nicotinamide nucleotide adenylyltransferase

Summary

Summary: An enzyme that catalyzes reversibly the transfer of the adenylyl moiety of ATP to the phosphoryl group of NMN to form NAD+ and pyrophosphate. The enzyme is found predominantly in the nuclei and catalyzes the final reaction in the major pathway for the biosynthesis of NAD in mammals.

Top Publications

  1. Sasaki Y, Vohra B, Lund F, Milbrandt J. Nicotinamide mononucleotide adenylyl transferase-mediated axonal protection requires enzymatic activity but not increased levels of neuronal nicotinamide adenine dinucleotide. J Neurosci. 2009;29:5525-35 pubmed publisher
    ..These results provide the possibility of a role for new Nmnat enzymatic activity in axonal protection in addition to NAD(+) synthesis. ..
  2. Conforti L, Fang G, Beirowski B, Wang M, Sorci L, Asress S, et al. NAD(+) and axon degeneration revisited: Nmnat1 cannot substitute for Wld(S) to delay Wallerian degeneration. Cell Death Differ. 2007;14:116-27 pubmed
    ..The full protective effect of Wld(S) requires more N-terminal sequences of the protein. ..
  3. Avery M, Sheehan A, Kerr K, Wang J, Freeman M. Wld S requires Nmnat1 enzymatic activity and N16-VCP interactions to suppress Wallerian degeneration. J Cell Biol. 2009;184:501-13 pubmed publisher
    ..Thus, nuclear Nmnat activity does not appear to be essential for Wld(S)-like axon protection. ..
  4. Zhang H, Zhou T, Kurnasov O, Cheek S, Grishin N, Osterman A. Crystal structures of E. coli nicotinate mononucleotide adenylyltransferase and its complex with deamido-NAD. Structure. 2002;10:69-79 pubmed
    ..The bacterial NaMN adenylyltransferase structures described here provide a foundation for structure-based design of specific inhibitors that may have therapeutic potential...
  5. Garavaglia S, D Angelo I, Emanuelli M, Carnevali F, Pierella F, Magni G, et al. Structure of human NMN adenylyltransferase. A key nuclear enzyme for NAD homeostasis. J Biol Chem. 2002;277:8524-30 pubmed
    ..Structural comparison of human and prokaryotic NMNATs may also lead to the rational design of highly selective antimicrobial drugs. ..
  6. Zhai R, Cao Y, Hiesinger P, Zhou Y, Mehta S, Schulze K, et al. Drosophila NMNAT maintains neural integrity independent of its NAD synthesis activity. PLoS Biol. 2006;4:e416 pubmed
    ..Our data indicate an NAD-independent requirement of NMNAT for maintaining neuronal integrity that can be exploited to protect neurons from neuronal activity-induced degeneration by overexpression of the protein. ..
  7. Yahata N, Yuasa S, Araki T. Nicotinamide mononucleotide adenylyltransferase expression in mitochondrial matrix delays Wallerian degeneration. J Neurosci. 2009;29:6276-84 pubmed publisher
    ..Alteration of mitochondrial function may constitute a novel tool for axonal protection, as well as a possible treatment of diseases involving axonopathy. ..
  8. Zhai R, Zhang F, Hiesinger P, Cao Y, Haueter C, Bellen H. NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration. Nature. 2008;452:887-91 pubmed publisher
    ..Our studies provide an entry point for understanding how normal neurons maintain activity, and offer clues for the common mechanisms underlying different neurodegenerative conditions. ..
  9. Araki T, Sasaki Y, Milbrandt J. Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration. Science. 2004;305:1010-3 pubmed
    ..These findings suggest that novel therapeutic strategies directed at increasing the supply of NAD and/or Sir2 activation may be effective for treatment of diseases characterized by axonopathy and neurodegeneration. ..

More Information

Publications62

  1. Raffaelli N, Sorci L, Amici A, Emanuelli M, Mazzola F, Magni G. Identification of a novel human nicotinamide mononucleotide adenylyltransferase. Biochem Biophys Res Commun. 2002;297:835-40 pubmed
  2. Emanuelli M, Carnevali F, Saccucci F, Pierella F, Amici A, Raffaelli N, et al. Molecular cloning, chromosomal localization, tissue mRNA levels, bacterial expression, and enzymatic properties of human NMN adenylyltransferase. J Biol Chem. 2001;276:406-12 pubmed
    ..5 mg of recombinant enzyme/liter of culture medium. The molecular and kinetic properties of recombinant human NMN adenylyltransferase provide new directions for investigating metabolic pathways involving this enzyme. ..
