NMNAT1

Nicotinamide nucleotide adenylyltransferase 1
PDB rendering based on 1gzu.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1GZU​, 1KKU​, 1KQN​, 1KQO​, 1KR2​
Identifiers
Symbols	NMNAT1 ; LCA9; NMNAT; PNAT1
External IDs	OMIM: 608700 MGI: 1913704 HomoloGene: 39074 GeneCards: NMNAT1 Gene
EC number	2.7.7.1, 2.7.7.18
Gene ontology Molecular function • nicotinamide-nucleotide adenylyltransferase activity • nicotinate-nucleotide adenylyltransferase activity • protein binding • ATP binding Cellular component • nucleus • nucleoplasm Biological process • vitamin metabolic process • water-soluble vitamin metabolic process • NAD biosynthetic process • NAD metabolic process • small molecule metabolic process Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	64802	66454
Ensembl	ENSG00000173614	ENSMUSG00000028992
UniProt	Q9HAN9	Q9EPA7
RefSeq (mRNA)	NM_001297778	NM_133435
RefSeq (protein)	NP_001284707	NP_597679
Location (UCSC)	Chr 1: 9.94 – 9.99 Mb	Chr 4: 149.47 – 149.49 Mb
PubMed search

Nicotinamide mononucleotide adenylyltransferase 1 is an enzyme that in humans is encoded by the NMNAT1 gene.^[1][2][3] It is a member of the nicotinamide-nucleotide adenylyltransferases.

Function

The coenzyme NAD and its derivatives are involved in hundreds of metabolic redox reactions and are utilized in protein ADP-ribosylation, histone deacetylation, and in some Ca²⁺ signaling pathways. NMNAT (EC 2.7.7.1) is a central enzyme in NAD biosynthesis, catalyzing the condensation of nicotinamide mononucleotide (NMN) or nicotinic acid mononucleotide (NaMN) with the AMP moiety of ATP to form NAD or NaAD.^[3]

NMNAT1 is the most widely expressed of three orthologous genes with nicotinamide-nucleotide adenylyltransferase (NMNAT) activity. Genetically engineered mice lacking NMNAT1 die during early embryogenesis, indicating a critical role of this gene in organismal viability. In contrast, mice lacking NMNAT2, which is expressed predominantly in neural tissues, complete development but die shortly after birth. However, NMNAT1 is dispensable for cell viability, as homozygous deletion of this gene occurs in glioblastoma tumors and cell lines. NMNAT enzymatic activity is probably essential at the cellular level, as complete ablation of NMNAT activity in model organisms leads to cellular inviability.Muller FL, Colla S, Aquilanti E, et al. (August 2012). "Passenger deletions generate therapeutic vulnerabilities in cancer". Nature 488 (7411): 337–42. doi:10.1038/nature11331. PMC 3712624. PMID 22895339.

Clinical relevance

Mutations in this gene have been shown associated to retinal degeneration pathologies, like Leber's congenital amaurosis.^[4]

References

1. Schweiger M, Hennig K, Lerner F, Niere M, Hirsch-Kauffmann M, Specht T, Weise C, Oei SL, Ziegler M (Mar 2001). "Characterization of recombinant human nicotinamide mononucleotide adenylyl transferase (NMNAT), a nuclear enzyme essential for NAD synthesis". FEBS Lett 492 (1–2): 95–100. doi:10.1016/S0014-5793(01)02180-9. PMID 11248244.
2. Emanuelli M, Carnevali F, Saccucci F, Pierella F, Amici A, Raffaelli N, Magni G (Feb 2001). "Molecular cloning, chromosomal localization, tissue mRNA levels, bacterial expression, and enzymatic properties of human NMN adenylyltransferase". J Biol Chem 276 (1): 406–12. doi:10.1074/jbc.M008700200. PMID 11027696.
3. "Entrez Gene: NMNAT1 nicotinamide nucleotide adenylyltransferase 1".
4. Koenekoop RK, Wang H, Majewski J, Wang X, Lopez I, Ren H, Chen Y, Li Y, Fishman GA, Genead M, Schwartzentruber J, Solanki N, Traboulsi EI, Cheng J, Logan CV, McKibbin M, Hayward BE, Parry DA, Johnson CA, Nageeb M, Poulter JA, Mohamed MD, Jafri H, Rashid Y, Taylor GR, Keser V, Mardon G, Xu H, Inglehearn CF, Fu Q, Toomes C, Chen R, Finding of Rare Disease Genes (FORGE) Canada, Consortium (September 2012). "Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration". Nat. Genet. 44 (9): 1035–9. doi:10.1038/ng.2356. PMC 3657614. PMID 22842230.

