NAD(P) signalling

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The new life of a centenarian: signalling functions of NAD (P).Find It @ MUgroup of 2 »
F Berger, MH Ramirez-Hernandez, M Ziegler – Trends Biochem Sci, 2004 –
Click here to read The new life of a centenarian: signalling functions of NAD(P).
Berger F, Ramirez-Hernandez MH, Ziegler M. Institut fur Biochemie, Freie
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New functions of a longknown moleculeEmerging roles of NAD in cellular signalinggroup of 6 »
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267, 1550-1564 (2000) © 2000 FEBS Review Article. New functions of a longknown
molecule. Emerging roles of NAD in cellular signaling. Mathias Ziegler
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 Enzymology of NAD+ homeostasis in mangroup of 3 »
G Magni, A Amici, M Emanuelli, G Orsomando, N … – Cellular and Molecular Life Sciences (CMLS), 2004 – Springer
Page 1. Review Enzymology of NAD + homeostasis in man Therefore, the present report
will be devoted to the enzymology of NAD + homeostasis in human.
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Reconstructing eukaryotic NAD metabolismFind It @ MUgroup of 3 »
A Rongvaux, F Andris, F Van Gool, O Leo – BioEssays, 2003 –
including quinolinic acid, a precursor of NAD (Fig. This enzyme catalyses the reaction
of L-tryptophan TDO controls serum tryptophan homeostasis and is induced
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 The new life of a centenarian: signalling functions of NAD(P).Berger F, Ramirez-Hernandez MH, Ziegler M. Institut fur Biochemie, Freie Universitat Berlin, Thielallee 63, 14195 Berlin, Germany.

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.

New functions of a long-known molecule

Emerging roles of NAD in cellular signaling

Mathias ZieglerFreie Universität Berlin, Institut für Biochemie, Germany Correspondence to M. Ziegler, Freie Universität Berlin, Institut für Biochemie, Thielallee 63, 14195 Berlin, Germany. Fax: +49 30 83856509, E-mail: 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.

Keywords: ADP ribosylation; calcium; cyclic ADP-ribose; mitochondria; NAD; pyridine nucleotides; signaling.

Abbreviations: 3-ABA, 3-aminobenzamide; ADPRT, ADP-ribosyl transferase; cADPR, cyclic ADP-ribose; cADPRP, 2′-phospho cyclic ADP-ribose; CICR, calcium-induced calcium release; InsP3, inositol-1,4,5-trisphosphate; mADPRT, monoADP-ribosyl transferase; NAADP+, nicotinic acid adenine dinucleotide phosphate; PARP1, poly(ADP-ribosyl) polymerase; PTP, permeability transition pore

Enzymology of NAD+ homeostasis in man  

Abstract  This review describes the enzymes involved in human pyridine nucleotide metabolism starting with a detailed consideration of their major kinetic, molecular and structural properties. The presentation encompasses all the reactions starting from the de novo pyridine ring formation and leading to nicotinamide adenine dinucleotide (NAD+) synthesis and utilization. The regulation of NAD+ homeostasis with respect to the physiological role played by the enzymes both utilizing NAD+ through the nonredox NAD+-dependent reactions and catalyzing the recycling of the common product, nicotinamide, is discussed. The salient features of other enzymes such as NAD+ pyrophosphatase, nicotinamide mononucleotide 5prime-nucleotidase, nicotinamide riboside kinase and nicotinamide riboside phosphorylase, described under lsquomiscellaneousrsquo, are likewise presented.

NAD+ homeostasis – pyridine nucleotides – structure biology – recombinant enzymes – chromatin expression 

Reconstructing eukaryotic NAD metabolism

In addition to its well-known role as a coenzyme in oxidation-reduction reactions, the distinct role of NAD as a precursor for molecules involved in cell regulation has been clearly established. The involvement of NAD in these regulatory processes is based on its ability to function as a donor of ADP-ribose; NAD synthesis is therefore required to avoid depletion of the intracellular pool. The rising interest in the biosynthetic routes leading to NAD formation and the highly conserved nature of the enzymes involved prompted us to reconstruct the NAD biosynthetic routes operating in distinct eukaryotic organisms. The evidence obtained from biochemical and computational analysis provides a good example of how complex metabolic pathways may evolve. In particular, it is proposed that the development of several NAD biosynthetic routes during evolution has led to partial functional redundancy, allowing a given pathway to freely acquire novel functions unrelated to NAD biosynthesis. BioEssays 25:683-690, 2003. © 2003 Wiley Periodicals, Inc.



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