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{{chembox {{chembox
| Verifiedfields = changed
⚫ | verifiedrevid = 413344066
| Watchedfields = changed
⚫ | ImageFile = Cyclic_ADP_Ribose.PNG
⚫ | verifiedrevid = 424586166
⚫ | ImageFile = Cyclic ADP ribose.svg
| ImageSize = 175px | ImageSize = 175px
| IUPACName = | IUPACName =
| OtherNames = | OtherNames =
| Section1 = {{Chembox Identifiers |Section1={{Chembox Identifiers
| CASNo_Ref = {{cascite|correct|??}}
| CASNo = 119340-53-3 | CASNo = 119340-53-3
⚫ | PubChem = 123847
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = Q780BR06V8
⚫ | PubChem = 123847
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI = 31445
| IUPHAR_ligand = 2445 | IUPHAR_ligand = 2445
⚫ | MeSHName = Cyclic+ADP-Ribose
| SMILES =
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
⚫ | MeSHName = Cyclic+ADP-Ribose
| ChemSpiderID = 21403087
| SMILES = O5(O)2O5COP(O)(=O)OP(O)(=O)OC4O(N3\C=N/c1c(ncn12)C3=N)(O)4O
| InChI = 1/C15H21N5O13P2/c16-12-7-13-18-4-19(12)14-10(23)8(21)5(31-14)1-29-34(25,26)33-35(27,28)30-2-6-9(22)11(24)15(32-6)20(13)3-17-7/h3-6,8-11,14-16,21-24H,1-2H2,(H,25,26)(H,27,28)/t5-,6-,8-,9-,10-,11-,14-,15-/m1/s1
| InChIKey = BQOHYSXSASDCEA-KEOHHSTQBN
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| StdInChI = 1S/C15H21N5O13P2/c16-12-7-13-18-4-19(12)14-10(23)8(21)5(31-14)1-29-34(25,26)33-35(27,28)30-2-6-9(22)11(24)15(32-6)20(13)3-17-7/h3-6,8-11,14-16,21-24H,1-2H2,(H,25,26)(H,27,28)/t5-,6-,8-,9-,10-,11-,14-,15-/m1/s1
| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
| StdInChIKey = BQOHYSXSASDCEA-KEOHHSTQSA-N
}} }}
| Section2 = {{Chembox Properties |Section2={{Chembox Properties
| Formula = C<sub>15</sub>H<sub>21</sub>N<sub>5</sub>O<sub>13</sub>P<sub>2</sub>
| Formula = C15H21N5O13P2
| MolarMass = 541.301 | MolarMass = 541.301
| Appearance = | Appearance =
| Density = | Density =
| MeltingPt = | MeltingPt =
| BoilingPt = | BoilingPt =
}} }}
| Section3 = {{Chembox Hazards |Section3={{Chembox Hazards
| Solubility = | MainHazards =
| MainHazards = | FlashPt =
| FlashPt = | AutoignitionPt =
| Autoignition =
}} }}
}} }}
'''Cyclic ADP Ribose''', frequently abbreviated as '''cADPR''', is a cyclic adenine nucleotide (like ]) with two phosphate groups present on 5' OH of the ] (like ]), further connected to another ] at the 5' position, which, in turn, closes the cycle by ]ing to the nitrogen 1 (N<sup>1</sup>) of the same ] base (whose position N<sup>9</sup> has the glycosidic bond to the other ])<ref>{{cite journal |author=Lee HC, Walseth TF, Bratt GT, Hayes RN, Clapper DL |title=Structural determination of a cyclic metabolite of NAD<sup>+</sup> with intracellular Ca<sup>2+</sup>-mobilizing activity |journal=J. Biol. Chem. |volume=264 |issue=3 |pages=1608–15 |year=1989 |pmid=2912976}}</ref><ref>{{cite journal |author=Lee HC, Aarhus R, Levitt D |title=The crystal structure of cyclic ADP-ribose |journal=Nat. Struct. Biol. |volume=1 |issue=3 |pages=143–4 |year=1994 |pmid=7656029 |doi=10.1038/nsb0394-143}}</ref>. The N<sup>1</sup>-glycosidic bond to adenine is what distinguishes cADPR from ] (ADPR), the non-cyclic analog. cADPR is produced from ] (NAD<sup>+</sup>) by ADP-ribosyl cyclases (EC 3.2.2.5) as part of a ]. '''Cyclic ADP-ribose''', frequently abbreviated as '''cADPR''', is a cyclic adenine nucleotide (like ]) with two phosphate groups present on 5' OH of the ] (like ]), further connected to another ] at the 5' position, which, in turn, closes the cycle by ]ing to the nitrogen 1 (N<sup>1</sup>) of the same ] base (whose position N<sup>9</sup> has the glycosidic bond to the other ]).