ライフサイエンスコーパス: G6Pase

1 gluconeogenic enzyme glucose-6-phosphatase (G6pase).

2 y RORalpha at an endogenous ROR target gene (G6Pase).

3 omes expressing either H119A or H176A mutant G6Pase.

4 g that His(176) is the phosphate acceptor in G6Pase.

5 ty (64.5%) of helical mutations destabilized G6Pase.

6 rs of enzymes of glucose synthesis PEPCK and G6Pase.

7 f the hepatic gluconeogenic genes, Pepck and G6pase.

8 f glucose 6-phosphate transporter (G6PT) and G6Pase.

9 edicted nine-transmembrane helical model for G6Pase.

10 e promoters of gluconeogenic enzymes such as G6Pase.

11 rms by controlling the expression of hepatic G6Pase.

12 The G6Pase(-146/-116) DNA containing AE-II formed multiple p

13 Deficiency of glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, causes gly

14 Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchore

15 ed by a deficiency in glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis.

16 The activation of glucose-6-phosphatase (G6Pase), a key enzyme of endogenous glucose production,

17 ed by a deficiency in glucose-6-phosphatase (G6Pase), a nine-helical endoplasmic reticulum transmembr

18 tal hepatoblasts) and glucose-6-phosphatase (G6Pase, a marker of mature hepatocytes) showed inverse e

19 rotein 1 (IGFBP1) and glucose-6-phosphatase (G6Pase), activating their expression.

20 Hepatic G6Pase activity determined from freshly isolated microso

21 Hepatic G6Pase activity in Ad-mG6Pase-infused mice was restored

22 r, we have generated a data base of residual G6Pase activity retained by G6Pase mutants, established

23 he 31 helical mutations completely abolished G6Pase activity, but only 5 of the 13 nonhelical mutants

24 Recently, we characterized a second G6Pase activity, that of G6Pase-beta (also known as G6PC

25 catalysis and that His-119 is essential for G6Pase activity.

26 iciency in microsomal glucose-6-phosphatase (G6Pase) activity.

27 glucagon, and hepatic glucose-6-phosphatase (G6Pase) activity/expression in G4Tg mice versus WT contr

28 -/-) mice expressing 3-63% of normal hepatic G6Pase-alpha activity (AAV mice) produce endogenous hepa

29 G6Pase-alpha activity depends on the G6P transporter (G6

30 finding that partial restoration of hepatic G6Pase-alpha activity in GSD-Ia mice not only attenuates

31 expressing more than 3% of wild-type hepatic G6Pase-alpha activity.

32 The functional coupling of G6Pase-alpha and G6PT maintains interprandial glucose ho

33 The role of the G6PT/G6Pase-alpha complex is well established and readily exp

34 not only attenuates the phenotype of hepatic G6Pase-alpha deficiency but also prevents the developmen

35 nhancer (GPE), completely normalizes hepatic G6Pase-alpha deficiency in GSD-Ia (G6pc(-/-) ) mice for

36 -GPE-mediated gene transfer corrects hepatic G6Pase-alpha deficiency in murine GSD-Ia and prevents ch

37 eno-associated virus (AAV) vector expressing G6Pase-alpha directed by the human G6PC promoter/enhance

38 wild-type mice may suggest relevance of the G6Pase-alpha enzyme to obesity and diabetes.

39 78 weeks of gene deletion, all mice lacking G6Pase-alpha in the liver develop HCA.

40 bit a similar Km toward G6P, but the Vmax of G6Pase-alpha is approximately 6-fold greater than that o

41 ociated virus (rAAV) vector expressing human G6Pase-alpha normalizes blood glucose homeostasis in the

42 ed by a lack of glucose-6-phosphatase-alpha (G6Pase-alpha or G6PC) activity.

