ライフサイエンスコーパス: AdoHcy

1 AdoHcy competes with tracer in the antibody/tracer compl

2 AdoHcy hydrolase achieves catalysis of AdoHcy hydrolysis

3 AdoHcy hydrolase, which was inactivated with compound a,

4 AdoHcy is present in normal human plasma at concentratio

5 AdoHcy nucleosidase (EC 3.2.2.9) irreversibly cleaves Ad

6 s4-NH 2 + AdoMet --> p53-Lys4-N(Me)H 2 (+) + AdoHcy] in the SET7/9 complex is Delta G (++) = 20.1 +/-

7 -Lys4-NH 3 (+), SET7/9.p53-Lys4-N(Me)H 2 (+).AdoHcy, or SET7/9.p53-Lys4-N(Me)H 2 (+).AdoMet complex.

8 Lys-NH(2).(+)AdoMet --> Enz.Lys-N(Me)H(2)(+).AdoHcy occurs.

9 nsfer (Lys-N(Me)2 + AdoMet --> Lys-N(Me)3+ + AdoHcy) is associated with an allowed DeltaG++ of 25.9 +

10 n [Lys27-N(Me)2 + AdoMet --> Lys27-N(Me)3+ + AdoHcy] is associated with a DeltaG++ of 23.1 +/- 4.0 kc

11 riphosphate (ATP) by 5'-methylthio-adenosine/AdoHcy nucleosidase (MTAN), adenine phosphoribosyl trans

12 increase in hepatic S-adenosylhomocysteine (AdoHcy) (p < 0.01) concentrations, resulting in a 75% re

13 rsible hydrolysis of S-adenosylhomocysteine (AdoHcy) has been determined at 2.8 A resolution.

14 Human placental S-adenosylhomocysteine (AdoHcy) hydrolase (EC 3.3.1.1) was inactivated by 5',5-d

15 ersible inhibitor of S-adenosylhomocysteine (AdoHcy) hydrolase (EC 3.3.1.1), express increased AdoMet

16 S-Adenosylhomocysteine (AdoHcy) hydrolase catalyzes the reversible hydrolysis of

17 Most inhibitors of S-adenosylhomocysteine (AdoHcy) hydrolase function as substrates for the "3'-oxi

18 n the active site of S-adenosylhomocysteine (AdoHcy) hydrolase have been mutated to alanine (A).

19 rystal structures of S-adenosylhomocysteine (AdoHcy) hydrolase in the substrate-free, NAD(+) form and

20 potent inhibitors of S-adenosylhomocysteine (AdoHcy) hydrolase, we investigated the mechanisms by whi

21 rs of human placenta S-adenosylhomocysteine (AdoHcy) hydrolase.

22 rsible inhibitors of S-adenosylhomocysteine (AdoHcy) hydrolase.

23 hionine (AdoMet) and S-adenosylhomocysteine (AdoHcy) in plasma can be measured by formation of the fl

24 eine (Hcy) precursor S-adenosylhomocysteine (AdoHcy) may cause cellular hypomethylation in the settin

25 Accumulation of the S-adenosylhomocysteine (AdoHcy) product, a feedback inhibitor of TPMT, slows the

26 thyltransfer product S-adenosylhomocysteine (AdoHcy) to homocysteine (Hcy) and adenosine (Ado).

27 h methylated DNA and S-adenosylhomocysteine (AdoHcy) were obtained and evaluated as double-reciprocal

28 s designed to detect S-adenosylhomocysteine (AdoHcy), a product of all S-adenosylmethionine (AdoMet)-

29 its reaction product S-adenosylhomocysteine (AdoHcy), and adenosine.

30 S-Adenosylhomocysteine (AdoHcy), formed after donation of the methyl group of Ad

31 cosine) and produces S-adenosylhomocysteine (AdoHcy), thereby controlling the methylating potential o

32 thylation reactions, S-adenosylhomocysteine (AdoHcy), which causes by-product inhibition of methyltra

33 the reaction product S-adenosylhomocysteine (AdoHcy).

34 thionine (AdoMet) to S-adenosylhomocysteine (AdoHcy).

35 d weak inhibition by S-adenosylhomocysteine (AdoHcy).