  3. Sasaki Y, Araki T, Milbrandt J. Stimulation of nicotinamide adenine dinucleotide biosynthetic pathways delays axonal degeneration after axotomy. J Neurosci. 2006;26:8484-91 pubmed
    ..These results indicate that stimulation of NAD biosynthetic pathways via a variety of interventions may be useful in preventing or delaying axonal degeneration. ..
  4. Saridakis V, Christendat D, Kimber M, Dharamsi A, Edwards A, Pai E. Insights into ligand binding and catalysis of a central step in NAD+ synthesis: structures of Methanobacterium thermoautotrophicum NMN adenylyltransferase complexes. J Biol Chem. 2001;276:7225-32 pubmed publisher
    ..In addition, the role of the conserved (16)HXGH(19) active site motif in catalysis was probed by mutagenic, enzymatic and crystallographic techniques, including the characterization of an NMN(+)/SO4(2-) complex of mutant H19A NMNATase...
  5. Rizzi M, Schindelin H. Structural biology of enzymes involved in NAD and molybdenum cofactor biosynthesis. Curr Opin Struct Biol. 2002;12:709-20 pubmed
    ..The recent progress made in the structural biology of enzymes involved in NAD and molybdenum cofactor biosynthesis presents a significant step toward these goals. ..
  6. Fang C, Bernardes Silva M, Coleman M, Perry V. The cellular distribution of the Wld s chimeric protein and its constituent proteins in the CNS. Neuroscience. 2005;135:1107-18 pubmed
    ..The increased Nmnat-1 activity in the nucleus of Wld s mice compared with wild-type mice seems to be a significant factor in the axon protection. It is not known whether the expression of the Nmnat-1 in the axon is significant...
  7. Laser H, Conforti L, Morreale G, Mack T, Heyer M, Haley J, et al. The slow Wallerian degeneration protein, WldS, binds directly to VCP/p97 and partially redistributes it within the nucleus. Mol Biol Cell. 2006;17:1075-84 pubmed
    ..We conclude that N-terminal sequences of Wld(S) protein influence the intranuclear location of both ubiquitin proteasome and NAD(+) synthesis machinery and that an evolutionary recent sequence mediates binding of mammalian Ube4b to VCP. ..
  8. Zhou T, Kurnasov O, Tomchick D, Binns D, Grishin N, Marquez V, et al. Structure of human nicotinamide/nicotinic acid mononucleotide adenylyltransferase. Basis for the dual substrate specificity and activation of the oncolytic agent tiazofurin. J Biol Chem. 2002;277:13148-54 pubmed
    ..The results from the analytical ultracentrifugation studies are consistent with the formation of a hexamer in solution under certain conditions. ..
  9. Sasaki Y, Vohra B, Baloh R, Milbrandt J. Transgenic mice expressing the Nmnat1 protein manifest robust delay in axonal degeneration in vivo. J Neurosci. 2009;29:6526-34 pubmed publisher
    ..These results highlight the importance of understanding the mechanism of Nmnat-mediated axonal protection for the development of new treatment strategies for neurological disorders. ..
  10. Zhang X, Kurnasov O, Karthikeyan S, Grishin N, Osterman A, Zhang H. Structural characterization of a human cytosolic NMN/NaMN adenylyltransferase and implication in human NAD biosynthesis. J Biol Chem. 2003;278:13503-11 pubmed
    ..The characterization of the cytosolic human PNAT-3 provided compelling evidence that the final steps of NAD biosynthesis pathways may exist in mammalian cytoplasm and mitochondria, potentially contributing to their NAD/NADP pool. ..
  11. Stancek M, Isaksson L, Ryden Aulin M. fusB is an allele of nadD, encoding nicotinate mononucleotide adenylyltransferase in Escherichia coli. Microbiology. 2003;149:2427-33 pubmed
    ..This mutation was designated nadD74. Thus, a small decrease in NAD+ levels affects ability to grow on minimal medium at 42 degrees C, while a large decrease leads to a more pleiotropic phenotype. ..
