ライフサイエンスコーパス: GGTase I

1 GGTase I, but not FTase, is inhibited in breast tumors a

2 GGTase-I catalyzes C-terminal lipidation of >100 protein

3 GGTase-I deficiency reduced the accumulation of choleste

4 GGTase-I discriminates against farnesyl diphosphate (FPP

5 equires both an FTase inhibitor as well as a GGTase I inhibitor, and that inhibition of human tumor g

6 We conclude that insulin activates GGTase I, increases the amounts of geranylgeranylated Rh

7 a selective, highly potent, and cell-active GGTase-I inhibitor, GGTI-DU40.

8 lybasic region does not significantly affect GGTase I-catalyzed reactions, as only minimal changes ar

9 a2X motif binds in the same location for all GGTase-I substrates, the X residue of FTase substrates c

10 Although GGTase-I inhibitors (GGTIs) have received less attention

11 Insulin increased FTase and GGTase I activities and the amounts of prenylated Ras an

12 tely blocked the insulin effect on FTase and GGTase I activities without interfering with insulin sig

13 -stimulated phosphorylation of the FTase and GGTase I alpha-subunit activation of FTase and GGTase I

14 Tase I alpha-subunit activation of FTase and GGTase I and subsequent increases in prenylated Ras and

15 FTase and GGTase I differ in both their substrate specificity and

16 Substrate overlap of FTase and GGTase I has not been determined to be biologically sign

17 horylation of the alpha-subunit of FTase and GGTase I in CHO-hIR-WT cells, but was without effect in

18 the results demonstrate that both FTase and GGTase I inhibitors are required for inhibition of K-Ras

19 e prenylation sensitivities to the FTase and GGTase I inhibitors is variable.

20 receptor to the prenyltransferases FTase and GGTase I is mediated by the Shc pathway, but not the IRS

21 B-derived hexapeptides (TKCVIX) to FTase and GGTase I modestly.

22 FTase and GGTase I modify several important signaling and regulato

23 In contrast to FTase and GGTase I, only a handful of RabGGTase inhibitors have be

24 ap1, proteins that are modified by FTase and GGTase I, respectively.

25 nd Cdc42Hs proteins, substrates of FTase and GGTase I, respectively.

26 and TC21, are substrates for both FTase and GGTase I.

27 y to mediate the insulin effect on FTase and GGTase I.

28 FTase and GGTase-I (also called the CaaX prenyltransferases) recog

29 adopt a common binding mode in the FTase and GGTase-I active site.

30 Although FTase and GGTase-I are highly homologous, they are quite selective

31 Thus, both FTase and GGTase-I are required for the homeostasis of skin kerati

32 have solved crystal structures of FTase and GGTase-I complexed with a total of eight cognate and cro

33 FTase and GGTase-I have attracted interest as therapeutic targets

34 FTase and GGTase-I have long been proposed to specifically recogni

35 Although FTase and GGTase-I have very similar active sites, L-778,123 adopt

36 (which encode the beta-subunits of FTase and GGTase-I, respectively) and a keratin 14-Cre transgene t

37 ase:GG pyrophosphate (GGPP), FTase:GGPP, and GGTase-I:GGPP complexes show 1:1 (enzyme:GGPP) stoichiom

38 s position allowed FTase beta to function as GGTase I beta.

39 ability of mutant FTase beta to function as GGTase I beta.

40 to that of geranylgeranylation catalyzed by GGTase I.

41 s were viable despite the lack of detectable GGTase I activity but were morphologically abnormal.

42 conditional allele of the gene that encodes GGTase-I (see the related article beginning on page 1294

43 onditional loss of Rhoa or the gene encoding GGTase-I, Pggt1b, in IECs exhibit spontaneous chronic in

44 We are evaluating GGTase I as a potential target for antimycotic therapy o

45 ), whereas GGTI-2154 is highly selective for GGTase I (21 nM) over FTase (IC50, 5600 nM).

46 dulated by a protein that is a substrate for GGTase I.

47 ogenesis in vivo and give strong support for GGTase I as a target for anticancer drug discovery.

48 roteins showed that their kcat/Km values for GGTase I substrate are increased about 20-fold compared

49 GGTI-DU40 is highly selective for GGTase-I both in vitro and in living cells.

50 nflammatory cell function are substrates for GGTase-I.

51 neslyltransferase as well as a substrate for GGTases I and II.

52 inhibiting their prenylating enzymes FTase, GGTase I, and RabGGTase.

53 erase (FTase) and geranylgeranyltransferase (GGTase) I as well as combinations of lovastatin with ger

54 the processing of geranylgeranyltransferase (GGTase) I and GGTase II protein substrates.