43 (ER)-associated glucose-6-phosphatase-alpha (G6Pase-alpha or G6PC) that hydrolyzes glucose-6-phosphat

44 Because G6Pase (renamed G6Pase-alpha) is primarily expressed only in the liver,

45 tine-restricted glucose-6-phosphatase-alpha (G6Pase-alpha) or by a ubiquitously expressed G6Pase-beta

46 tine-restricted glucose-6-phosphatase-alpha (G6Pase-alpha) to maintain glucose homeostasis between me

47 Glucose-6-phosphatase-alpha (G6Pase-alpha), which facilitates microsomal G6P uptake b

48 ngle ER enzyme, glucose-6-phosphatase-alpha (G6Pase-alpha), whose activity--limited to the liver, kid

49 ed G6PT-proteoliposomes, suggesting that the G6Pase-alpha-mediated stimulation is caused by decreasin

50 reticulum-associated phosphohydrolase, like G6Pase-alpha.

51 Deficiency of glucose-6-phosphatase (G6Pase), an endoplasmic reticulum transmembrane glycopro

52 the protein levels of a gluconeogenic enzyme G6Pase and a co-activator PGC-1alpha were all markedly d

53 Deficiencies in G6Pase and G6PT cause GSD-1a and GSD-1b, respectively.

54 determine rates of EGP and the activities of G6Pase and GK in obese patients scheduled for gastric by

55 by suppressing FOXO1-dependent activation of G6pase and inhibition of glucokinase, respectively.

56 suggests that a coordinate increase in both G6Pase and PEPCK gene transcription is likely to contrib

57 e gluconeogenic genes glucose-6-phosphatase (G6pase) and phosphoenolpyruvate carboxykinase (Pepck).

58 y gluconeogenic genes glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK).

59 cription of PEPCK and glucose-6-phosphatase (G6Pase) and provides a possible therapeutic target in in

60 boxykinase 2 (PEPCK), glucose-6-phosphatase (G6Pase) and suppressed hepatic gluconeogenesis.

61 ykinase 1 (Pck-1) and glucose 6-phosphatase (G6Pase) and this effect was absent in mice lacking liver

62 gested that increased glucose-6-phosphatase (G6Pase) and/or decreased glucokinase (GK) may explain th

63 a catalytic subunit (glucose-6-phosphatase (G6Pase)) and putative accessory transport proteins.

64 nes, including PEPCK, glucose-6-phosphatase (G6Pase), and glucose-6-phosphate dehydrogenase (G6PDHase

65 xykinase (PEPCK), and glucose-6-phosphatase (G6Pase), and NAD(+) levels, and increased PARP activity

66 activity in the insulin regulation of PEPCK, G6Pase, and a third insulin-regulated gene, IGF-binding

67 gluconeogenic genes (glucose-6-phosphatase [G6Pase] and PEPCK) contributes to hyperglycemia.

68 During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosp

69 racterized a second G6Pase activity, that of G6Pase-beta (also known as G6PC), which is also capable

70 During pregnancy, the absence of G6Pase-beta activity also leads to impaired energy homeo

71 A deficiency in G6Pase-beta activity in neutrophils impairs both their e

72 Characterization of G6Pase-beta and generation of mice lacking either G6PT o

73 have shown that neutrophils express the G6PT/G6Pase-beta complex capable of producing endogenous gluc

74 on of glucose and G6P metabolism by the G6PT/G6Pase-beta complex.

75 Most importantly, G6Pase-beta couples with the G6P transporter to form an

76 A G6Pase-beta deficiency prevents recycling of ER glucose

77 Accordingly, a G6Pase-beta deficiency would impair glycolysis and hexos

78 nd generation of mice lacking either G6PT or G6Pase-beta have shown that neutrophils express the G6PT

79 deficiency, but the exact functional role of G6Pase-beta in neutrophils remains unknown.

80 establish that in nonapoptotic neutrophils, G6Pase-beta is essential for normal energy homeostasis.