<ref>{{cite journal |vauthors=Lee HC, Walseth TF, Bratt GT, Hayes RN, Clapper DL |title=Structural determination of a cyclic metabolite of NAD<sup>+</sup> with intracellular Ca<sup>2+</sup>-mobilizing activity |journal=J. Biol. Chem. |volume=264 |issue=3 |pages=1608–15 |year=1989 |doi=10.1016/S0021-9258(18)94230-4 |pmid=2912976|doi-access=free }}</ref><ref>{{cite journal |vauthors=Lee HC, Aarhus R, Levitt D |title=The crystal structure of cyclic ADP-ribose |journal=Nat. Struct. Biol. |volume=1 |issue=3 |pages=143–4 |year=1994 |pmid=7656029 |doi=10.1038/nsb0394-143|s2cid=9049850 }}</ref> The N<sup>1</sup>-glycosidic bond to adenine is what distinguishes cADPR from ] (ADPR), the non-cyclic analog. cADPR is produced from ] (NAD<sup>+</sup>) by ADP-ribosyl cyclases (]) as part of a ].


==Function== ==Function==
cADPR is a cellular messenger for ].<ref>{{cite journal |author=Guse AH |title=Regulation of calcium signaling by the second messenger cyclic adenosine diphosphoribose (cADPR) |journal=Curr. Mol. Med. |volume=4 |issue=3 |pages=239–48 |year=2004 |pmid=15101682 |doi=10.2174/1566524043360771}}</ref> It is the physiological allosteric modulator of the ] (RyR), which stimulates calcium-induced calcium release at lower cytosolic concentrations of Ca<sup>2+</sup>. RyR activation with high concentration of ] is partly due to caffeine's mimicking the binding of cADPR to RyRs. Whether the action is by direct binding to RyR or indirect (through binding with FKBP12.6) is debated. Some reports suggest that cADPR binding makes FKBP12.6, which normally binds RyR2, to fall off the RYR2. cADPR is a cellular messenger for ].<ref>{{cite journal |author=Guse AH |title=Regulation of calcium signaling by the second messenger cyclic adenosine diphosphoribose (cADPR) |journal=Curr. Mol. Med. |volume=4 |issue=3 |pages=239–48 |year=2004 |pmid=15101682 |doi=10.2174/1566524043360771}}</ref> It stimulates calcium-induced calcium release at lower cytosolic concentrations of Ca<sup>2+</sup>. The primary target of cADPR is the ] Ca<sup>2+</sup> uptake mechanism. cADPR mobilizes Ca<sup>2+</sup> from the endoplasmic reticulum by activation of ]s,<ref name="pmid31646518">{{cite book | vauthors = Galione A, Chuang K | title = Calcium Signaling | chapter = Pyridine Nucleotide Metabolites and Calcium Release from Intracellular Stores | series = Advances in Experimental Medicine and Biology | volume = 1131 | pages = 371–394 | date=2020 | doi = 10.1007/978-3-030-12457-1_15 | pmid = 31646518| isbn = 978-3-030-12456-4 | s2cid = 204865377 }}</ref> a critical step in muscle contraction.<ref name="pmid25966694">{{cite journal | vauthors = Santulli G, Marks AR | title = Essential Roles of Intracellular Calcium Release Channels in Muscle, Brain, Metabolism, and Aging | journal = Current Molecular Pharmacology | volume = 8 | issue = 2 | pages = 206–22 | year = 2015 | pmid = 25966694 | doi = 10.2174/1874467208666150507105105 }}</ref>

