Chemistry and biochemistry of cyclic ADP-ribose and its analogs

Abstract

Cyclic ADP-ribose (cADPR, 1) is a newly discovered general mediator involved in Ca2+ signaling. The synthesis of cADPR analogs has been extensively studied by enzymatic and chemo-enzymatic methods using ADP-ribosylcyclase, due to their biological importance. ADP-ribosylcyclase from Aplysia Californica mediates the intramolecular ribosylation of NAD+ and some modified NAD+, which are prepared chemically or enzymatically, at the N-1-position of the purine moiety to yield cADPR or the corresponding analogs. However, the analogs that can be obtained by this method are limited due to the substrate-specificity of the enzyme. We developed an efficient method for the chemical synthesis of cADPR analogs and synthesized cyclic ADP-carbocyclic-ribose (cADPcR, 2) and its inosine congener (3, cIDPcR) as stable mimics of cADPR, in which an oxygen atom in the ribose ring of cADPR is replaced by a methylene group. Biological activities of cADPR and its analogs were also described.