81 We now report that the absence of G6Pase-beta led to neutropenia; defects in neutrophil re

82 Glucose-6-phosphatase-beta (G6Pase-beta or G6PC3) deficiency, also known as severe c

83 ulum (ER) enzyme glucose-6-phosphatase-beta (G6Pase-beta or G6PC3) that converts glucose-6-phosphate

84 express the ubiquitously expressed G6PT and G6Pase-beta that together transport G6P into the endopla

85 with the enzyme glucose-6-phosphatase-beta (G6Pase-beta) to regulate the availability of G6P/glucose

86 e-related protein, PAP2.8/UGRP, renamed here G6Pase-beta, is an acid-labile, vanadate-sensitive, endo

87 Consistent with this, G6Pase-beta-deficient (G6pc3-/-) mice with experimental

88 We hypothesized that the ER recycles G6Pase-beta-generated glucose to the cytoplasm, thus reg

89 is approximately 6-fold greater than that of G6Pase-beta.

90 G6Pase-alpha) or by a ubiquitously expressed G6Pase-beta.

91 Pase isoform was identified, designated UGRP/G6Pase-beta.

92 nd mRNA expression of PEPCK by 48 +/- 4% and G6Pase by 64 +/- 3%.

93 site was critical for the full induction of G6Pase-CAT expression by PKA.

94 explain why insulin potently inhibits basal G6Pase-CAT expression.

95 ent protein kinase (PKA) markedly stimulated G6Pase-CAT fusion gene expression, and mutational analys

96 his disorder, to delineate the mechanisms of G6Pase catalysis, and to develop future therapeutic appr

97 odified translocase catalytic unit model for G6Pase catalysis.

98 a novel gene that encodes an islet-specific G6Pase catalytic subunit-related protein (IGRP).

99 ity mechanisms control the expression of the G6Pase catalytic unit (G6pc).

100 Islet-specific glucose-6-phosphatase (G6Pase) catalytic subunit-related protein (IGRP) is a ho

101 Glucose-6-phosphatase (G6Pase) catalyzes the final step in the gluconeogenic an

102 used recombinant adenoviruses containing the G6Pase cDNA (AdCMV-G6Pase) or the beta-galactosidase gen

103 c subunit of glucose-6-phosphatase (G6Pase), G6Pase-chloramphenicol acetyltransferase (CAT) fusion ge

104 of insulin on the basal expression of mouse G6Pase-chloramphenicol acetyltransferase (CAT) fusion ge

105 PKA markedly stimulated G6Pase-chloramphenicol acetyltransferase fusion gene exp

106 transiently co-transfected with a series of G6Pase-chloramphenicol acetyltransferase fusion genes an

107 s with the G6P transporter to form an active G6Pase complex that can hydrolyze G6P to glucose.

108 lacking a functional liver/kidney/intestine G6Pase complex, are still capable of endogenous glucose

109 zed to glucose by the glucose-6-phosphatase (G6Pase) complex.

110 We have recently shown that human G6Pase contains an odd number of transmembrane segments,

111 Human G6Pase contains five methionine residues at positions 1,

112 redicts that Arg-83, His-119, and His-176 in G6Pase contribute to the active site and that His-176 is

113 e encoding the enzyme glucose-6-phosphatase (G6Pase) contributes to the increased production of gluco

114 glucose flux through glucose-6-phosphatase (G6Pase) decreased with Acrp30, whereas the activity of t

115 Whereas G6Pase deficiency in GSD-1a patients arises from mutatio

116 reported the development of a mouse model of G6Pase deficiency that closely mimics human GSD-Ia.

117 In addition to G6Pase deficiency, GSD-1b patients suffer neutropenia, n

118 ing the murine G6Pase gene (Ad-mG6Pase) into G6Pase-deficient (G6Pase(-/-)) mice that manifest sympto

119 The expression profiles of murine GSD-1b and G6Pase differ both in the liver and in the kidney; the G

120 o decreased expression of PEPCK, FBPase, and G6Pase due to increased acetylation of signal transducer

121 His-176 could be the phosphoryl acceptor in G6Pase during catalysis.

122 SRC-2 modulates G6Pase expression directly by acting as a coactivator wi

123 or-mediated gene transfer leads to sustained G6Pase expression in both the liver and the kidney and c

124 -/-) mice, consistent with observations that G6Pase expression is increased in diabetic animals.

