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Cyclic ADP-ribose

Identifiers
CAS Number	119340-53-3
3D model (JSmol)	Interactive image
ChEBI	CHEBI:31445
ChemSpider	21403087
ECHA InfoCard	100.162.252
IUPHAR/BPS	2445
MeSH	Cyclic+ADP-Ribose
PubChem CID	123847
UNII	Q780BR06V8
CompTox Dashboard (EPA)	DTXSID50896995
InChI InChI=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/s1Key: BQOHYSXSASDCEA-KEOHHSTQSA-N 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/s1Key: BQOHYSXSASDCEA-KEOHHSTQBN
SMILES O5(O)2O5COP(O)(=O)OP(O)(=O)OC4O(N3\C=N/c1c(ncn12)C3=N)(O)4O
Properties
Chemical formula	C15H21N5O13P2
Molar mass	541.301
Except where otherwise noted, data are given for materials in their standard state (at 25 °C , 100 kPa). N verify (what is  ?) Infobox references

Cyclic ADP-ribose, frequently abbreviated as cADPR, is a cyclic adenine nucleotide (like cAMP) with two phosphate groups present on 5' OH of the adenosine (like ADP), further connected to another ribose at the 5' position, which, in turn, closes the cycle by glycosidic bonding to the nitrogen 1 (N) of the same adenine base (whose position N has the glycosidic bond to the other ribose). The N-glycosidic bond to adenine is what distinguishes cADPR from ADP-ribose (ADPR), the non-cyclic analog. cADPR is produced from nicotinamide adenine dinucleotide (NAD) by ADP-ribosyl cyclases (EC 3.2.2.5) as part of a second messenger system.

Function

cADPR is a cellular messenger for calcium signaling. It stimulates calcium-induced calcium release at lower cytosolic concentrations of Ca. The primary target of cADPR is the endoplasmic reticulum Ca uptake mechanism. cADPR mobilizes Ca from the endoplasmic reticulum by activation of ryanodine receptors, a critical step in muscle contraction.

cADPR also acts as an agonist for the TRPM2 channel, but less potently than ADPR. cADPR and ADPR act synergistically, with both molecules enhancing the action of the other molecule in activating the TRPM2 channel.

Potentiation of Ca release by cADPR is mediated by increased accumulation of Ca in the sarcoplasmic reticulum.

Metabolism

cADPR and ADPR are synthesized from NAD by the bifunctional ectoenzymes of the CD38 family (also includes the GPI-anchored CD157 and the specific, monofunctional ADP ribosyl cyclase of the mollusc Aplysia). The same enzymes are also capable of hydrolyzing cADPR to ADPR. 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-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.

SARM1 and other TIR domain-containing proteins also catalyze the formation of cADPR from NAD.

Isomers

Variants of cADPR that differ in their HPLC retention times compared to canonical cADPR have been identified as products of bacterial and plant TIR domain-containing enzymes. v-cADPR (also referred to as 2'cADPR or 1''-2' glycocyclic ADPR (gcADPR)) and v2-cADPR (also referred to as 3'cADPR or 1''-3' gcADPR) isomers are cyclized by O-glycosidic bond formation between the ribose moieties in ADPR. 3'cADPR produced by bacterial TIR domain-containing proteins can act as an activator of bacterial antiphage defense systems and as a suppressor of plant immunity.

