ライフサイエンスコーパス: ADPR

1 ADPR and ADP caused membrane hyperpolarization that, lik

2 ADPR binds to the TRPM2 C-terminal NUDT9-H domain, activ

3 ADPR hydrolysis experiments conducted in the presence of

4 ADPR like its precursor, beta-NAD(+), mimicked the effec

5 ADPR's breakdown product adenosine monophosphate (AMP) s

6 ADPR-cyclase from VSMCs, but not CD38 ADPR-cyclase from

7 ADPR-cyclase in VSMC membranes was more sensitive than C

8 We conclude the following: (1) ADPR-cyclase in VSMCs has enzymatic properties distinct

9 vity to inhibition by Zn(2+) and Cu(2+); (2) ADPR-cyclase in VSMCs is upregulated by various retinoid

10 Zn(2+) stimulated the activity of CD38 HL-60 ADPR-cyclase and other known types of ADPR-cyclases.

11 membranes was more sensitive than CD38 HL-60 ADPR-cyclase to inactivation by N-endoglycosidase F and

12 In this study we characterize 8-bromo (8Br)-ADPR, a novel compound that specifically inhibits ADPR-a

13 ors of ADPR-gated calcium entry, such as 8Br-ADPR, have the potential to be used as anti-inflammatory

14 Using 8Br-ADPR, we demonstrate that ADPR controls calcium influx a

15 es reveal a binding cavity that accommodates ADPR and analogs via local structural changes within the

16 lated proteins, nicotinamide and 2'-O-acetyl-ADPR.

17 degrade NAD to ADP-ribose (ADPR), and adding ADPR to T cells leads to slow but not rapid cell death.

18 An ADPR analog, alpha-beta-methylene-ADPR (AMPCPR), was sho

19 m of deacetylation is proposed to involve an ADPR-peptidylimidate, whereas the mechanism of ADP-ribos

20 We report here that an ADPR cyclase purified from Aplysia californica readily c

21 TRPM2 activation is independent of ADPR and ADPR-binding sites, both [Ca(2+)](i) and the CaM-binding

22 Both cADPR and ADPR are calcium messengers that can mobilize intracellu

23 lic adenosine 5'-diphosphoribose (cADPR) and ADPR were also present in the superfusates collected dur

24 Exogenous beta-NAD, cADPR, and ADPR (all 100 nm) reduced the release of NE in CMA at 16

25 erve-evoked overflow of beta-NAD, cADPR, and ADPR in vascular and non-vascular smooth muscles, beta-N

26 d-type colons, but responses to beta-NAD and ADPR were completely abolished in P2ry1(-/-) mice.

27 Degradation of beta-NAD(+) and ADPR was greater per unit mass in muscles containing onl

28 alcium release from intracellular stores and ADPR controls cation entry through the plasma membrane c

29 fer from the well-characterized CD38-antigen ADPR-cyclase, expressed in HL-60 cells.

30 is plants, induced expression of the Aplysia ADPR cyclase gene resulted in an increase in ADPR cyclas

31 atively stable covalent intermediate between ADPR and the acetyl oxygen of the acetyllysine-protein s

32 in complex with Ca(2+) alone, and with both ADPR and Ca(2+), resolved to ~4.3 angstrom, ~3.8 angstro

33 yllysine residue which forms an enzyme-bound ADPR-peptidylimidate intermediate and nicotinamide.

34 Activation is induced by ADPR binding to the cytosolic C-terminal NudT9-homology

35 The C1"- and C3"-ADPR analogues were evaluated electrophysiologically by

36 talyze an enzyme reaction and produce cADPR, ADPR, and/or nicotinamide.

37 atic properties distinct from "classic" CD38 ADPR-cyclase, especially sensitivity to inhibition by Zn

38 ADPR-cyclase from VSMCs, but not CD38 ADPR-cyclase from HL-60 cells, was inhibited by ganglios

39 ly, these sensors detect changes in cellular ADPR levels in response to physiological cues (e.g., hor

40 specificity, in comparison to the classical ADPR interaction site within NUDT9H that is highly homol

41 which, when expressed in isolation, cleaves ADPR into AMP and ribose-5-phosphate.