125 this blocks insulin regulation of PEPCK and G6Pase expression.

126 d PKB is required to fully repress PEPCK and G6Pase expression.

127 stradiol (E2) induced ESR1 binding to Pck-1, G6Pase, Fas and Acc1 promoters.

128 dministration, EGP was slightly reduced, but G6Pase flux and GC were markedly lower compared with the

129 creased EGP is mediated in part by increased G6Pase flux in type 2 diabetes.

130 ble for 46 and 51% of glucose-6-phosphatase (G6Pase) flux, respectively.

131 uggest that the stimulatory effect of PKA on G6Pase fusion gene transcription in HepG2 cells may be m

132 catalytic subunit of glucose-6-phosphatase (G6Pase), G6Pase-chloramphenicol acetyltransferase (CAT)

133 used adenoviral vector containing the murine G6Pase gene (Ad-mG6Pase) into G6Pase-deficient (G6Pase(-

134 -II mediated transcription activation of the G6Pase gene by cAMP.

135 bound to its cognate site and transactivated G6Pase gene expression.

136 t link the insulin receptor to the PEPCK and G6Pase gene promoters.

137 whereas insulin strongly inhibits both basal G6Pase gene transcription and the stimulatory effect of

138 It also partially represses G6Pase gene transcription and yet has no effect on the e

139 strated that the maximum repression of basal G6Pase gene transcription by insulin requires two distin

140 ct of insulin, mediated through region B, on G6Pase gene transcription.

141 ely abolishes the effect of insulin on basal G6Pase gene transcription.

142 ct of insulin, mediated through region B, on G6Pase gene transcription.

143 ongly inhibits both this induction and basal G6Pase gene transcription.

144 optimal and liver-specific expression of the G6Pase gene were contained within nucleotides -234 to +3

145 GSD-1a patients arises from mutations in the G6Pase gene, this gene is normal in GSD-1b patients, ind

146 regulating liver-specific expression of the G6Pase gene, we characterized G6Pase promoter activity b

147 oxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) gene expression, however net liver glycogenolysi

148 sal glucose-6-phosphatase catalytic subunit (G6Pase) gene transcription by insulin requires two disti

149 phatase (FBPase), and glucose-6-phosphatase (G6Pase) gene transcription, we hypothesized that reducin

150 ection increased the expression of PEPCK and G6Pase genes and led to elevated glucose production.

151 activation of the promoter of the Bmal1 and G6pase genes, targets of RORalpha, and 20(OH)D3 and 20,2

152 panied with enhanced expression of PEPCK and G6Pase genes.

153 kinase 1 (PEPCK1) and glucose-6-phosphatase (G6Pase) genes, thereby increasing glucose production in

154 rboxylase (PEPCK) and glucose-6-phosphatase (G6Pase) genes.

155 the glucose-6-phosphatase catalytic subunit (G6Pase) give rise to glycogen storage disease (GSD) type

156 However, the phosphate acceptor in G6Pase has eluded molecular characterization.

157 Our studies show that overexpression of G6Pase in liver is sufficient to perturb whole animal gl

158 By examining G6Pase in the liver and kidney, the primary gluconeogeni

159 The activity of UGRP relative to G6Pase in vitro is disputed, raising the question as to

160 ate carboxykinase and glucose-6-phosphatase (G6Pase) in KO mice further support this conclusion.

161 ino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and

162 stion of a non-glycosylated [(32)P]phosphate-G6Pase intermediate by cyanogen bromide, the [(32)P]phos

163 A 40-kDa [(32)P]phosphate-G6Pase intermediate was identified after incubating [(32

164 r, detailed analyses reveal that these three G6Pase IRSs are functionally distinct.