cADPR also acts as an ] for the ] channel, but less potently than ].<ref name="pmid33092205">{{cite journal | vauthors = Yu P, Cai X, Liang Y, Yang W | title = Roles of NAD + and Its Metabolites Regulated Calcium Channels in Cancer | journal = ] | volume = 25 | issue = 20 | pages = 4826 | date=2019 | doi = 10.3390/molecules25204826 | pmc =7587972 | pmid = 33092205| doi-access = free }}</ref> cADPR and ADPR act ], with both molecules enhancing the action of the other molecule in activating the TRPM2 channel.<ref name="pmid21786193">{{cite journal | author = Lee HC | title = Cyclic ADP-ribose and NAADP: fraternal twin messengers for calcium signaling | journal = Science China Life Sciences | volume = 54 | issue = 8 | pages = 699–711 | date=2011 | doi = 10.1007/s11427-011-4197-3 | pmid = 21786193| s2cid = 24286381 | doi-access = free }}</ref>

Potentiation of Ca<sup>2+</sup> release by cADPR is mediated by increased accumulation of Ca<sup>2+</sup> in the ].<ref>{{Cite journal|pages=614–22|pmid=11577027|doi=10.1161/hh1901.098066|year=2001|last1=Lukyanenko|first1=V|title=Potentiation of Ca(2+) release by cADP-ribose in the heart is mediated by enhanced SR Ca(2+) uptake into the sarcoplasmic reticulum|journal=Circulation Research|volume=89|issue=7|last2=Györke|first2=I|last3=Wiesner|first3=T. F.|last4=Györke|first4=S|doi-access=free}}</ref>


==Metabolism== ==Metabolism==
cADPR and ADPR are synthesized from NAD<sup>+</sup> by the bifunctional ectoenzymes of the ] family (also includes the GPI-anchored ] and the specific, monofunctional ADP ribosyl cyclase of the mollusc ]).<ref>{{cite journal |author=Prasad GS, McRee DE, Stura EA, Levitt DG, Lee HC, Stout CD |title=Crystal structure of Aplysia ADP-ribosyl cyclase, a homolog of the bifunctional ectozyme CD38 |journal=Nat. Struct. Biol. |volume=3 |issue=11 |pages=957–64 |year=1996 |pmid=8901875 |doi=10.1038/nsb1196-957}}</ref><ref>{{cite journal |author=Liu Q, Kriksunov IA, Graeff R, Munshi C, Lee HC, Hao Q |title=Crystal structure of the human CD38 extracellular domain |journal=Structure |volume=13 |issue=9 |pages=1331–9 |year=2005 |pmid=16154090 |doi=10.1016/j.str.2005.05.012}}</ref><ref>{{cite journal |author=Guse AH |title=Biochemistry, biology, and pharmacology of cyclic adenosine diphosphoribose (cADPR) |journal=Curr. Med. Chem. |volume=11 |issue=7 |pages=847–55 |year=2004 |pmid=15078169 |doi=10.2174/0929867043455602}}</ref> The same enzymes are also capable of hydrolyzing cADPR to ]. Catalysis proceeds via a covalently bound intermediate. The hydrolysis reaction is inhibited by ATP, and cADPR may accumulate. Synthesis and degradation of cADPR by enzymes of the CD38 family involve, respectively, the formation and the hydrolysis of the N<sup>1</sup>-glycosidic bond. In 2009, the first enzyme able to hydrolyze the phosphoanhydride linkage of cADPR, i.e. the one between the two phosphate groups, has been reported.