A multifunctional enzyme adds to its repertoire

Abstract

ADP-ribosyl cyclases are a family of multifunctional enzymes that appear to be expressed ubiquitously in eukaryotic systems (reviewed in refs. 1 and 2). These enzymes are known to metabolize NAD+ and produce at least three molecules that have been demonstrated to be involved in calcium signaling. These enzymes are named for their ability to convert NAD+ to cyclic ADP-ribose (cADPR), a signaling molecule that has been shown to mobilize calcium from intracellular stores by means of a ryanodine receptor/calcium channeldependent system (reviewed in refs. 3 and 4). In addition to cADPR, ADP-ribosyl cyclases have been shown to produce ADP-ribose (ADPR) and nicotinic acid adenine dinucleotide 2′-phosphate (NAADP) (1, 2, 5). These molecules are also involved in regulating calcium signaling: ADPR has been shown to regulate plasma membrane LTRPC2 calcium channels in mammalian cells (6), and NAADP induces calcium mobilization from intracellular stores in several systems (7). In mammalian systems, the ectoenzymes CD38 and CD157 appear to be the major enzymes with ADP-ribosyl cyclase activity (2), although a non-CD38/CD157 ADP-ribosyl cyclase has been detected recently in brains from CD38 knockout mice (8). The work of Basile et al. (9) in a recent issue of PNAS demonstrates that, in addition to producing cADPR, ADPR, and NAADP, ADP-ribosyl cyclases can also generate three adenine dinucleotides (9). Interestingly, these adenine dinucleotides are shown to exist naturally and to have biological activity (9). These findings have several important implications, including expanding the signaling capabilities of the ADP-ribosyl cyclase …