36 hionine (AdoMet) and S-adenosylhomocysteine (AdoHcy).

37 ne in all tissues is S-adenosylhomocysteine (AdoHcy).

38 gin versus AdoMet or S-adenosylhomocysteine (AdoHcy).

39 uilibrium dissociation constants for AdoMet, AdoHcy and sinefungin were determined using an intrinsic

40 7) methyltransferase in complex with AdoMet, AdoHcy, and the cap guanylate.

41 suited for regulation of the cellular AdoMet/AdoHcy ratio.

42 yl carbon of AdoMet, or the sulfur of AdoMet/AdoHcy (the leaving group).

43 The changes in the AdoMet/AdoHcy ratio could not be attributed to increases in the

44 Because changes in the AdoMet/AdoHcy ratio could potentially alter the overall excitat

45 % reduction in methylation potential (AdoMet:AdoHcy) (p < 0.01).

46 Hcy by AdoHcy nucleosidase, which alleviates AdoHcy product feedback inhibition of S-adenosylmethioni

47 An AdoHcy binds to the consensus AdoMet binding site observ

48 An AdoHcy molecule has entered the site occupied in the "cl

49 introducing any major structural changes, an AdoHcy molecule can be placed in the catalytic domain.

50 The fluorescent derivatives of AdoMet and AdoHcy are then chromatographed by HPLC on a C-18 column

51 A number of analogs of AdoMet and AdoHcy have been considered as possible antiviral, antic

52 involves an initial separation of AdoMet and AdoHcy in deproteinized plasma by HPLC on a C-8 column f

53 y addition of known quantities of AdoMet and AdoHcy to plasma.

54 AdoMet and AdoHcy were measured in mice lacking PCMT1 (Pcmt1-/-), a

55 A methyltransferases analogous to AdoMet and AdoHcy would affect the rate of enzyme-induced deaminati

56 sence and presence of co-factors, AdoMet and AdoHcy.

57 and 10(4)-fold in the absence of AdoMet and AdoHcy.

58 ternary complexes containing M.HhaI, DNA and AdoHcy.

59 t mice exhibited increased (>6-fold) Hcy and AdoHcy levels in all tissues examined compared with cont

60 resent severe accumulation of tissue Hcy and AdoHcy, protein arginine hypomethylation in liver and br

61 24(28)-Methylenecycloartanol and AdoHcy generated competitive and noncompetitive kinetic

62 ence of AdoMet to C-24 methylated sterol and AdoHcy, was analyzed for amino acid residues that contri

63 We employed commercially available anti-AdoHcy antibody and fluorescein-AdoHcy conjugate tracer

64 and must be released from the enzyme before AdoHcy.

65 more than a 150-fold preference for binding AdoHcy relative to AdoMet.

66 DNMT2 binds AdoHcy in the same conformation as confirmed m(5)C MTase

67 Mock methyltransferase reactions using both AdoHcy and AdoMet indicated that the assay tolerated 1 t

68 ostatic potential originating from the bound AdoHcy extends to the DNA phosphate groups flanking the

69 the flipped cytosine, protein and the bound AdoHcy.

70 The two bound AdoHcy moieties are buried at the bottom of deep clefts.

71 f this assay is the destruction of AdoHcy by AdoHcy nucleosidase, which alleviates AdoHcy product fee

72 enosine, or compounds that can be cleaved by AdoHcy nucleosidase.

73 hydrolyzed to adenosine and homocysteine by AdoHcy hydrolase.

74 ncentration, and is only weakly inhibited by AdoHcy.

75 tion reactions that can both be inhibited by AdoHcy.

76 Inhibition by AdoHcy was apparently competitive versus AdoMet and unco

77 ss-linking to m7GpppA(pA)n was stimulated by AdoHcy, whereas cross-linking to GpppA(pA)n was unaffect

78 ross-linking to GpppA(pA)n was unaffected by AdoHcy, but stimulated by AdoMet.

79 n the presence of the methyl donor byproduct AdoHcy.