165 te is formed, and the phosphoryl acceptor in G6Pase is a His residue.

166 activity of this phosphatase, and shown that G6Pase is a substrate for proteasome-mediated degradatio

167 G6Pase is an endoplasmic reticulum-associated transmembr

168 and in vitro translation studies showed that G6Pase is glycosylated only at Asn96, further validating

169 hat degradation of both wild-type and mutant G6Pase is inhibited by lactacystin, a potent proteasome

170 f the gene encoding the catalytic subunit of G6Pase is stimulated by glucocorticoids, whereas insulin

171 e of UGRP(-/-) mice is mild, indicating that G6Pase is the major glucose-6-phosphatase of physiologic

172 Glucose-6-phosphatase (G6Pase) is a multicomponent system located in the endopl

173 Glucose-6-phosphatase (G6Pase) is an essential, rate-limiting enzyme that serve

174 the glucose-6-phosphatase catalytic subunit (G6Pase) is stimulated by cAMP and glucocorticoids wherea

175 Recently, a novel G6Pase isoform was identified, designated UGRP/G6Pase-be

176 A G6Pase knockout mouse which mimics the pathophysiology o

177 quired nor sufficient for the stimulation of G6Pase-luciferase fusion gene expression by PGC-1alpha.

178 OXO1/phospho-FOXO1 protein content and PEPCK/G6Pase messenger RNA (mRNA) expression did not reveal di

179 -infused mice was restored to 19% of that in G6Pase(+/+) mice at 7-14 days post-infusion; the activit

180 ase infusion also greatly improved growth of G6Pase(-/-) mice and normalized plasma glucose, choleste

181 However, in contrast to G6Pase(-/-) mice and patients with GSD type 1a, UGRP(-/-

182 P(-/-) mice exhibit growth retardation as do G6Pase(-/-) mice and patients with GSD type 1a.

183 Whereas <15% of G6Pase(-/-) mice under glucose therapy survived weaning,

184 ning, a 100% survival rate was achieved when G6Pase(-/-) mice were infused with Ad-mG6Pase, 90% of wh

185 ase gene (Ad-mG6Pase) into G6Pase-deficient (G6Pase(-/-)) mice that manifest symptoms characteristic

186 ulated phosphoenolpyruvate carboxykinase and G6Pase mRNA abundance and raised the blood glucose level

187 ey; the GSD-1b transcript appears before the G6Pase mRNA during development.

188 On the other hand, hepatic G6Pase mRNA expression and activity are up-regulated in

189 Interestingly, although the G6Pase mRNA is expressed primarily in the liver, kidney,

190 nzymes phosphoenolpyruvate carboxykinase and G6Pase mRNAs was reduced by more than 50% following Acrp

191 base of residual G6Pase activity retained by G6Pase mutants, established the critical roles of transm

192 To date, 75 G6Pase mutations have been identified, including 48 muta

193 enoviruses containing the G6Pase cDNA (AdCMV-G6Pase) or the beta-galactosidase gene into normal rats.

194 The potential role of G6Pase overexpression in the pathophysiology of MODY3 an

195 ucing hepatic gluconeogenic genes, including G6Pase, PEPCK, and FOXO1.

196 -fed mice reduces expression in the liver of G6Pase, Pepck, Cyp7a1, Cd36, L-Fabp, Srebp, and Fas gene

197 Our results demonstrate that G6Pase possesses an odd number of transmembrane helices,

198 3 sites 3, 4, and 5 were essential for basal G6Pase promoter activity and transactivation by HNF3gamm

199 ression of the G6Pase gene, we characterized G6Pase promoter activity by transient expression assays.