42 sors are mediated by CD38 and the consequent ADPR-mediated TRPM2 gating.

43 lates cADPR synthesis by ADP ribose cyclase (ADPR cyclase) in cultured epithelial cells.

44 We investigated whether ADP-ribosyl cyclase (ADPR-cyclase) in rat vascular smooth muscle cells (VSMCs

45 ynthesized from NAD by ADP-ribosyl cyclases (ADPR cyclases).

46 with just Ca(2+), just ADPR, Ca(2+) + cyclic ADPR, or H(2)O(2) pretreatment only marginally activates

47 i) on NAD-RNA specifically produces a cyclic ADPR-RNA, which can be further decapped in vitro by know

48 eaving NAD(+) into ADP-ribose (ADPR), cyclic ADPR, and nicotinamide, with nicotinamide serving as a f

49 nicotinamide, ADP-ribose (ADPR), and cyclic ADPR (cADPR).

50 enosine diphosphate ribose (ADPR) and cyclic ADPR, regulating several processes including calcium sig

51 both ADP-ribose (ADPR) and canonical cyclic ADPR with a N1-glycosidic bond (cADPR, also referred to

52 Similarly, SPN was unable to catalyze cyclic ADPR hydrolysis, and could not catalyze methanolysis or

53 ergistic facilitation by [Ca(2+)](i), cyclic ADPR, H(2)O(2), NAADP, and negative feedback regulation

54 the calcium-release second messenger cyclic ADPR (cADPR), has no defined role as an intracellular si

55 osphate/diphosphate (pRib-AMP/ADP) or cyclic ADPR (cADPR) isomers.

56 nd nicotinamide; (2) the formation of cyclic-ADPR (cADPR[P]); or (3) a base exchange reaction with ni

57 d upon a hybrid structure, 8-phenyl-2'-deoxy-ADPR (86, IC50 = 3 muM), is more potent than 8-Ph-ADPR (

58 utes to novel analogues of ADPR and 2'-deoxy-ADPR that were modified only by removal of a single hydr

59 AR Trackers have broad utility for detecting ADPR in many different experimental and biological syste

60 Adenosine 5'-diphosphoribose (ADPR) activates TRPM2, a Ca(2+), Na(+), and K(+) permeab

61 derivative of adenosine 5'-diphosphoribose (ADPR), 1,N6-etheno-ADPR (epsilon-ADPR), at low femtomola

62 G-protein and adenosine 5'-diphosphoribose (ADPR)-activated nonselective cation channel, is also exp

63 by intracellular adenosine diphosphoribose (ADPR) binding to the channel's enzymatic Nudix domain.

64 second messenger, adenosine diphosphoribose (ADPR), and nicotinamide.

65 emonstrate that TRPM2 mutants with disrupted ADPR-binding sites can be activated readily by [Ca(2+)](

66 bosomes complexed with ADP-ribosylated eEF2 (ADPR-eEF2), before and after GTP hydrolysis, providing a

67 croM have a potentiating effect that enables ADPR to gate the channel at nanomolar concentrations.

68 and NAADP lead to mobilization of endogenous ADPR presumably via metabolic conversion.

69 indeed reduced cADPR production but enhanced ADPR production, converting the cyclase to be more CD38-

70 epsilon-ADPR was detected by fluorescence at an excitation wavel

71 epsilon-ADPR was formed by the reaction of ADPR with chloroaceta

72 sphoribose (ADPR), 1,N6-etheno-ADPR (epsilon-ADPR), at low femtomolar concentration range in vascular

73 The detection sensitivity for epsilon-ADPR was approximately 10 fmol.

74 d in the range from 0.0125 to 1 pmol epsilon-ADPR.

75 osine 5'-diphosphoribose (ADPR), 1,N6-etheno-ADPR (epsilon-ADPR), at low femtomolar concentration ran

76 ts the ADPRase function of NUDT9H and evokes ADPR accumulation.

