Cyclic ADP-ribose


Cyclic ADP Ribose, frequently abbreviated as cADPR, is a cyclic adenine nucleotide with two phosphate groups present on 5' OH of the adenosine, further connected to another ribose at the 5' position, which, in turn, closes the cycle by glycosidic bonding to the nitrogen 1 of the same adenine base. The N1-glycosidic bond to adenine is what distinguishes cADPR from ADP-ribose, the non-cyclic analog. cADPR is produced from nicotinamide adenine dinucleotide by ADP-ribosyl cyclases 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 Ca2+. Primary target of cADPR is the endoplasmic reticulum Ca2+ uptake mechanism. Potentiation of Ca2+ release by cADPR is mediated by increased accumulation of Ca2+ in the sarcoplasmic reticulum.

Metabolism

cADPR and ADPR are synthesized from NAD+ by the bifunctional ectoenzymes of the CD38 family. 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 N1-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.
The SARM1 enzyme also catalyzes the formation of cADPR from NAD+.