Further reading

• Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
• Garavaglia S, D'Angelo I, Emanuelli M, et al. (2002). "Structure of human NMN adenylyltransferase. A key nuclear enzyme for NAD homeostasis". J. Biol. Chem. 277 (10): 8524–30. doi:10.1074/jbc.M111589200. PMID 11751893.
• Werner E, Ziegler M, Lerner F, et al. (2002). "Crystallization and preliminary X-ray analysis of human nicotinamide mononucleotide adenylyltransferase (NMNAT)". Acta Crystallogr. D Biol. Crystallogr. 58 (Pt 1): 140–2. doi:10.1107/S0907444901017437. PMID 11752792.
• Zhou T, Kurnasov O, Tomchick DR, et al. (2002). "Structure of human nicotinamide/nicotinic acid mononucleotide adenylyltransferase. Basis for the dual substrate specificity and activation of the oncolytic agent tiazofurin". J. Biol. Chem. 277 (15): 13148–54. doi:10.1074/jbc.M111469200. PMID 11788603.
• Fernando FS, Conforti L, Tosi S, et al. (2002). "Human homologue of a gene mutated in the slow Wallerian degeneration (C57BL/Wld(s)) mouse". Gene 284 (1–2): 23–9. doi:10.1016/S0378-1119(02)00394-3. PMID 11891043.
• Werner E, Ziegler M, Lerner F, et al. (2002). "Crystal structure of human nicotinamide mononucleotide adenylyltransferase in complex with NMN". FEBS Lett. 516 (1–3): 239–44. doi:10.1016/S0014-5793(02)02556-5. PMID 11959140.
• Raffaelli N, Sorci L, Amici A, et al. (2002). "Identification of a novel human nicotinamide mononucleotide adenylyltransferase". Biochem. Biophys. Res. Commun. 297 (4): 835–40. doi:10.1016/S0006-291X(02)02285-4. PMID 12359228.
• Zhang X, Kurnasov OV, Karthikeyan S, et al. (2003). "Structural characterization of a human cytosolic NMN/NaMN adenylyltransferase and implication in human NAD biosynthesis". J. Biol. Chem. 278 (15): 13503–11. doi:10.1074/jbc.M300073200. PMID 12574164.
• Yalowitz JA, Xiao S, Biju MP, et al. (2004). "Characterization of human brain nicotinamide 5'-mononucleotide adenylyltransferase-2 and expression in human pancreas". Biochem. J. 377 (Pt 2): 317–26. doi:10.1042/BJ20030518. PMC 1223862. PMID 14516279.
• Suzuki Y, Yamashita R, Shirota M, et al. (2004). "Sequence comparison of human and mouse genes reveals a homologous block structure in the promoter regions". Genome Res. 14 (9): 1711–8. doi:10.1101/gr.2435604. PMC 515316. PMID 15342556.
• Berger F, Lau C, Dahlmann M, Ziegler M (2006). "Subcellular compartmentation and differential catalytic properties of the three human nicotinamide mononucleotide adenylyltransferase isoforms". J. Biol. Chem. 280 (43): 36334–41. doi:10.1074/jbc.M508660200. PMID 16118205.
• Olsen JV, Blagoev B, Gnad F, et al. (2006). "Global, in vivo, and site-specific phosphorylation dynamics in signaling networks". Cell 127 (3): 635–48. doi:10.1016/j.cell.2006.09.026. PMID 17081983.
• Berger F, Lau C, Ziegler M (2007). "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. 104 (10): 3765–70. doi:10.1073/pnas.0609211104. PMC 1820658. PMID 17360427.