55 d the activity of geranylgeranyltransferase (GGTase) I and increased the amounts of geranylgeranylate

56 he type I protein geranylgeranyltransferase (GGTase-I), FTase can also geranylgeranylate methionine-

57 In humans, GGTase-I and the homologous protein farnesyltransferase

58 Geranylgeranyltransferase I (GGTase I) catalyzes the transfer of a prenyl group from

59 c mice with the geranylgeranyltransferase I (GGTase I) inhibitor GGTI-2154 results not only in haltin

60 ensitive to the geranylgeranyltransferase I (GGTase I) inhibitor GGTI-286 than it is to FTI-277 in K-

61 ase (FTase) and geranylgeranyltransferase I (GGTase I) using Chinese hamster ovary (CHO) cells that o

62 tion by protein geranylgeranyltransferase I (GGTase I) was not detected.

63 s recognized by geranylgeranyltransferase I (GGTase I).

64 d family member geranylgeranyltransferase I (GGTase I).

65 se) or geranylgeranyl protein transferase I (GGTase I) were used to conjugate FPP and GGPP with fluor

66 zed by protein geranylgeranyl transferase I (GGTase I).

67 r geranylgeranyl-protein transferase type I (GGTase I) (K(i) = 0.06 microM, IC(50) = 20 microM) or sq

68 ed enzyme, geranylgeranyltransferase type I (GGTase I) by a single amino acid change at one of the th

69 nd protein geranylgeranyltransferase type I (GGTase I) catalyze the attachment of a farnesyl or geran

70 nd protein geranylgeranyltransferase type I (GGTase I) catalyze the attachment of lipid groups from f

71 Protein geranylgeranyltransferase type I (GGTase I) catalyzes the attachment of a geranylgeranyl l

72 Protein geranylgeranyltransferase I (GGTase-I) and Rab geranylgeranyltransferase (RabGGTase)

73 se) and protein geranylgeranyltransferase I (GGTase-I), enzymes involved in the prenylation of Ras.

74 se) and protein geranylgeranyltransferase-I (GGTase-I) catalyze the prenylation of proteins with a ca

75 Protein geranylgeranyltransferase-I (GGTase-I) catalyzes the transfer of a 20-carbon isopreno

76 tumor cells the geranylgeranyltransferase-I (GGTase-I) inhibitor GGTI-298 blocked cells in G0/G1, whe

77 fied by protein geranylgeranyltransferase-I (GGTase-I).

78 nsferase enzyme geranylgeranyltransferase-I (GGTase-I).

79 nylation enzyme geranylgeranyltransferase-I (GGTase-I).

80 Geranylgeranyltransferase type I (GGTase-I) inhibitors (GGTIs) have therapeutic potential

81 (FTase) or geranylgeranyltransferase type I (GGTase-I) is essential for the function of many signal t

82 of protein geranylgeranyltransferase type I (GGTase-I) is widely believed to promote membrane associa

83 ferase and geranylgeranyltransferase type I (GGTase-I).

84 nd protein geranylgeranyltransferase type I (GGTase-I).

85 e known as geranylgeranyltransferase type I (GGTase-I).

86 or protein geranylgeranyltransferase type I (GGTase-I).

87 e, protein geranylgeranyltransferase type I (GGTase-I).

88 or protein geranylgeranyltransferase type-I (GGTase-I) for proper function and for the transforming a

89 Protein geranylgeranyltransferase type-I (GGTase-I), one of two CaaX prenyltransferases, is an ess

90 ranylgeranyl (GG) by FTase or GGTase type-I (GGTase-I), respectively.

91 nd protein geranylgeranyltransferase type-I (GGTase-I).

92 tein geranylgeranyltransferase type I or II (GGTase-I and GGTase-II).

93 In GGTase I, lysine beta311 is substituted for this asparta

94 Mutation of lysine beta311 in GGTase I to alanine (Kbeta311A) or aspartate (Kbeta311D)

95 Macrophages that were deficient in GGTase I or p110delta exhibited constitutive release of

96 action between the aryl groups and Ser 48 in GGTase-I binding site could be one possible reason to ex

97 Tase (T49beta and F324beta, respectively, in GGTase-I).

98 itive with the protein substrate, whereas in GGTase-I, L-778,123 is competitive with the lipid substr

99 Insulin increased GGTase I activity 3-fold and augmented the amounts of ge

100 lysates, GGTI-DU40 was confirmed to inhibit GGTase-I activity in a dose-dependent manner.