77 activity in infected neutrophils, and exoST(ADPR-) mutants replicated the DeltaexoST phenotype in vi

78 and hydrogen peroxide (H2O2) can facilitate ADPR-mediated activation of heterologously expressed TRP

79 For ADPR, that range matches, but for Ca(2+), it exceeds bul

80 stablish TRPM2 as a coincidence detector for ADPR and cADPR signaling and provide a functional contex

81 ce the affinity of the C-terminal domain for ADPR.

82 ) and the CaM-binding motif are required for ADPR-mediated TRPM2 gating.

83 n channel that is specifically gated by free ADPR.

84 al of either C1" or C3" hydroxyl groups from ADPR resulted in loss of agonist activity.

85 ue chemical structure of 1 ''-2' glycocyclic ADPR (gcADPR).

86 viously shown to contain NAD glycohydrolase, ADPR cyclase, and cADPR hydrolase activities also utiliz

87 The higher ADPR cyclase activity in response to E2 was due to the i

88 His-ADPR is generated in response to phage infection and act

89 in, we describe the structural basis for His-ADPR and its recognition and show its role by biochemica

90 acid histidine conjugated to ADP-ribose (His-ADPR).

91 f phage proteins that bind and sequester His-ADPR signalling molecules, enabling phages to evade TIR-

92 A detailed understanding of how ADPR interacts with the TRPM2 ligand binding domain is l

93 Collectively, these data identify ADPR as a new and important second messenger of mouse ne

94 ADPR cyclase gene resulted in an increase in ADPR cyclase activity and cADPR levels, as well as eleva

95 (0.2 mg/kg per day) prevented an increase in ADPR cyclase.

96 ond formation between the ribose moieties in ADPR.

97 m VSMCs, with anti-CD38 antibodies increased ADPR-cyclase activity; CD38 antigen was detected both in

98 3) administration of atRA and T(3) increases ADPR-cyclase in aorta in vivo.

99 to its nuclear receptors in vivo, increases ADPR cyclase activity in uterus.

100 ne monophosphate (AMP) specifically inhibits ADPR, but not cADPR-mediated gating of TRPM2, whereas th

101 a novel compound that specifically inhibits ADPR-activated cation influx without affecting other key

102 ew questions about the role of intracellular ADPR and depletion of NAD(+).

103 These results indicate that intracellular ADPR regulates calcium entry into cells that express LTR

104 The key iso-ADPR-binding residues we identified are highly conserved

105 PAR) by interacting with iso-ADP-ribose (iso-ADPR), the smallest internal PAR structural unit contain

106 one or in combination with just Ca(2+), just ADPR, Ca(2+) + cyclic ADPR, or H(2)O(2) pretreatment onl

107 ins with significant similarity to the known ADPR cyclases have been reported in any plant genome dat

108 Although recombinant, antibody-like ADPR detection reagents containing these readers have fa

109 domains, act as 'readers' for protein-linked ADPR.

110 fferent fluorescence-based assays to measure ADPR cyclase activity in Arabidopsis and found that this

111 f the C-terminal NUDT9H domain that mediates ADPR-directed gating in hTRPM2.

112 10) hydrolyzes to give the linear 6-N-methyl ADPR (adenosine 5'-diphosphoribose, 11), whereas 6-thio

113 established by isolation of beta-1- O-methyl-ADPR when methanol was added as a cosolvent.

114 on of methanol which forms alpha-1- O-methyl-ADPR.

115 An ADPR analog, alpha-beta-methylene-ADPR (AMPCPR), was shown to be entirely resistant to hyd

116 ain, homologous to the soluble mitochondrial ADPR pyrophosphatase (ADPRase) NUDT9.

117 dependent post-translational modifications, "ADPR spray," and PAR-mediated biomolecular condensate fo

118 tivity relationship, systematically modified ADPR analogues were designed, synthesized, and evaluated

119 The resulting small-molecule ADPR adducts are highly potent and confer compelling neu

120 n be used for simultaneous detection of mono ADPR and poly ADPR at single-cell resolution in various

121 dioactive assay, we present evidence of mono-ADPR (MAR) hydrolase activity.

122 rus, but in liver, brain, or skeletal muscle ADPR cyclase was unchanged.

