Enzymology of Nad
            <sup>+</sup>
            Synthesis

Magni, Giulio; Amici, Adolfo; Emanuelli, Monica; Raffaelli, Nadia; Ruggieri, Silverio

doi:10.1002/9780470123195.ch5

Cited by 189 publications

(199 citation statements)

References 258 publications

(185 reference statements)

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“…2), indicating the localization of human enzyme in cytosol. We cultured these transfected HepG2 cells in the presence of [ 14 C]NA and determined the amounts of 14 C-labeled compounds formed in these cells. Analysis of the radioactive compounds in cell extracts by TLC 14 C]NA and 50 M PRPP for the indicated times, and the amounts of NaMN formed (circles) and of remaining NA (squares) were determined by TLC assay, as described under "Experimental Procedures."…”

Section: Resultsmentioning

confidence: 99%

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Elevation of Cellular NAD Levels by Nicotinic Acid and Involvement of Nicotinic Acid Phosphoribosyltransferase in Human Cells

Hara

Yamada

Shibata

et al. 2007

Journal of Biological Chemistry

181

172

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NAD plays critical roles in various biological processes through the function of SIRT1. Although classical studies in mammals showed that nicotinic acid (NA) is a better precursor than nicotinamide (Nam) in elevating tissue NAD levels, molecular details of NAD synthesis from NA remain largely unknown. We here identified NA phosphoribosyltransferase (NAPRT) in humans and provided direct evidence of tight link between NAPRT and the increase in cellular NAD levels. The enzyme was abundantly expressed in the small intestine, liver, and kidney in mice and mediated [ 14 C]NAD synthesis from [ 14 C]NA in human cells. In cells expressing endogenous NAPRT, the addition of NA but not Nam almost doubled cellular NAD contents and decreased cytotoxicity by H 2 O 2 . Both effects were reversed by knockdown of NAPRT expression. These results indicate that NAPRT is essential for NA to increase cellular NAD levels and, thus, to prevent oxidative stress of the cells. Kinetic analyses revealed that NAPRT, but not Nam phosphoribosyltransferase (NamPRT, also known as pre-B-cell colony-enhancing factor or visfatin), is insensitive to the physiological concentration of NAD. Together, we conclude that NA elevates cellular NAD levels through NAPRT function and, thus, protects the cells against stress, partly due to lack of feedback inhibition of NAPRT but not NamPRT by NAD. The ability of NA to increase cellular NAD contents may account for some of the clinically observed effects of the vitamin and further implies a novel application of the vitamin to treat diseases such as those associated with the depletion of cellular NAD pools.

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Section: Resultsmentioning

confidence: 99%

“…1) (14). In the salvage pathway Nam is recycled to NAD by two enzymes, Nam phosphoribosyltransferase (NamPRT, also known as pre-B-cell colony-enhancing factor (15), or visfatin (16)), and Nam mononucleotide (NMN) adenylyltransferase, which convert Nam to NMN and NMN to NAD, respectively.…”

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confidence: 99%

Elevation of Cellular NAD Levels by Nicotinic Acid and Involvement of Nicotinic Acid Phosphoribosyltransferase in Human Cells

Hara

Yamada

Shibata

et al. 2007

Journal of Biological Chemistry

181

172

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“…MN adenylyl transferase (NMNAT) is an essential enzyme because it catalyzes the final step of NAD ϩ biosynthesis (1). There are three isoforms in humans that exhibit tissue-and organelle-specific expression (2).…”

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confidence: 99%

Regulation of poly(ADP-ribose) polymerase 1 activity by the phosphorylation state of the nuclear NAD biosynthetic enzyme NMN adenylyl transferase 1

Berger

Lau

Ziegler

2007

Proc. Natl. Acad. Sci. U.S.A.