  12. Conforti L, Wilbrey A, Morreale G, Janeckova L, Beirowski B, Adalbert R, et al. Wld S protein requires Nmnat activity and a short N-terminal sequence to protect axons in mice. J Cell Biol. 2009;184:491-500 pubmed publisher
    ..Enzyme-dead Wld(S) is unable to delay Wallerian degeneration in mice. Thus, neither domain is effective without the function of the other. Wld(S) requires both of its components to protect axons from degeneration. ..
  13. Gerdes S, Scholle M, D Souza M, Bernal A, Baev M, Farrell M, et al. From genetic footprinting to antimicrobial drug targets: examples in cofactor biosynthetic pathways. J Bacteriol. 2002;184:4555-72 pubmed
    ..Several drug targets within these pathways, including three distantly related adenylyltransferases (orthologs of the E. coli genes nadD, coaD, and ribF), are discussed in detail. ..
  14. Wang J, Zhai Q, Chen Y, Lin E, Gu W, McBurney M, et al. A local mechanism mediates NAD-dependent protection of axon degeneration. J Cell Biol. 2005;170:349-55 pubmed
    ..Furthermore, we provide evidence that such Nmnat1/NAD-mediated protection is primarily mediated by their effects on local bioenergetics. Together, our results suggest a novel molecular pathway for axon degeneration. ..
  15. Mehl R, Kinsland C, Begley T. Identification of the Escherichia coli nicotinic acid mononucleotide adenylyltransferase gene. J Bacteriol. 2000;182:4372-4 pubmed
    ..The rate of adenylation of nicotinate mononucleotide is at least 20 times faster than the rate of adenylation of nicotinamide mononucleotide. ..
  16. Magni G, Amici A, Emanuelli M, Raffaelli N, Ruggieri S. Enzymology of NAD+ synthesis. Adv Enzymol Relat Areas Mol Biol. 1999;73:135-82, xi pubmed
  17. Berger F, Lau C, Dahlmann M, Ziegler M. Subcellular compartmentation and differential catalytic properties of the three human nicotinamide mononucleotide adenylyltransferase isoforms. J Biol Chem. 2005;280:36334-41 pubmed
    ..Their existence appears to be consistent with important compartment-specific functions rather than to reflect simple functional redundance. ..
  18. Press C, Milbrandt J. Nmnat delays axonal degeneration caused by mitochondrial and oxidative stress. J Neurosci. 2008;28:4861-71 pubmed publisher
  19. Fainzilber M, Twiss J. Tracking in the Wlds--the hunting of the SIRT and the luring of the Draper. Neuron. 2006;50:819-21 pubmed
  20. Saridakis V, Pai E. Mutational, structural, and kinetic studies of the ATP-binding site of Methanobacterium thermoautotrophicum nicotinamide mononucleotide adenylyltransferase. J Biol Chem. 2003;278:34356-63 pubmed publisher
    ..3%, respectively, of WT NMNATase activity indicating that His-19 is a key catalytic group. Surprisingly, this H19A mutant displayed a novel and distinct mode of NAD+ binding when co-crystallized in the presence of NAD+ and SO42-...
  21. Gillingwater T, Thomson D, Mack T, Soffin E, Mattison R, Coleman M, et al. Age-dependent synapse withdrawal at axotomised neuromuscular junctions in Wld(s) mutant and Ube4b/Nmnat transgenic mice. J Physiol. 2002;543:739-55 pubmed
    ..Thus, Wld expression unmasks age-dependent, compartmentally organised programmes of synapse withdrawal and degeneration. ..
  22. Mack T, Reiner M, Beirowski B, Mi W, Emanuelli M, Wagner D, et al. Wallerian degeneration of injured axons and synapses is delayed by a Ube4b/Nmnat chimeric gene. Nat Neurosci. 2001;4:1199-206 pubmed
    ..Nmnat enzyme activity, but not NAD+ content, was increased fourfold in WldS tissues. Thus, axon protection is likely to be mediated by altered ubiquitination or pyridine nucleotide metabolism. ..