See also

• NAADP
• IP3
• ADP-ribose

References

1. Lee HC, Walseth TF, Bratt GT, Hayes RN, Clapper DL (1989). "Structural determination of a cyclic metabolite of NAD with intracellular Ca-mobilizing activity". J. Biol. Chem. 264 (3): 1608–15. doi:10.1016/S0021-9258(18)94230-4. PMID 2912976.
2. Lee HC, Aarhus R, Levitt D (1994). "The crystal structure of cyclic ADP-ribose". Nat. Struct. Biol. 1 (3): 143–4. doi:10.1038/nsb0394-143. PMID 7656029. S2CID 9049850.
3. Guse AH (2004). "Regulation of calcium signaling by the second messenger cyclic adenosine diphosphoribose (cADPR)". Curr. Mol. Med. 4 (3): 239–48. doi:10.2174/1566524043360771. PMID 15101682.
4. Galione A, Chuang K (2020). "Pyridine Nucleotide Metabolites and Calcium Release from Intracellular Stores". Calcium Signaling. Advances in Experimental Medicine and Biology. Vol. 1131. pp. 371–394. doi:10.1007/978-3-030-12457-1_15. ISBN 978-3-030-12456-4. PMID 31646518. S2CID 204865377.
5. Santulli G, Marks AR (2015). "Essential Roles of Intracellular Calcium Release Channels in Muscle, Brain, Metabolism, and Aging". Current Molecular Pharmacology. 8 (2): 206–22. doi:10.2174/1874467208666150507105105. PMID 25966694.
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8. Lukyanenko, V; Györke, I; Wiesner, T. F.; Györke, S (2001). "Potentiation of Ca(2+) release by cADP-ribose in the heart is mediated by enhanced SR Ca(2+) uptake into the sarcoplasmic reticulum". Circulation Research. 89 (7): 614–22. doi:10.1161/hh1901.098066. PMID 11577027.
9. Prasad GS, McRee DE, Stura EA, Levitt DG, Lee HC, Stout CD (1996). "Crystal structure of Aplysia ADP-ribosyl cyclase, a homolog of the bifunctional ectozyme CD38". Nat. Struct. Biol. 3 (11): 957–64. doi:10.1038/nsb1196-957. PMID 8901875. S2CID 21978229.
10. Liu Q, Kriksunov IA, Graeff R, Munshi C, Lee HC, Hao Q (2005). "Crystal structure of the human CD38 extracellular domain". Structure. 13 (9): 1331–9. doi:10.1016/j.str.2005.05.012. PMID 16154090.
11. Guse AH (2004). "Biochemistry, biology, and pharmacology of cyclic adenosine diphosphoribose (cADPR)". Curr. Med. Chem. 11 (7): 847–55. doi:10.2174/0929867043455602. PMID 15078169.
12. Canales J, Fernández A, Rodrigues JR, Ferreira R, Ribeiro JM, Cabezas A, Costas MJ, Cameselle JC (2009). "Hydrolysis of the phosphoanhydride linkage of cyclic ADP-ribose by the Mn-dependent ADP-ribose/CDP-alcohol pyrophosphatase". FEBS Lett. 583 (10): 1593–8. doi:10.1016/j.febslet.2009.04.023. hdl:10400.8/3028. PMID 19379742. S2CID 28571921.
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15. Wan, Li; Essuman, Kow; Anderson, Ryan G.; Sasaki, Yo; Monteiro, Freddy; Chung, Eui-Hwan; Osborne Nishimura, Erin; DiAntonio, Aaron; Milbrandt, Jeffrey; Dangl, Jeffery L.; Nishimura, Marc T. (2019-08-23). "TIR domains of plant immune receptors are NAD+-cleaving enzymes that promote cell death". Science. 365 (6455): 799–803. doi:10.1126/science.aax1771. ISSN 1095-9203. PMC 7045805. PMID 31439793.
16. ^ Manik, Mohammad K.; Shi, Yun; Li, Sulin; Zaydman, Mark A.; Damaraju, Neha; Eastman, Samuel; Smith, Thomas G.; Gu, Weixi; Masic, Veronika; Mosaiab, Tamim; Weagley, James S.; Hancock, Steven J.; Vasquez, Eduardo; Hartley-Tassell, Lauren; Kargios, Nestoras (2022-09-30). "Cyclic ADP ribose isomers: Production, chemical structures, and immune signaling". Science. 377 (6614): eadc8969. doi:10.1126/science.adc8969. ISSN 1095-9203. PMID 36048923. S2CID 252010170.
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External links

• The web page of Dr. Hon Cheung Lee, the discoverer of cyclic ADP-ribose.
• Cyclic ADP-ribose and NAADP. The first book on these two second messengers.

• Nucleotides
• Cyclic nucleotides