123 (900 mg/kg) significantly increased NR, NMN, ADPR, NAM, and m-NAM levels.

124 in complex with Mg(2+) and a nonhydrolyzable ADPR analogue, alpha,beta-methylene ADP-ribose, reveals

125 NAD but not ADPR provides the substrate for ADP-ribosyltransferase (

126 sis that cell surface ART-2 uses NAD but not ADPR to attach ADP-ribosyl groups to the cell surface, a

127 allow further characterization of the novel ADPR interaction site.

128 ) binding proteins using naturally occurring ADPR binding domains (ARBDs), including macrodomains and

129 nd assaying loss of cADPR or accumulation of ADPR.

130 -NAD(+) and for termination of the action of ADPR are likely to be present near sites of neurotransmi

131 Our results suggest that activation of ADPR cyclase is an early ABA-signaling event partially i

132 but to a much lesser degree than activity of ADPR cyclase.

133 The specific activity of ADPR-cyclase in membranes from VSMCs was >20-fold higher

134 igned synthetic routes to novel analogues of ADPR and 2'-deoxy-ADPR that were modified only by remova

135 el activation of TRPM2 induced by binding of ADPR in two indispensable locations, and the binding of

136 her a single ADP-ribose (ADPR) or a chain of ADPR units to proteins using NAD as the source of ADPR.

137 marker, we observe conformational changes of ADPR-eEF2 that are due strictly to GTP hydrolysis.

138 the presence of a range of concentrations of ADPR or AMPCPR, identify TRPM2 as a simple ligand-gated

139 se readers have facilitated the detection of ADPR, they are limited in their ability to capture the d

140 Thus, mechanisms for generation of ADPR from beta-NAD(+) and for termination of the action

141 ute for cADPR synthesis or that a homolog of ADPR cyclase with low similarity might exist in plants.

142 in an approximately Delta + 300% increase of ADPR cyclase activity in extracts from uterus, but in li

143 n of atRA to rats resulted in an increase of ADPR-cyclase activity in aorta ( congruent with+60%) and

144 ne (T(3)) to rats resulted in an increase of ADPR-cyclase activity in aorta ( congruent with+89%), bu

145 -mediated TRPM2 activation is independent of ADPR and ADPR-binding sites, both [Ca(2+)](i) and the Ca

146 Ca(2+)](i) gating of TRPM2 is independent of ADPR.

147 these cells, and indicate that inhibitors of ADPR-gated calcium entry, such as 8Br-ADPR, have the pot

148 The conformation and binding interactions of ADPR substrate are predicted to differ from those observ

149 ought to determine whether the low levels of ADPR cyclase activity reported in Arabidopsis are indica

150 od was applied to quantitate the overflow of ADPR upon electrical field stimulation (8 Hz, 0.3 ms, 15

151 epsilon-ADPR was formed by the reaction of ADPR with chloroacetaldehyde at 80 degrees C and pH 4.0.

152 presence of an etheno ring after reaction of ADPR with chloroacetaldehyde.

153 gn of modulators, but the terminal ribose of ADPR is known to be essential for activation.

154 rase 1 (PARP-1), another potential source of ADPR in some leukocytes.

155 r than PARP-1, may be an important source of ADPR in these cells, and indicate that inhibitors of ADP

156 units to proteins using NAD as the source of ADPR.

157 HL-60 ADPR-cyclase and other known types of ADPR-cyclases.

158 ventricle (+18%), but atRA had no effect on ADPR-cyclases in lungs, spleen, intestinal smooth muscle

159 Adding either NAD or ADPR also triggers a different set of mechanisms, not re

160 it Ca2+ release following conversion to 2'-P-ADPR by the action of canine spleen NAD glycohydrolase.

161 chanism and the existence of a 1'-O-peptidyl-ADPR.Sir2 intermediate.

162 8-Ph-ADPR (5) inhibits Ca(2+) signalling and chemotaxis in hu

163 (86, IC50 = 3 muM), is more potent than 8-Ph-ADPR (5).

164 activity, and an 8-phenyl substitution (8-Ph-ADPR, 5) is very effective.