  23. Schweiger M, Hennig K, Lerner F, Niere M, Hirsch Kauffmann M, Specht T, et al. Characterization of recombinant human nicotinamide mononucleotide adenylyl transferase (NMNAT), a nuclear enzyme essential for NAD synthesis. FEBS Lett. 2001;492:95-100 pubmed
    ..Endogenous and recombinant NMNAT were phosphorylated in nuclear extracts in the presence of [gamma-(32)P]ATP. We propose that NMNAT's activity or interaction with nuclear proteins are likely to be modulated by phosphorylation. ..
  24. Conforti L, Tarlton A, Mack T, Mi W, Buckmaster E, Wagner D, et al. A Ufd2/D4Cole1e chimeric protein and overexpression of Rbp7 in the slow Wallerian degeneration (WldS) mouse. Proc Natl Acad Sci U S A. 2000;97:11377-82 pubmed
    ..These data reveal both a candidate gene for Wld and the potential of the Wld(S) mutant for studies of ubiquitin and retinoid metabolism. ..
  25. d Angelo I, Raffaelli N, Dabusti V, Lorenzi T, Magni G, Rizzi M. Structure of nicotinamide mononucleotide adenylyltransferase: a key enzyme in NAD(+) biosynthesis. Structure. 2000;8:993-1004 pubmed
  26. Zhai R, Rizzi M, Garavaglia S. Nicotinamide/nicotinic acid mononucleotide adenylyltransferase, new insights into an ancient enzyme. Cell Mol Life Sci. 2009;66:2805-18 pubmed publisher
    ..The resultant wealth of biochemical data has built a robust framework upon which design of NMNAT activators, inhibitors or enzyme variants of potential medical interest can be based. ..
  27. Emanuelli M, Carnevali F, Lorenzi M, Raffaelli N, Amici A, Ruggieri S, et al. Identification and characterization of YLR328W, the Saccharomyces cerevisiae structural gene encoding NMN adenylyltransferase. Expression and characterization of the recombinant enzyme. FEBS Lett. 1999;455:13-7 pubmed
    ..Molecular and kinetic properties of recombinant NMN adenylyltransferase are reported and compared with those already known for the enzyme obtained from different sources. ..
  28. Magni G, Di Stefano M, Orsomando G, Raffaelli N, Ruggieri S. NAD(P) biosynthesis enzymes as potential targets for selective drug design. Curr Med Chem. 2009;16:1372-90 pubmed
    ..The involvement of human NMNAT in neurodegenerative disorders and its role in neuroprotection is also discussed. ..
  29. Berger F, Lau C, Ziegler M. Regulation of poly(ADP-ribose) polymerase 1 activity by the phosphorylation state of the nuclear NAD biosynthetic enzyme NMN adenylyl transferase 1. Proc Natl Acad Sci U S A. 2007;104:3765-70 pubmed
    ..We conclude that, depending on its state of phosphorylation, NMNAT-1 binds to activated, automodifying PARP-1 and thereby amplifies poly(ADP-ribosyl)ation. ..
  30. Kitaoka Y, Hayashi Y, Kumai T, Takeda H, Munemasa Y, Fujino H, et al. Axonal and cell body protection by nicotinamide adenine dinucleotide in tumor necrosis factor-induced optic neuropathy. J Neuropathol Exp Neurol. 2009;68:915-27 pubmed publisher
  31. Barile M, Passarella S, Danese G, Quagliariello E. Rat liver mitochondria can synthesize nicotinamide adenine dinucleotide from nicotinamide mononucleotide and ATP via a putative matrix nicotinamide mononucleotide adenylyltransferase. Biochem Mol Biol Int. 1996;38:297-306 pubmed
    ..C. 2.7.7.1.), inhibited by PPi, AMP and ADP-ribose. Some features of this enzyme, including the substrate, pH and temperature dependence were also investigated. ..
  32. Sestini S, Jacomelli G, Pescaglini M, Micheli V, Pompucci G. Enzyme activities leading to NAD synthesis in human lymphocytes. Arch Biochem Biophys. 2000;379:277-82 pubmed
    ..The reported findings, together with the previous ones in human erythrocytes, can provide an useful base to investigate NAD metabolism in humans through the study of blood cells. ..