<ref>{{cite journal |author=Canales J, Fernández A, Rodrigues JR, Ferreira R, Ribeiro JM, Cabezas A, Costas MJ, Cameselle JC |title=Hydrolysis of the phosphoanhydride linkage of cyclic ADP-ribose by the Mn<sup>2+</sup>-dependent ADP-ribose/CDP-alcohol pyrophosphatase |journal=FEBS Lett. |volume=583 |year=2009 |issue=10 |pages=1593–8 |pmid=19379742 |doi=10.1016/j.febslet.2009.04.023}}</ref> cADPR and ADPR are synthesized from NAD<sup>+</sup> by the bifunctional ectoenzymes of the ] family (also includes the ]-anchored ] and the specific, monofunctional ADP ribosyl cyclase of the mollusc '']'').<ref>{{cite journal |vauthors=Prasad GS, McRee DE, Stura EA, Levitt DG, Lee HC, Stout CD |title=Crystal structure of Aplysia ADP-ribosyl cyclase, a homolog of the bifunctional ectozyme CD38 |journal=Nat. Struct. Biol. |volume=3 |issue=11 |pages=957–64 |year=1996 |pmid=8901875 |doi=10.1038/nsb1196-957|s2cid=21978229 }}</ref><ref>{{cite journal |vauthors=Liu Q, Kriksunov IA, Graeff R, Munshi C, Lee HC, Hao Q |title=Crystal structure of the human CD38 extracellular domain |journal=Structure |volume=13 |issue=9 |pages=1331–9 |year=2005 |pmid=16154090 |doi=10.1016/j.str.2005.05.012|doi-access=free }}</ref><ref>{{cite journal |author=Guse AH |title=Biochemistry, biology, and pharmacology of cyclic adenosine diphosphoribose (cADPR) |journal=Curr. Med. Chem. |volume=11 |issue=7 |pages=847–55 |year=2004 |pmid=15078169 |doi=10.2174/0929867043455602}}</ref> The same enzymes are also capable of hydrolyzing cADPR to ]. Catalysis proceeds via a covalently bound intermediate. The hydrolysis reaction is inhibited by ], and cADPR may accumulate. Synthesis and degradation of cADPR by enzymes of the CD38 family involve, respectively, the formation and the hydrolysis of the N<sup>1</sup>-glycosidic bond. In 2009, the first enzyme able to hydrolyze the phosphoanhydride linkage of cADPR, i.e. the one between the two phosphate groups, was reported.<ref>{{cite journal |vauthors=Canales J, Fernández A, Rodrigues JR, Ferreira R, Ribeiro JM, Cabezas A, Costas MJ, Cameselle JC |title=Hydrolysis of the phosphoanhydride linkage of cyclic ADP-ribose by the Mn<sup>2+</sup>-dependent ADP-ribose/CDP-alcohol pyrophosphatase |journal=FEBS Lett. |volume=583 |year=2009 |issue=10 |pages=1593–8 |pmid=19379742 |doi=10.1016/j.febslet.2009.04.023|hdl=10400.8/3028 |s2cid=28571921 |hdl-access=free }}</ref>

] and other ]-containing proteins also catalyze the formation of cADPR from NAD<sup>+</sup>.<ref name="pmid31672920">{{cite journal | vauthors=Lee HC, Zhao YJ | title=Resolving the topological enigma in Ca 2+ signaling by cyclic ADP-ribose and NAADP | journal= ] | volume=294 | issue=52 | pages=19831–19843 | year=2019 | url=https://www.jbc.org/content/294/52/19831.long | doi = 10.1074/jbc.REV119.009635 | pmc=6937575 | pmid=31672920| doi-access=free }}</ref><ref name=":0">{{Cite journal |last1=Essuman |first1=Kow |last2=Summers |first2=Daniel W. |last3=Sasaki |first3=Yo |last4=Mao |first4=Xianrong |last5=Yim |first5=Aldrin Kay Yuen |last6=DiAntonio |first6=Aaron |last7=Milbrandt |first7=Jeffrey |date=2018-02-05 |title=TIR Domain Proteins Are an Ancient Family of NAD+-Consuming Enzymes |journal=Current Biology |volume=28 |issue=3 |pages=421–430.e4 |doi=10.1016/j.cub.2017.12.024 |issn=1879-0445 |pmc=5802418 |pmid=29395922}}</ref>

