NAADP + synthesis from cADPRP and nicotinic acid by ADP-ribosyl cyclases

Abstract

ADP-ribosyl cyclases (ADPRCs) are present from lower Metazoa to mammals and synthesize the Ca 2+-active (di)nucleotides cyclic ADP-ribose (cADPR), NAADP +, and ADP-ribose (ADPR), involved in the regulation of important cellular functions. NAADP + can be synthesized by ADPRCs from NADP + through a base-exchange reaction, which substitutes nicotinamide for nicotinic acid (NA). Here we demonstrate that ADPRCs from both lower and higher Metazoa (including human CD38) can also synthesize NAADP + starting from 2′-phospho-cyclic ADP-ribose (cADPRP) and NA. Comparison, on the two substrates cADPRP and NADP +, of the relative rates of the reactions introducing NA and hydrolyzing/cyclizing the substrate, respectively, indicates that with all ADPRCs tested cADPRP is preferentially transformed into NAADP +, while NADP + is preferentially cyclized or hydrolyzed to cADPRP/2′-phospho-ADP-ribose. cADPRP was detectable in retinoic acid-differentiated, CD38 + HL-60 cells, but not in undifferentiated, CD38 − cells. These results suggest that cADPRP may be a NAADP + precursor in ADPRC + cells.