101 esyltransferase (15-C prenyl substrate) into GGTase-I (20-C prenyl substrate) with a single point mut

102 dition of Mg(II) for Kbeta311A and Kbeta311D GGTase I 2-5-fold compared with wild type GGTase I with

103 Aortic lesions in mice lacking GGTase-I in macrophages (Pggt1btriangle up/triangle up)

104 serine, or glutamine (FTase), or to leucine (GGTase-I).

105 e first structural information for mammalian GGTase-I, including a series of substrate and product co

106 ndence, where the activity of FTase, but not GGTase I, is activated by magnesium.

107 ng II in VSMCs by increasing the activity of GGTase I and the availability of geranylgeranylated Rho-

108 e results demonstrate that lysine beta311 of GGTase I partially replaces the catalytic function of Mg

109 GGTI-286, an inhibitor of GGTase I, blocked both effects of insulin.

110 inhibited in the presence of an inhibitor of GGTase I, GGTI-286 (3 microm) or by an expression of a d

111 the insulin were blocked by an inhibitor of GGTase I, GGTI-286.

112 ino acid increases whereas the reactivity of GGTase I increases with the hydrophobicity of the X-grou

113 The alpha and beta subunits of GGTase I from Saccharomyces cerevisiae are encoded by RA

114 in substrate specificity of FTase to that of GGTase I can be accomplished by introducing a distinct s

115 Analyses of GGTase-I-deficient macrophages revealed upregulation of

116 ese compounds exhibit specific inhibition of GGTase-I and act by competing with a substrate protein.

117 nt, was a classical competitive inhibitor of GGTase-I and not a time-dependent inhibitor.

118 A selective small molecular inhibitor of GGTase-I, GGTI-DU40, was tested in this study to investi

119 acterization of small molecule inhibitors of GGTase-I (GGTI) with two novel scaffolds from a library

120 However, we recently showed that knockout of GGTase-I in macrophages activates RHO proteins and proin

121 The results also point to the potential of GGTase-I inhibitors as agents capable of restoring growt

122 ther the increased inflammatory signaling of GGTase-I-deficient macrophages would influence the devel

123 Here we present the crystal structure of GGTase-I from C. albicans (CaGGTase-I) in complex with i

124 Dpr1 mutants can function as either FTase or GGTase I beta subunit in vivo, although some differences

125 ein/peptide confers specificity for FTase or GGTase I.

126 affect the activity of recombinant FTase or GGTase I.

127 re transgene to create mice lacking FTase or GGTase-I in skin keratinocytes.

128 of more specific inhibitors toward FTase or GGTase-I.

129 tor) and are highly selective for FTase over GGTase I (geranylgeranyltransferase I).

130 ghly selective for FTase (IC50, 1.4 nM) over GGTase I (IC50, 1700 nM), whereas GGTI-2154 is highly se

131 Two compounds that are potent GGTase I inhibitors in vitro but that have poor antifung

132 unds with novel scaffolds and high predicted GGTase-I inhibitory activities were tested in vitro, and

133 at lacked substrate overlap with the protein GGTase-I made possible an analysis of the role of substr

134 mmalian FTase and complexed with the related GGTase-I enzyme.

135 Targeting GGTase-I activates RHOA and leads to increased macrophag

136 These results demonstrate that GGTase-I inhibitors arrest cells in G0/G1 and induce acc

137 alidating in a genetic model the theory that GGTase-I is a good target for anti-cancer drug developme

138 They found that ablation of the GGTase-I-encoding gene in cells destined to produce lung

139 This study indicates that the GGTase-I enzyme is a promising molecular target for lowe

140 (when FTase is inhibited) in cancer therapy; GGTase I inhibitors (GGTIs) as antitumor agents; effects

141 both Zn(II) and Mg(II) for maximal turnover, GGTase I turnover is dependent only on Zn(II).

142 The subcellular distribution of two GGTase I substrates, Rho1p and Cdc42p, was shifted from

143 ylation rate constant catalyzed by wild type GGTase I (k(chem) = 0.18 +/- 0.02 s(-1)) is not dependen

144 1D GGTase I 2-5-fold compared with wild type GGTase I with K(Mg) of 140 +/- 10 mm and 6.4 +/- 0.8 mm,

145 C. albicans can be prenylated by FTase when GGTase I is absent or limiting and that elevation of the

146 the JCI, Khan et al. examined mice in which GGTase-I was conditionally deleted in macrophages.

147 In contrast, treatment of these cells with GGTase I inhibitor GGTI-298 strongly inhibited receptor

148 pressed intestinal inflammation in mice with GGTase-I-deficient IECs, our findings suggest new avenue