80 cleosidase (EC 3.2.2.9) irreversibly cleaves AdoHcy to adenine and S-ribosylhomocysteine, significant

81 Under optimized conditions, AdoHcy and AdoMet titrations demonstrated that the antib

82 hough the crystal structure does not contain AdoHcy or its analogue, there is a well-formed AdoHcy-bi

83 l studies of base flipping in the M.HhaI-DNA-AdoHcy ternary complex indicate that the south-constrain

84 The mutant/DNA/AdoHcy structure (2.88 A resolution) provides a direct c

85 The structures of the ternary protein/DNA/AdoHcy complexes for both the Glu119Ala and Glu119Gln mu

86 , and (iii) methyl transfer providing enzyme.AdoHcy.Lys-N(Me)H2+ and the dissociation of AdoHcy.

87 ailable anti-AdoHcy antibody and fluorescein-AdoHcy conjugate tracer to measure AdoHcy generated as a

88 SE) for AdoMet were 102.7 nM +/- 9.9 and for AdoHcy were 22.7 +/- 3.1.

89 A recently published rapid immunoassay for AdoHcy in human plasma should make measurement of this i

90 C terminus that harbors the binding site for AdoHcy.

91 acts with 2-nitro-5-thiobenzoic acid to form AdoHcy and 2-nitro-5-methylthiobenzoic acid.

92 oHcy or its analogue, there is a well-formed AdoHcy-binding crevice in the catalytic domain.

93 In wild-type, substrate-free AdoHcy hydrolase (NAD(+) cofactor in each subunit), reor

94 Subsequently, adenine generated from AdoHcy is further hydrolyzed to hypoxanthine and ammonia

95 l transfer reaction (AdoMet + Lys-N(Me)H --> AdoHcy + Lys-N(Me)2H+) at the QM/MM level is 20.5 +/- 3.

96 transfer reaction [AdoMet + Lys27-N(Me)H --> AdoHcy + Lys27-N(Me)2H+] at the QM/MM level is 22.6 +/-

97 by LSMT (Lys-NH2 + AdoMet --> Lys-N(Me)H2+ + AdoHcy) is DeltaG++ = 22.8 +/- 3.3 kcal/mol.

98 ET7/9 [Lys4-NH2 + AdoMet --> Lys4-N(Me)H2+ + AdoHcy] complex is DeltaG++ = 19.0 +/- 1.6 kcal/mol.

99 SET [Lys27-NH2 + AdoMet --> Lys27-N(Me)H2+ + AdoHcy] equals 22.5 +/- 4.3 kcal/mol, which is in excell

100 ely after methyl transfer (LSMT.Lys-N(Me)H2+.AdoHcy).

101 ies SET7/9.Lys4-NH3+ or SET7/9.Lys4-N(Me)H2+.AdoHcy.

102 n be maintained even in the presence of high AdoHcy concentrations.

103 rmD) complexed with S-adenosyl homocysteine (AdoHcy) has been determined at 2.5A resolution.

104 In this assay, S-adenosyl-l-homocysteine (AdoHcy or SAH), a common product of AdoMet-dependent tra

105 nd to the product S-adenosyl-L-homocysteine (AdoHcy) and magnesium, both with and without the natural

106 and the products, S-adenosyl-L-homocysteine (AdoHcy) and N(5)-methylglutamine.

107 of the reaction, S-adenosyl-L-homocysteine (AdoHcy) and N,N-dimethyltryptamine, as well as antimigra

108 cofactor product S-adenosyl-l-homocysteine (AdoHcy) at 2.8 A resolution and identify a glutamate res

109 T2 complexed with S-adenosyl-L-homocysteine (AdoHcy) has been determined at 1.8 A resolution.

110 for binding with S-adenosyl-l-homocysteine (AdoHcy) hydrolase and/or addition of enzyme-bound water

111 S-Adenosyl-L-homocysteine (AdoHcy) hydrolase has been shown to have (5'/6') hydroly

112 Domain motions of S-adenosyl-l-homocysteine (AdoHcy) hydrolase have been detected by time-resolved fl

113 t inactivation of S-adenosyl-L-homocysteine (AdoHcy) hydrolase producing significant decreases in the

114 ytic activity" of S-adenosyl-L-homocysteine (AdoHcy) hydrolase.

115 ytic activity" of S-adenosyl-l-homocysteine (AdoHcy) hydrolase.

