The new life of a centenarian: signalling functions of NAD(P)

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Abstract

Since the beginning of the last century, seminal discoveries have identified pyridine nucleotides as the major redox carriers in all organisms. Recent research has unravelled an unexpectedly wide array of signalling pathways that involve nicotinamide adenine dinucleotide (NAD) and its phosphorylated form, NADP. NAD serves as substrate for protein modification including protein deacetylation, and mono- and poly-ADP-ribosylation. Both NAD and NADP represent precursors of intracellular calcium-mobilizing molecules. It is now beyond doubt that NAD(P)-mediated signal transduction does not merely regulate metabolic pathways, but might hold a key position in the control of fundamental cellular processes. The comprehensive molecular characterization of NAD biosynthetic pathways over the past few years has further extended the understanding of the multiple roles of pyridine nucleotides in cell biology.

Section snippets

NAD biosynthesis – a key to longer life?

NAD synthesis is essential for all organisms. Given that the hydrogen transfer reactions do not involve a net consumption of pyridine nucleotides, their biosynthesis was long regarded to be of minor importance. However, in all known NAD-dependent signalling pathways, the N-glycosidic bond between the ADP-ribose moiety and nicotinamide is cleaved [see Box 2, Figure Ib(i–iv)]. In particular, poly-ADP-ribosylation might cause a marked decrease in the NAD level [2]. Consequently, there is a

Cyclic ADP-ribose and NAADP – a new calcium wave

Early studies on sea urchin eggs demonstrated a significant change in pyridine nucleotide concentrations after fertilization, and suggested an influence on the concomitant changes of intracellular calcium. Indeed, both NAD+ and NADP+ trigger calcium release from intracellular stores following conversion into cADPR and NAADP, respectively [25] (Box 3).

Calcium regulates many cellular processes [26]. The existence of two additional intracellular calcium-releasing agents, besides the well-known

Poly-ADP ribosylation – nuclear chain reactions

Forty years ago, NMN-stimulated formation of adenine-containing polymers was observed in nuclear extracts [40]. These polymers were eventually identified as poly-ADP-ribose, a molecule that is formed from NAD+ by poly-ADP-ribose polymerases [PARPs; see Box 2, Figure Ib(iii)]. Poly-ADP-ribosylation has been established as post-translational protein modification occurring in nearly all cells of higher eukaryotes. PARPs are currently a major focus of biological and medical investigations because

Mono-ADP-ribosylation – a bacterial invention

Mono-ADP-ribosylation was initially identified as a catalytic activity of bacterial toxins. Classical examples are the toxins of Vibrio cholerae, Bordetella pertussis and Corynebacterium diphtheriae [57]. Today, a variety of bacterial toxins that deregulate important physiological functions by modifying host cell proteins with ADP-ribose are known.

Endogenous mono-ADP-ribosylation in higher eukaryotes appears to modulate the immune response, cell adhesion, signal and energy metabolism [58]. The

NAD-dependent protein deacetylation – a silencer makes noise

Another exciting contribution highlighting the versatility of NAD is the discovery that yeast silent information regulator protein 2 (Sir2p) is an NAD-dependent histone deacetylase 18, 19 [see Box 2, Figure Ib(iv)]. Sir2p has been recognized as an essential factor in gene silencing in the yeast Saccharomyces cerevisiae. It mediates hypoacetylation of histones to form transcriptionally inactive chromatin. The requirement of Sir2p for NAD distinguishes its reaction from all other known

Concluding remarks

Although the potential involvement of NAD in regulatory pathways has been realized for quite some time, our knowledge about the underlying mechanisms and new discoveries of NAD-mediated processes have grown at an astonishing pace over the past few years. The concurrent molecular characterization of NAD biosynthetic pathways has not only facilitated these advancements but, by itself, largely contributed to the understanding of the multiple roles of pyridine nucleotides in cell biology. The

Acknowledgements

We thank the Nobel Foundation for providing photographs of Nobel Prize Laureates. Financial support by the Deutsche Forschungsgemeinschaft (ZI 541/3, ZI 541/4) is gratefully acknowledged.

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