ADP-ribosyl cyclases generate two unusual adenine homodinucleotides with cytotoxic activity on mammalian cells

ADP-ribosyl cyclases are ubiquitous enzymes responsible for synthesis from NAD of the intracellular calcium-releasing signal molecules cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP). Here, we show that cyclases from lower and higher Metazoa also synthesize three adenylic dinucleotides from cADPR and adenine: diadenosine diphosphate and two isomers thereof. These dinucleotides are present and metabolized in mammalian cells and affect intracellular calcium and cell proliferation. The diadenosine diphosphate isomers are naturally occurring nucleotides containing an N-glycosidic bond different from the usual C1–N9. The identification of these members of the family of NAD+-derived, calcium-active nucleotides opens new areas of investigation into their functional cooperation with cADPR and NAADP and into their involvement in the physiology and pathology of calcium-controlled cell functions.