novo BH4 synthesis and BH4 redox recycling in the regulation

257 contains BH4 and has genes that function in BH4 synthesis and regeneration.

258 SPR is part of the BH4 synthesis cascade and is also upregulated by nerve i

259 Finally, transgenic mice with enhanced BH4 synthesis confined to endothelial cells were unprote

260 his study demonstrates an important role for BH4 synthesis in angiogenesis by the activation of eNOS

261 ity to increase vascular GCH1 expression and BH4 synthesis in response to inflammation preserves endo

262 Because BH4 synthesis is controlled enzymatically by GTP cyclohy

263 Our findings suggest that BH4 synthesis may be a rational target for antiangiogene

264 We hypothesized that induction of BH4 synthesis might be an endothelial defense mechanism

265 olase I (the rate-limiting enzyme in de novo BH4 synthesis) under doxycycline control potentiated in

266 lase 1 (GTPCH-1, the rate-limiting enzyme in BH4 synthesis), and NOS activity ((14)C L-arginine to L-

267 drolase 1 (GCH), the rate limiting enzyme in BH4 synthesis, increased levels of tetrahydrobiopterin (

268 olase I (GCH1), the rate-limiting enzyme for BH4 synthesis, restored cellular BH4 levels and nitric o

269 yclohydrolase I, the rate-limiting enzyme in BH4 synthesis, to determine the importance of BH4 and Tr

270 H I) is the rate-limiting enzyme for de novo BH4 synthesis.

271 reductase (SPR), the final enzyme in de novo BH4 synthesis.

272 ecome rate limiting in conditions of reduced BH4 synthesis.

273 Knockout mutants for putative BH4 synthetic enzyme genes lack the predicted enzymatic

274 tion of BH4 salvage/reduction versus de novo BH4 synthetic pathways.

275 pressure overload, indicating that exogenous BH4 targeted myocytes and fibroblasts.

276 Here we report on a novel function of BH4 that might contribute to the beneficial vascular eff

277 Despite greater depletion of BH4, the hph(+/-) and hph1(-/-) groups did not show exac

278 ype eNOS, and this was sufficient to oxidize BH4 to 7,8-dihydrobiopterin.

279 with BH4 ex vivo revealed rapid oxidation of BH4 to BH2 with predominant BH2 uptake by vascular tissu

280 ant increases in oxidative stress, oxidizing BH4 to enzymatically incompetent dihydrobiopterin.

281 determine the mechanisms relating exogenous BH4 to human vascular function and to determine oral BH4

282 identify novel pathways linking endothelial BH4 to inflammation and vascular remodeling.

283 Oral BH4 treatment augments total biopterin levels in patient

284 ugmentation of endogenous BH4 levels by oral BH4 treatment has been proposed as a potential therapeut

285 There was no effect of BH4 treatment on vascular function or superoxide product

286 Oral BH4 treatment significantly augmented BH4 levels in plas

287 We found that supplementation of BH4 (via the pterin salvage pathway with Sep) increased

288 BH4 was also decreased in the plasma of female Fabry pat

289 High vascular BH4 was associated with greater vasorelaxations to acety

290 acetylcholine (P<0.05), whereas high plasma BH4 was associated with lower vasorelaxations in respons

291 High vascular (but not plasma) BH4 was associated with reduced total and N(G)-nitro-L-a

292 We found that BH4 was decreased in the heart and kidney but not in the

293 of nNOS by Na2S in the absence of Arg and/or BH4 was markedly potentiated by the NO donor 1-(hydroxy-

294 roximately 1.0-6.1.10(-4) m) when Arg and/or BH4 was omitted.

295 If BH4 was started at the onset of pressure overload, it di

296 Oral BH4 was then administered for 5 more weeks of pressure o

297 Since certain bacteria are known to generate BH4, we hypothesize that generation of this biopterin by

298 dy, we demonstrated that radiation disrupted BH4, which resulted in nitric oxide synthases uncoupling

299 2-BH4 domain antagonist, BDA-366, that binds BH4 with high affinity and selectivity.

300 atively identified by NMR in the reaction of BH4(-) with a large excess of HN(NO2 )2 .

301 The reaction of BH4(-) with two equivalents of HN(NO2 )2 afforded the di