== Isomers ==
Variants of cADPR that differ in their ] retention times compared to canonical cADPR have been identified as products of bacterial and plant ]-containing enzymes.<ref name=":0" /><ref>{{Cite journal |last1=Wan |first1=Li |last2=Essuman |first2=Kow |last3=Anderson |first3=Ryan G. |last4=Sasaki |first4=Yo |last5=Monteiro |first5=Freddy |last6=Chung |first6=Eui-Hwan |last7=Osborne Nishimura |first7=Erin |last8=DiAntonio |first8=Aaron |last9=Milbrandt |first9=Jeffrey |last10=Dangl |first10=Jeffery L. |last11=Nishimura |first11=Marc T. |date=2019-08-23 |title=TIR domains of plant immune receptors are NAD+-cleaving enzymes that promote cell death |journal=Science |volume=365 |issue=6455 |pages=799–803 |doi=10.1126/science.aax1771 |issn=1095-9203 |pmc=7045805 |pmid=31439793}}</ref> v-cADPR (also referred to as 2'cADPR or 1<nowiki>''</nowiki>-2' glycocyclic ADPR (gcADPR)) and v2-cADPR (also referred to as 3'cADPR or 1<nowiki>''</nowiki>-3' gcADPR) isomers are cyclized by O-glycosidic bond formation between the ribose moieties in ADPR.<ref name=":1">{{Cite journal |last1=Manik |first1=Mohammad K. |last2=Shi |first2=Yun |last3=Li |first3=Sulin |last4=Zaydman |first4=Mark A. |last5=Damaraju |first5=Neha |last6=Eastman |first6=Samuel |last7=Smith |first7=Thomas G. |last8=Gu |first8=Weixi |last9=Masic |first9=Veronika |last10=Mosaiab |first10=Tamim |last11=Weagley |first11=James S. |last12=Hancock |first12=Steven J. |last13=Vasquez |first13=Eduardo |last14=Hartley-Tassell |first14=Lauren |last15=Kargios |first15=Nestoras |date=2022-09-30 |title=Cyclic ADP ribose isomers: Production, chemical structures, and immune signaling |journal=Science |volume=377 |issue=6614 |pages=eadc8969 |doi=10.1126/science.adc8969 |issn=1095-9203 |pmid=36048923|s2cid=252010170 |doi-access=free }}</ref><ref>{{Cite journal |last1=Leavitt |first1=Azita |last2=Yirmiya |first2=Erez |last3=Amitai |first3=Gil |last4=Lu |first4=Allen |last5=Garb |first5=Jeremy |last6=Herbst |first6=Ehud |last7=Morehouse |first7=Benjamin R. |last8=Hobbs |first8=Samuel J. |last9=Antine |first9=Sadie P. |last10=Sun |first10=Zhen-Yu J. |last11=Kranzusch |first11=Philip J. |last12=Sorek |first12=Rotem |date=2022-09-29 |title=Viruses inhibit TIR gcADPR signaling to overcome bacterial defense |url=https://pubmed.ncbi.nlm.nih.gov/36174646 |journal=Nature |volume=611 |issue=7935 |pages=326–331 |doi=10.1038/s41586-022-05375-9 |issn=1476-4687 |pmid=36174646|s2cid=248529724 }}</ref> 3'cADPR produced by bacterial ]-containing proteins can act as an activator of bacterial antiphage defense systems and as a suppressor of plant immunity.<ref name=":1" />


==See also== ==See also==
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==External links== ==External links==
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{{Calcium signaling}} {{Calcium signaling}}
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