Cyclic ADP-ribose and its metabolic enzymes

Cyclic ADP-ribose (cADPR) is a recently discovered cyclic nucleotide with Ca2+ signaling functions. There is a growing recognition that it is an endogenous modulator of the Ca(2+)-induced Ca2+ release mechanism in cells. The cyclic structure of cADPR has now been confirmed by x-ray crystallography. A series of analogs of cADPR has been synthesized, including antagonists and a novel analog, cyclic GDP-ribose. Considerable progress has been made in characterizing ADP-ribosyl cyclase, the synthetic enzyme, and cADPR hydrolase, the hydrolytic enzyme. A new class of bifunctional enzymes has been identified which catalyses both the synthesis and hydrolysis of cADPR. CD38, a lymphocyte differentiation antigen, is a member of this class. The understanding of the mechanisms of regulation of the metabolic enzymes and signaling by cADPR is likely to have important implications and several possibilities are discussed in this article.