116 ent inhibitors of S-adenosyl-L-homocysteine (AdoHcy) hydrolase.

117 ent inhibitors of S-adenosyl-L-homocysteine (AdoHcy) hydrolase.

118 The S-adenosyl- l-homocysteine (AdoHcy) hydrolases (SAHH) from Homo sapiens (Hs-SAHH) an

119 The S-adenosyl-l-homocysteine (AdoHcy) hydrolases catalyze the reversible conversion of

120 cofactor product S-adenosyl-l-homocysteine (AdoHcy) provides the molecular basis for recognition of

121 zes its substrate S-adenosyl-L-homocysteine (AdoHcy) to L-homocysteine (Hcy).

122 e cofactor analog S-adenosyl-L-homocysteine (AdoHcy), has been determined.

123 Met), the product S-adenosyl-l-homocysteine (AdoHcy), the inhibitor sinefungin, as well as a mutant a

124 NA, and AdoMet or S-adenosyl-L-homocysteine (AdoHcy).

125 hyl-donor product S-adenosyl-L-homocysteine (AdoHcy).

126 In this assay, S-adenosyl-L-homocysteine (AdoHcy/SAH), the transmethylation product of AdoMet-depe

127 doMet), affording S-adenosyl-L-homocysteine (AdoHcys) and a proton as the remaining products.

128 In this assay, S-adenosyl-l-homocystine (AdoHcy/SAH), the by-product of PMT-involved methylation,

129 denosine analogs for the inhibition of human AdoHcy hydrolase.

130 S-Adenosylhomocysteine hydrolase (AdoHcy hydrolase) crystallizes from solutions containing

131 mocysteine nucleosidase is used to hydrolyze AdoHcy to adenine.

132 contrast, compound c completely inactivated AdoHcy hydrolase by converting 2 equiv of E-NAD(+) to E-

133 ssible mechanism by which BDDFHA inactivates AdoHcy hdyrolase is proposed: enzyme-mediated water addi

134 ese data suggest that compound c inactivates AdoHcy hydrolase by a mechanism similar to the acetyleni

135 ydro-5'-fluoroaristeromycin are inactivating AdoHcy hydrolase by directly reducing NAD+ to NADH and n

136 ional advantage of this assay which includes AdoHcy nucleosidase is the destruction of AdoHcy, thus a

137 eparture of the potentially potent inhibitor AdoHcy from the active site and thus facilitates the met

138 why Cys421 does not occur in any other known AdoHcy hydrolases.

139 -dependent methyltransferases undergo marked AdoHcy-mediated product inhibition.

140 uorescein-AdoHcy conjugate tracer to measure AdoHcy generated as a result of methyltransferase activi

141 ntify the residues that bind the Hcy moiety, AdoHcy was docked to the closed form of AdoHcy hydrolase

142 der Waals' contacts with the sulfur atom of AdoHcy.

143 It is likely that binding of AdoHcy induces a large conformational change so as to pl

144 o further probe the hydrolytic capability of AdoHcy hydrolase.

145 AdoHcy hydrolase achieves catalysis of AdoHcy hydrolysis to adenosine (Ado) and homocysteine (H

146 udies) that a higher plasma concentration of AdoHcy is a more sensitive indicator of vascular disease

147 acceleration of the reversible conversion of AdoHcy to adenosine (Ado) and homocysteine (Hcy).

148 olases catalyze the reversible conversion of AdoHcy to adenosine and homocysteine, making use of a ca

149 dvantage of this assay is the destruction of AdoHcy by AdoHcy nucleosidase, which alleviates AdoHcy p

150 es AdoHcy nucleosidase is the destruction of AdoHcy, thus alleviating product inhibition.

151 for the deprotonation after dissociation of AdoHcy (S-adenosyl-L-homocysteine) and before binding of

152 .AdoHcy.Lys-N(Me)H2+ and the dissociation of AdoHcy.

153 s been grown in the presence of an excess of AdoHcy, and its crystal structure has been determined at

154 ety, AdoHcy was docked to the closed form of AdoHcy hydrolase.

155 inhibitors with the closed and open forms of AdoHcy hydrolase.