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Nuclear NAD ؉ metabolism constitutes a major component of signaling pathways. It includes NAD ؉ -dependent protein deacetylation by members of the Sir2 family and protein modification by poly(ADP-ribose) polymerase 1 (PARP-1). PARP-1 has emerged as an important mediator of processes involving DNA rearrangements. High-affinity binding to breaks in DNA activates PARP-1, which attaches poly(ADP-ribose) (PAR) to target proteins. NMN adenylyl transferases (NMNATs) catalyze the final step of NAD ؉ biosynthesis. We report here that the nuclear isoform NMNAT-1 stimulates PARP-1 activity and binds to PAR. Its overexpression in HeLa cells promotes the relocation of apoptosis-inducing factor from the mitochondria to the nucleus, a process known to depend on poly(ADP-ribosyl)ation. Moreover, NMNAT-1 is subject to phosphorylation by protein kinase C, resulting in reduced binding to PAR. Mimicking phosphorylation, substitution of the target serine residue by aspartate precludes PAR binding and stimulation of PARP-1. We conclude that, depending on its state of phosphorylation, NMNAT-1 binds to activated, automodifying PARP-1 and thereby amplifies poly(ADP-ribosyl)ation.apoptosis ͉ NAD biosynthesis ͉ poly(ADP-ribosyl)ation ͉ protein phosphorylation N MN adenylyl transferase (NMNAT) is an essential enzyme because it catalyzes the final step of NAD ϩ biosynthesis (1). There are three isoforms in humans that exhibit tissue-and organelle-specific expression (2). Because the biological role of NAD ϩ and NADH (collectively termed NAD) has long been thought to be confined to their function as electron carriers, the nuclear localization of the major isoforms, human NMNAT-1 (3) and yeast Nma2 (4), was somewhat puzzling. However, recent research has revealed many important regulatory functions of the pyridine nucleotides, some of which take place within the nucleus (5).NAD ϩ serves as substrate for covalent protein modifications such as mono(ADP-ribosyl)ation (6), poly(ADP-ribosyl)ation (7,8), and protein deacetylation by sirtuins, proteins of the silent information regulator 2 (Sir2) family (9). Pyridine nucleotides are also direct precursors of two calcium-mobilizing messengers, cyclic ADP ribose and nicotinic acid adenine dinucleotide phosphate (NAADP ϩ ) (10 -13). The predominant NAD ϩ -consuming activity, poly(ADP-ribosyl)ation by poly(ADPribose) polymerase 1 (PARP-1), occurs within the nucleus, as does NAD ϩ -dependent protein deacetylation by sirtuins. Consequently, substrate supply by NMNAT-1 may directly influence these processes. Overexpression of NMNAT-1 extends the lifespan of eukaryotic cells, which has been attributed to augmented NAD ϩ -dependent histone deacetylation catalyzed by Sir2p or its homologs (4,(14)(15)(16)(17)(18). Increased NMNAT activity is also required for the axon-sparing activity of the chimeric slow Wallerian degeneration (Wld s ) protein, which is composed of 19 amino acids of the ubiquitin assembly protein Ufd2a and full-length NMNAT-1 (19).Although suggested previously (3, 20, 21), a functional intera...

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“…Nicotinamidases are the first enzymes of the NAD þ salvage pathway in invertebrates, using nicotinamide (NAM) as a substrate (Magni et al, 1999). Administration of high levels of nicotinamide causes uv1 cells to die by necrosis at high frequency in wild-type animals.…”

Section: Vulva Cell Necrosismentioning

confidence: 99%

Non‐apoptotic cell death in Caenorhabditis elegans

Vlachos

Tavernarakis

2010

Developmental Dynamics

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The simple nematode worm Caenorhabditis elegans has been instrumental in deciphering the molecular mechanisms underlying apoptosis. Beyond apoptosis, several paradigms of non-apoptotic cell death, either genetically or extrinsically triggered, have also been described in C. elegans. Remarkably, non-apoptotic cell death in worms and pathological cell death in humans share numerous key features and mechanistic aspects. Such commonalities suggest that similarly to apoptosis, non-apoptotic cell death mechanisms are also conserved, and render the worm a useful organism, in which to model and dissect human pathologies. Indeed, the genetic malleability and the sophisticated molecular tools available for C. elegans have contributed decisively to advance our understanding of non-apoptotic cell death. Here, we review the literature on the various types of non-apoptotic cell death in C. elegans and discuss the implications, relevant to pathological conditions in humans. Developmental Dynamics 239:1337-1351, 2010.V C 2010 Wiley-Liss, Inc.

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Enzymology of Nad ⁺ Synthesis

Cited by 189 publications

References 258 publications

Elevation of Cellular NAD Levels by Nicotinic Acid and Involvement of Nicotinic Acid Phosphoribosyltransferase in Human Cells

Elevation of Cellular NAD Levels by Nicotinic Acid and Involvement of Nicotinic Acid Phosphoribosyltransferase in Human Cells

Regulation of poly(ADP-ribose) polymerase 1 activity by the phosphorylation state of the nuclear NAD biosynthetic enzyme NMN adenylyl transferase 1

Non‐apoptotic cell death in Caenorhabditis elegans

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Enzymology of Nad + Synthesis

Cited by 189 publications

References 258 publications

Elevation of Cellular NAD Levels by Nicotinic Acid and Involvement of Nicotinic Acid Phosphoribosyltransferase in Human Cells

Elevation of Cellular NAD Levels by Nicotinic Acid and Involvement of Nicotinic Acid Phosphoribosyltransferase in Human Cells

Regulation of poly(ADP-ribose) polymerase 1 activity by the phosphorylation state of the nuclear NAD biosynthetic enzyme NMN adenylyl transferase 1

Non‐apoptotic cell death in Caenorhabditis elegans

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Enzymology of Nad ⁺ Synthesis