  33. Revollo J, Grimm A, Imai S. The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltransferase regulates Sir2 activity in mammalian cells. J Biol Chem. 2004;279:50754-63 pubmed
    ..These findings suggest that NAD biosynthesis mediated by Nampt regulates the function of Sir2alpha and thereby plays an important role in controlling various biological events in mammals. ..
  34. Lau C, Dölle C, Gossmann T, Agledal L, Niere M, Ziegler M. Isoform-specific targeting and interaction domains in human nicotinamide mononucleotide adenylyltransferases. J Biol Chem. 2010;285:18868-76 pubmed publisher
    ..Insertion of unique domains thus provides a yet unrecognized enzyme targeting mode, which has also been adapted to modulate subcellular NAD supply. ..
  35. Paulik E, Jayaram H, Weber G. Determination of NAD pyrophosphorylase activity in biological samples. Anal Biochem. 1991;197:143-8 pubmed
    ..The range of NAD produced during the assay was 2 to 200 microM. NAD pyrophosphorylase activities in the mononuclear cells of leukemic patients, human ovarian carcinoma cells, and rat liver were assayed. ..
  36. Fernando F, Conforti L, Tosi S, Smith A, Coleman M. Human homologue of a gene mutated in the slow Wallerian degeneration (C57BL/Wld(s)) mouse. Gene. 2002;284:23-9 pubmed
    ..We have also determined the intron/exon structure of the gene, which will facilitate the screening of these exons for mutations in human neurodegenerative disorders. ..
  37. Chen L, Petrelli R, Felczak K, Gao G, Bonnac L, Yu J, et al. Nicotinamide adenine dinucleotide based therapeutics. Curr Med Chem. 2008;15:650-70 pubmed
    ..This review focuses on key representative opportunities for research in this area, which extends beyond the scope of this article. ..
  38. Kim H, Yoon H, Ha J, Lee B, Lee H, Mikami B, et al. Crystallization and preliminary X-ray crystallographic analysis of nicotinic acid mononucleotide adenylyltransferase from Pseudomonas aeruginosa. Acta Crystallogr D Biol Crystallogr. 2004;60:948-9 pubmed
    ..02, c = 109.80 A. The presence of one monomer in the asymmetric unit gives a reasonable V(M) of 2.15 A(3) Da(-1), with a solvent content of 42.7%. ..
  39. Magni G, Amici A, Emanuelli M, Orsomando G, Raffaelli N, Ruggieri S. Enzymology of NAD+ homeostasis in man. Cell Mol Life Sci. 2004;61:19-34 pubmed
  40. Lu S, Smith C, Yang Z, Pruett P, Nagy L, McCombs D, et al. Structure of nicotinic acid mononucleotide adenylyltransferase from Bacillus anthracis. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2008;64:893-8 pubmed publisher
    ..Comparison of these and other less related bacterial NaMNAT structures support the presence of considerable conformational heterogeneity and flexibility in three loops surrounding the substrate-binding area. ..
  41. Olland A, Underwood K, Czerwinski R, Lo M, Aulabaugh A, Bard J, et al. Identification, characterization, and crystal structure of Bacillus subtilis nicotinic acid mononucleotide adenylyltransferase. J Biol Chem. 2002;277:3698-707 pubmed
    ..Interactions of the nicotinic acid with backbone atoms indicate the structural basis for specificity. ..
  42. Yalowitz J, Jayaram H. Modulation of cytotoxicity of benzamide riboside by expression of NMN adenylyltransferase. Curr Med Chem. 2002;9:749-58 pubmed
    ..Therefore, it can be concluded that IMPDH inhibitors directly inhibit PARP. Presumably, the shared IMP-NAD active site of IMPDH has a similar architecture to the NAD-binding pocket of PARP. ..
  43. Sorci L, Cimadamore F, Scotti S, Petrelli R, Cappellacci L, Franchetti P, et al. Initial-rate kinetics of human NMN-adenylyltransferases: substrate and metal ion specificity, inhibition by products and multisubstrate analogues, and isozyme contributions to NAD+ biosynthesis. Biochemistry. 2007;46:4912-22 pubmed
    ..Distinctive differences in their substrate specificity and metal ion selectivity also permitted us to quantify individual isozyme contributions to NAD+ formation in human cell extracts...