165 simultaneous detection of mono ADPR and poly ADPR at single-cell resolution in various antibody-based

166 olase and base-exchange reactions to produce ADPR and NAADP(+).

167 to rates with dcDNA, which showed product [(ADPR)n] inhibition.

168 is not known whether the other CD38 product, ADPR, also regulates leukocyte trafficking In this study

169 o Clinic Alzheimer Disease Patient Registry (ADPR), which follows patients with Alzheimer disease ver

170 Reported ADPR hydrolysis classified TRPM2 as a channel-enzyme, bu

171 -length TRPM2 with soluble chimeras retained ADPR-dependent channel gating (K1/2~1-5 muM), confirming

172 It is activated by cytosolic ADP ribose (ADPR) and contains a nudix-type motif 9 (NUDT9)-homology

173 TRPM2 is activated by ADP ribose (ADPR) binding to its C-terminal cytosolic NUDT9-homology

174 ins that recognize and hydrolyze ADP ribose (ADPR) modifications of intracellular proteins.

175 TRPM2 is opened by binding of ADP ribose (ADPR) to its C-terminal cytosolic nudix-type motif 9 (NU

176 TRPM2's activation by Ca(2+) and ADP ribose (ADPR), an NAD(+)-metabolite produced under oxidative str

177 inding to PAR and recognizes iso-ADP ribose (ADPR), the linkage between two ADPR units.

178 The Ca(2+) and ADP ribose (ADPR)-activated cation channel TRPM2 is the closest homo

179 s of beta-NAD(+) and ATP, namely ADP-ribose (ADPR) and ADP in colonic muscles from cynomolgus monkeys

180 ivation requires binding of both ADP-ribose (ADPR) and Ca(2+).

181 is an NADase that produces both ADP-ribose (ADPR) and canonical cyclic ADPR with a N1-glycosidic bon

182 TRPM2 is gated by ADP-ribose (ADPR) and modulated by physiological processes that prod

183 set of recombinant antibody-like ADP-ribose (ADPR) binding proteins using naturally occurring ADPR bi

184 of cyclic ADP-ribose (cADPR) and ADP-ribose (ADPR) from its substrate, NAD(+).

185 though TRPM2 can be activated by ADP-ribose (ADPR) in vitro, it was unknown how TRPM2 is gated in viv

186 tion channel hTRPM2, is gated by ADP-ribose (ADPR) independently of the C-terminal NUDT9H domain that

187 ng in the covalent attachment of ADP-ribose (ADPR) moieties on substrate proteins.

188 covalently link either a single ADP-ribose (ADPR) or a chain of ADPR units to proteins using NAD as

189 Escherichia coli ADP-ribose (ADPR) pyrophosphatase (ADPRase), a Nudix enzyme, catalyz

190 NUDT9 gene as a highly specific ADP-ribose (ADPR) pyrophosphatase.

191 The enzyme hydrolyzes ADP-ribose (ADPR) to AMP and ribose 5'-phosphate.

192 , as well as the activity of the ADP-ribose (ADPR) transferase enzymes (PARP family members) that cat

193 Free ADP-ribose (ADPR), a product of NAD hydrolysis and a breakdown produ

194 n complex with three inhibitors: ADP-ribose (ADPR), adenosine 5'-diphosphate (hydroxymethyl)pyrrolidi

195 T cells degrade NAD to ADP-ribose (ADPR), and adding ADPR to T cells leads to slow but not

196 rsion of NAD+ into nicotinamide, ADP-ribose (ADPR), and cyclic ADPR (cADPR).

197 se activity-cleaving NAD(+) into ADP-ribose (ADPR), cyclic ADPR, and nicotinamide, with nicotinamide

198 of the reaction product to free ADP-ribose (ADPR), resulting in much shorter PAR chains compared to

199 ribose (cADPR) and from cADPR to ADP-ribose (ADPR).

200 de, which increase production of ADP-ribose (ADPR).

