New functions of a long-known molecule. Emerging roles of NAD in cellular signaling.

Abstract

Over the past decades, the pyridine nucleotides have been established as important molecules in signaling pathways, besides their well known function in energy transduction. Similarly to another molecule carrying such dual functions, ATP, NAD(P)+ may serve as substrate for covalent protein modification or as precursor of biologically active compounds. Protein modification is catalyzed by ADP-ribosyl transferases that attach the ADP-ribose moiety of NAD+ to specific amino-acid residues of the acceptor proteins. For a number of ADP ribosylation reactions the specific transferases and their target proteins have been identified. As a result of the modification, the biological activity of the acceptor proteins may be severely changed. The cell nucleus contains enzymes catalyzing the transfer of ADP-ribose polymers (polyADP-ribose) onto the acceptor proteins. The best known enzyme of this type is poly(ADP-ribose) polymerase 1 (PARP1), which has been implicated in the regulation of several important processes including DNA repair, transcription, apoptosis, neoplastic transformation and others. The second group of reactions leads to the synthesis of an unusual cyclic nucleotide, cyclic ADP-ribose (cADPR). Moreover, the enzymes catalyzing this reaction may also replace the nicotinamide of NADP+ by nicotinic acid resulting in the synthesis of nicotinic acid adenine dinucleotide phosphate (NAADP+). Both cADPR and NAADP+ have been reported to be potent intracellular calcium-mobilizing agents. In concert with inositol 1,4,5-trisphosphate, they participate in cytosolic calcium regulation by releasing calcium from intracellular stores.