  44. Hagan M, Yacoub A, Dent P. Radiation-induced PARP activation is enhanced through EGFR-ERK signaling. J Cell Biochem. 2007;101:1384-93 pubmed
    ..MEK inhibitor PD 184352 also reduced PARP activation and improved LNCaP survival following EGF and IR treatment. These data imply that PARP activation following exposure to ionizing radiation is enhanced through EGFR-ERK signaling. ..
  45. Watanabe M, Tsukiyama T, Hatakeyama S. Protection of vincristine-induced neuropathy by WldS expression and the independence of the activity of Nmnat1. Neurosci Lett. 2007;411:228-32 pubmed
    ..Taken together, Nmnat1 is considerably weaker than WldS for protection from toxic injury in vitro, suggesting that amino-terminal region of WldS is likely to be more significant for protection from axonal degeneration. ..
  46. Gillingwater T, Wishart T, Chen P, Haley J, Robertson K, MacDonald S, et al. The neuroprotective WldS gene regulates expression of PTTG1 and erythroid differentiation regulator 1-like gene in mice and human cells. Hum Mol Genet. 2006;15:625-35 pubmed
    ..Targeting Wld(S)-induced gene expression may lead to novel therapies for neurodegeneration induced by trauma or by disease in humans. ..
  47. Han S, Forman M, Loulakis P, Rosner M, Xie Z, Wang H, et al. Crystal structure of nicotinic acid mononucleotide adenylyltransferase from Staphyloccocus aureus: structural basis for NaAD interaction in functional dimer. J Mol Biol. 2006;360:814-25 pubmed
    ..Taken together, these structural results provide a molecular basis for understanding the coupled activity and recognition specificity for S. aureus NaMNAT and for rational design of selective inhibitors. ..
  48. Magni G, Amici A, Emanuelli M, Orsomando G, Raffaelli N, Ruggieri S. Structure and function of nicotinamide mononucleotide adenylyltransferase. Curr Med Chem. 2004;11:873-85 pubmed
    ..The possibility that NMNAT may represent an interesting candidate as a target for the rational design of selective chemotherapeutic agents has been suggested. ..
  49. Werner E, Ziegler M, Lerner F, Schweiger M, Heinemann U. Crystal structure of human nicotinamide mononucleotide adenylyltransferase in complex with NMN. FEBS Lett. 2002;516:239-44 pubmed
    ..Human NMNAT displays a different oligomerization compared to the archaeal enzyme. The protein-nicotinamide mononucleotide interaction pattern provides insight into ligand binding in the human enzyme. ..
  50. Jia H, Yan T, Feng Y, Zeng C, Shi X, Zhai Q. Identification of a critical site in Wld(s): essential for Nmnat enzyme activity and axon-protective function. Neurosci Lett. 2007;413:46-51 pubmed
    ..Therefore, we have identified a Phe residue that critical for both enzyme activity of Nmnat and the axon-protective function of Wld(s), and further confirmed that Nmnat1 enzyme activity is required in Wld(s) function. ..
  51. Stancek M, Schnell R, Ryden Aulin M. Analysis of Escherichia coli nicotinate mononucleotide adenylyltransferase mutants in vivo and in vitro. BMC Biochem. 2005;6:16 pubmed
    ..On the other hand, our data has lead us to assign amino acid residues His-19, Arg-46 and Asp-109 to the active site. We have also shown that the nadD gene is essential for growth in E. coli. ..
  52. Jiang P, Peliska J, Ninfa A. Enzymological characterization of the signal-transducing uridylyltransferase/uridylyl-removing enzyme (EC 2.7.7.59) of Escherichia coli and its interaction with the PII protein. Biochemistry. 1998;37:12782-94 pubmed
    ..Our kinetic data were consistent with the hypothesis that both transferase and uridylyl-removal reactions occurred at a single active center on the enzyme. ..
  53. Zhang T, Kraus W. SIRT1-dependent regulation of chromatin and transcription: linking NAD(+) metabolism and signaling to the control of cellular functions. Biochim Biophys Acta. 2010;1804:1666-75 pubmed publisher
    ..The collective molecular actions of SIRT1 control specific patterns of gene expression that modulate a wide variety of physiological outcomes. ..