Cyclic ADP-ribose

Cyclic ADP Ribose, popularly known 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 Nitrogen1 of the same Adenine base (whose position 9 has the glycosidic bond to the other ribose). It is produced from nicotinamide adenine dinucleotide (NAD+) by ADP-ribosyl cyclases (EC 3.2.2.5) as part of a second messenger system.

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Function

cADPR is a cellular messanger for calcium signaling.^[1] It is the physiological allosteric modulator of the ryanodine receptor (RyR), which stimulates calcium-induced calcium release (CICR) at lower cytosolic concentrations. RyR activation with high concentration of caffeine is partly due to caffeine's mimicking the binding of cADPRs 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.

Metabolism

cADPR is synthesized from NAD+ by the bifunctional ectoenzymes of the CD38 family (also includes ADP ribosyl cyclase of Aplysia and GPI anchored CD157).^[2] The same enzymes are also capable of hydrolyzing it to ADPR. Catalysis proceeds via a covalently-bound intermediate. The hydrolysis reaction is inhibited by ATP, and the cyclic form of APDR may accumulate.

See also

• NAADP
• IP3

References

Lee, H.C., Walseth, T.F., Bratt, G.T., Hayes, R.N., and Clapper, D.L. (1989) Structural determination of a cyclic metabolite of NAD+ with intracellular Ca+2 mobilizing activity. J. Biol. Chem. 264, 1608-1615.

Lee, H.C., Aarhus, R. and Levitt, D. (1994) The crystal structure of cyclic ADP-ribose. Nature Structural Biology 1, 143-144.

Prasad, G.S., McRee, D.E., Stura, E.A., Levitt, D.G., Lee, H.C., Stout, C.D. (1996) Crystal structure of Aplysia ADP-ribosyl cyclase, a homolog of the bifunctional ectozyme CD38. Nature Struct. Biol. 3, 957-964.

Liu, Q., Kriksunov, I.A., Graeff, R., Munshi, C. Lee, H.C. and Hao, Q. (2005) Crystal structure of the human CD38 extracellular domain. Structure 13, 1331-1339.