200 hrough the cAMP response element by altering G6Pase promoter conformation or accessibility rather tha

201 The G6Pase promoter contained five HNF3 motifs, 1 (-180/-174

202 Deletion analysis revealed that the G6Pase promoter contained three activation elements (AEs

203 assays demonstrate that FKHR also binds the G6Pase promoter in situ and that insulin inhibits this b

204 The G6Pase promoter is active in HepG2 hepatoma cells, but i

205 One of these elements was mapped to the G6Pase promoter region between -114 and -99, and this se

206 The G6Pase promoter region between -198 and -159 contains an

207 e expression, and mutational analysis of the G6Pase promoter revealed that multiple cis-acting elemen

208 e expression, and mutational analysis of the G6Pase promoter revealed that multiple regions are requi

209 Deletion of the G6Pase promoter sequence between -271 and -199 partially

210 A sequence in the G6Pase promoter that resembles a cAMP response element i

211 y the insulin response sequence (IRS) in the G6Pase promoter through which insulin mediates its actio

212 Moreover, in the context of the G6Pase promoter, IRS 1 and 2, but not IRS 3, are require

213 In liver cells transfected with G6Pase promoter, PST caused transcriptional activation i

214 r HNF3gamma-activated transcription from the G6Pase promoter.

215 tin (TTR) promoter or glucose-6-phosphatase (G6Pase) promoter.

216 ated loss of FoxO1 binding to the IGFBP1 and G6Pase promoters in HepG2 cells significantly reduces bi

217 pyruvate carboxykinase (PEPCK), IGFBP-1, and G6Pase promoters.

218 onhelical mutants supported the synthesis of G6Pase protein in a manner similar to that of the wild-t

219 e demonstrate that a novel, widely expressed G6Pase-related protein, PAP2.8/UGRP, renamed here G6Pase

220 Because G6Pase (renamed G6Pase-alpha) is primarily expressed onl

221 Mutations in G6Pase result in Von Gierke's disease (glycogen storage

222 cterization of the transmembrane topology of G6Pase should facilitate the identification of amino aci

223 ty of transmembrane helices is essential for G6Pase stability and catalytic activity.

224 uced enzymatic activity and had no effect on G6Pase synthesis or degradation, suggesting that oligosa

225 The G6Pase system, essential for the maintenance of glucose

226 G6PT deficiency and by perturbations of the G6Pase system.

227 een HNF1alpha deficiency and function of the G6Pase system.

228 ents deficient in the glucose-6-phosphatase (G6Pase) system (e.g. growth retardation, hepatomegaly, h

229 iciency of microsomal glucose-6-phosphatase (G6Pase), the key enzyme in glucose homeostasis, causes g

230 The gene for glucose-6-phosphatase (G6Pase), the key enzyme in glucose homeostasis, is expre

231 iciency in microsomal glucose-6-phosphatase (G6Pase), the key enzyme in glucose homeostasis.

232 use glucose-6-phosphatase catalytic subunit (G6Pase), the liver-derived HepG2 cell line was transient

233 RP) is a homolog of the catalytic subunit of G6Pase, the enzyme that catalyzes the terminal step of t

234 potential contribution of increased hepatic G6Pase to development of diabetes, we infused recombinan

235 plasmic reticulum where it is metabolized by G6Pase to glucose and phosphate.

236 ategies, but somatic gene therapy, targeting G6Pase to the liver and the kidney, is an attractive pos

237 stent with a lineage that begins with GGT(+)/G6Pase(-) to GGT(-)/G6Pase(+) within a single SHPC clust

238 PEPCK and G6Pase transcript levels are downregulated in hepatocyte

239 lpha (PGC1alpha), a coactivator of PEPCK and G6Pase transcription.

240 AdCMV-G6Pase-treated animals exhibited several of the abnormal

241 1.6-3-fold in microsomes isolated from AdCMV-G6Pase-treated animals in all three protocols, and the r

242 Net flux through G6Pase was significantly increased in type 2 diabetic pa

243 Using N- and C-terminal tagged G6Pase, we show that in intact microsomes, the N terminu

244 generated recombinant adenoviruses carrying G6Pase wild type and active site mutants.

245 that begins with GGT(+)/G6Pase(-) to GGT(-)/G6Pase(+) within a single SHPC cluster.