Emerging roles of NAD and NAD-metabolites in cell signalling

Nicotinamide adenine dinucleotide, NAD+, is the universal currency of energy metabolism and electron transfer. Exciting results from recent studies indicate that - apart from its role as a coenzyme - NAD+ and its metabolites play important roles also in cell signalling, i.e. as substrates for nucleotide-metabolizing enzymes and by providing ligands for extra- and intracellular receptors (1-8). NAD-metabolites such as ADP-ribose, cyclic ADP-ribose, and NAADP have emerged as a key second messengers in calcium signalling (9-13). The symposium will focus on ADP-ribosyltransferases (ARTs), ADP-ribosylcyclases (ARCs), and calcium signalling. The meeting will bring together researchers from diverse fields that are engaged in the molecular characterization of the key players of NAD signalling, each of which constitutes a potential novel therapeutic target (14, 15).

Key Players in Cell-Signalling by NAD.

ADP-ribosyltransferases (ARTs), poly-ADP-ribose polymerases (PARPs), sirtuins (SIR), ADP-ribosylcylcases (ARCs) utilize the high energy bond in NAD between nicotinamide and ADP-ribose (red line). ARTs, PARPs, and SIRs transfer the ADP-ribose moiety onto acceptors (X = proteins, DNA, sugars, small molecules, water). ADP-ribosylhydrolases (ARHs) and Poly-ADP-ribose-glycohydrolases (PARGs) de-ADP-ribosylate acceptors. ARCs catalyze multiple reactions, including NAD-hydrolysis, ADPR-cyclization, and base exchange of nicotinamide by nicotinic acid, thereby generating the calcium (Ca++)-mobilizing second messengers ADP-ribose, cyclic ADP-ribose, and NAADP. NAD can act as a ligand for the P2Y11 purinoreceptor, ADPR as a ligand for the ryanodin receptor (RyR) and for proteins harboring a macro-domain. The NAD-2008 Hamburg meeting will focus on ARTs, ARCs, and calcium-mobilization (yellow highlights).

1. Billington, R. A., Bruzzone, S., De Flora, A., Genazzani, A. A., Koch-Nolte, F., Ziegler, M., and Zocchi, E. (2006) Emerging functions of extracellular pyridine nucleotides. Mol Med 12, 324-327
2. Haag, F., Adriouch, S., Braß, A., Jung, C., Möller, M., Scheuplein, F., Bannas, P., Seman, M., and Koch-Nolte, F. (2007) Extracellular NAD and ATP: Partners in immune cell modulation. Purinergic Signalling 3, 71-81
3. Lin, H. (2007) Nicotinamide adenine dinucleotide: beyond a redox coenzyme. Organic & Biomolecular Chemistry 5, 2541-2554
4. Zolkiewska, A. (2005) Ecto-ADP-ribose transferases: cell-surface response to local tissue injury. Physiology (Bethesda) 20, 374-381
5. Berger, F., Ramirez-Hernandez, M. H., and Ziegler, M. (2004) The new life of a centenarian: signalling functions of NAD(P). Trends Biochem Sci 29, 111-118
6. Corda, D., and Di Girolamo, M. (2003) Functional aspects of protein mono-ADP-ribosylation. Embo J 22, 1953-1958
7. Lazarowski, E. R., Boucher, R. C., and Harden, T. K. (2003) Mechanisms of release of nucleotides and integration of their action as P2X- and P2Y-receptor activating molecules. Mol Pharmacol 64, 785-795
8. Ziegler, M. (2000) New functions of a long-known molecule. Emerging roles of NAD in cellular signaling. Eur. J. Biochem. 267, 1550-1564.
9. Fliegert, R., Gasser, A., and Guse, A. H. (2007) Regulation of calcium signalling by adeninebased second messengers. Biochem Soc Trans 35, 109-114
10. Guse, A. H. (2004) Regulation of calcium signaling by the second messenger cyclic adenosine diphosphoribose (cADPR). Curr Mol Med 4, 239-248
11. Schuber, F., and Lund, F. E. (2004) Structure and enzymology of ADP-ribosyl cyclases: conserved enzymes that produce multiple calcium mobilizing metabolites. Curr Mol Med 4, 249-261
12. Lee, H. C. (2005) Nicotinic acid adenine dinucleotide phosphate (NAADP)-mediated calcium signaling. J Biol Chem 280, 33693-33696
13. Berridge, M. J., Bootman, M. D., and Roderick, H. L. (2003) Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol 4, 517-529
14. Seman, M., Adriouch, S., Haag, F., and Koch-Nolte, F. (2004) Ecto-ADP-ribosyltransferases (ARTs): emerging actors in cell communication and signaling. Curr Med Chem 11, 857-872
15. Khan, J. A., Forouhar, F., Tao, X., and Tong, L. (2007) Nicotinamide adenine dinucleotide metabolism as an attractive target for drug discovery. Expert Opin Ther Targets 11, 695-705

© 2008 disclaimer