201 PR, whereas CD38 produces mainly ADP-ribose (ADPR).

202 (1) NAD(P)(+) hydrolysis to form ADP-ribose (ADPR[P]) and nicotinamide; (2) the formation of cyclic-A

203 D primarily to adenosine diphosphate ribose (ADPR) and a small amount of cyclic adenosine diphosphate

204 izes NAD(+) to adenosine diphosphate ribose (ADPR) and cyclic ADPR, regulating several processes incl

205 s also produce adenosine diphosphate ribose (ADPR) and nicotinic acid adenine dinucleotide phosphate

206 o both TIR and adenosine diphosphate ribose (ADPR) cyclase.

207 mitochondrial adenosine diphosphate ribose (ADPR) or nicotinamide adenine dinucleotide (NAD+).

208 intracellular adenosine diphosphate ribose (ADPR) through a diphosphoribose hydrolase domain in its

209 nucleotide adenosine 5'-diphosphate ribose (ADPR) to the cytosolic NUDT9 homology (NUDT9 H) domain a

210 action product adenosine diphosphate ribose (ADPR).

211 NAD (and its primary metabolite, ADP-ribose, ADPR) caused transient hyperpolarization responses in wi

212 esponsible for cADPR synthesis, ADP-ribosyl (ADPR) cyclase, is rapidly induced by ABA in both wild-ty

213 se that converts PR-Ub into ADP-ribosylated (ADPR)-Ub.

214 int mutations in the ADP ribosyltransferase (ADPR) regions of ExoS or ExoT also impaired proapoptotic

215 The NUDT9-H domain binds to a second ADPR to assist channel activation in vertebrates, but no

216 ive cation channel both function as specific ADPR pyrophosphatases.

217 l domain retaining essentially full specific ADPR pyrophosphatase activity and a proteolytically labi

218 dary immunological tools, recognize specific ADPR moieties, and can be used for simultaneous detectio

219 s likely to be identical with the N-terminal ADPR binding pocket in zebra fish DrTRPM2.

220 Using 8Br-ADPR, we demonstrate that ADPR controls calcium influx and chemotaxis in mouse neu

221 The ADPR analogues were obtained by coupling nucleoside phos

222 from Danio rerio in the ligand-free and the ADPR/Ca(2+)-bound conditions represent the channel in cl

223 agonists can be partially suppressed by the ADPR antagonist adenosine monophosphate (AMP), which sug

224 synchronous substitution mechanism forms the ADPR-peptidylimidate intermediate of the sirtuin deacety

225 Patients who were enrolled in the ADPR (Alzheimer disease n = 100, non-Alzheimer disease c

226 sents further evidence on recognition of the ADPR modification for hydrolysis.

227 ith the C-terminal cytoplasmic domain of the ADPR-gated calcium channel TRPM2, which exhibits low but

228 cing strains is almost entirely due to their ADPR activities, which subvert the host response by targ

229 ess active than CD38 in hydrolyzing cADPR to ADPR.

230 DT9)-homology (NUDT9-H) domain homologous to ADPR phosphohydrolases (ADPRases).

231 TRPM2 identified recently are insensitive to ADPR, and their gating mechanisms remain unclear.

232 Degradation of beta-NAD(+) to ADPR and other metabolites appears to be mediated by pat

233 ll as on the enzymatic conversion of NAD+ to ADPR (ADP Ribose) products by the SARM1's TIR domain.

234 IJPs and hyperpolarization responses to ADPR, but not ADP, were inhibited by the P2Y1 receptor a

235 o-ADP ribose (ADPR), the linkage between two ADPR units.

236 Most of the E2-stimulated uterine ADPR cyclase was associated with membranes.

237 With various ADPR analogues, key differences of the two sites were id

238 Most importantly, VSMC ADPR-cyclase was inhibited by Zn(2+) and Cu(2+) ions; th

239 2)-Vitamin D(3) (calciferol) stimulated VSMC ADPR-cyclase dose dependently at subnanomolar concentrat

240 agonist 9-cis-retinoic acid-upregulated VSMC ADPR-cyclase; the stimulatory effect of atRA was blocked

241 luding the U937 monocyte cell line, in which ADPR induces large cation currents (designated IADPR) th

242 de that cADPR and NAADP, in combination with ADPR, represent physiological co-activators of TRPM2 tha

243 can regulate TRPM2 activity in synergy with ADPR.