156 olase catalyzes the reversible hydrolysis of AdoHcy to adenosine (Ado) and homocysteine (Hcy), playin

157 Incubation of AdoHcy hydrolase with 100 microM of 5b resulted in parti

158 Incubation of AdoHcy hydrolase with 5a, 5b, and 6 resulted in time- an

159 Incubation of AdoHcy hydrolase with 7 or 15 resulted in irreversible i

160 nt and concentration-dependent inhibition of AdoHcy hydrolase (K(i), 0.55 and 118.5 microM, respectiv

161 methylene)adenosine 2a, a known inhibitor of AdoHcy hydrolase not modified with a cyclopropyl ring at

162 potent type-I mechanism-based inhibitors of AdoHcy hydrolase with k2/Ki values of 4.4 x 10(6) and 8.

163 s were found to be inactive as inhibitors of AdoHcy hydrolase.

164 in kcat, caused by the perturbed kinetics of AdoHcy release.

165 Higher levels of AdoMet and lower levels of AdoHcy were found in the brains of Pcmt1-/- mice, and to

166 l change so as to place the ribose moiety of AdoHcy in close proximity to the nicotinamide moiety of

167 of a redox partial reaction (3'-oxidation of AdoHcy at the beginning and 3'-reduction of Ado at the e

168 bits a broad dynamic range (0.1-1000 pmol of AdoHcy).

169 oHcy and the ultrasensitivity to 0.3 pmol of AdoHcy.

170 dro-5'-fluoraristeromycin in the presence of AdoHcy hydrolase did not release fluoride ion or generat

171 did cross-link to the cap in the presence of AdoHcy, suggesting that this mutation affects the chemic

172 d or fully methylated DNA in the presence of AdoHcy.

173 to cross-link to the cap in the presence of AdoHcy.

174 pically fall within the activity spectrum of AdoHcy hydrolase inhibitors.

175 ggests elements of the catalytic strategy of AdoHcy hydrolase for acceleration of the reversible conv

176 here do not exhibit an inhibitory effect on AdoHcy hydrolase and displayed only marginal antiviral a

177 otency for the inhibition of human placental AdoHcy hydrolase was: DZNep approximately NepA >> DZAri

178 Incubation of human placental AdoHcy hydrolase with BDDFHA results in a maximum inacti

179 both is a reason that measurement of plasma AdoHcy has not generally been carried out in large studi

180 Advantages of the measurement of plasma AdoHcy include 1) a smaller overlap of values between co

181 detection was approximately 5 nM (0.15 pmol) AdoHcy in the presence of 3 muM AdoMet.

182 l for designing and screening of more potent AdoHcy hydrolase inhibitors and antiviral agents.

183 be used to assay other enzymes that produce AdoHcy, 5'-methylthioadenosine, or compounds that can be

184 SET domain in complex with cofactor product AdoHcy and a histone H3 peptide.

185 AdoMet is inhibited by the reaction product AdoHcy (IC(50) 4 microm) and by substrate analogs sinefu

186 alytic core in complex with reaction product AdoHcy, determined at 2.0 A resolution.

187 The product AdoHcy and the competitive inhibitor sinefungin bind wit

188 on and for the forced release of the product AdoHcy have been revealed in the GNMT structure.

189 eactions, is first hydrolyzed by recombinant AdoHcy nucleosidase (EC 3.2.2.9) into adenine and S-ribo

190 h sinefungin binds 900-fold more avidly than AdoHcy or AdoMet.

191 The results indicate that AdoHcy hydrolase exists in equilibrium of open and close

192 attern of the catalytic domain suggests that AdoHcy molecules can travel freely to and from AdoHcyase

193 e loop extending from each knot embraces the AdoHcy adenine ring.

194 This AdoHcy binding site supports the glycine binding site (A

195 ations showed that binding of L-adenosine to AdoHcy hydrolase is weaker (higher energy) and less spec

196 ectly correlated with the ratio of AdoMet to AdoHcy (P = 0.0001).

197 ured for its quantitative linear response to AdoHcy and the ultrasensitivity to 0.3 pmol of AdoHcy.

198 However, 7b and 16b upon incubation with AdoHcy hydrolase were not metabolized suggesting that th