NMNAT1

Nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) is an enzyme that in humans is encoded by the NMNAT1 gene.[4][5][6] It is a member of the nicotinamide-nucleotide adenylyltransferases (NMNATs) which catalyze nicotinamide adenine dinucleotide (NAD) synthesis.[7]

NMNAT1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1GZU, 1KKU, 1KQN, 1KQO, 1KR2
Identifiers
Aliases	NMNAT1, LCA9, NMNAT, PNAT1, nicotinamide nucleotide adenylyltransferase 1
External IDs	OMIM: 608700 MGI: 1913704 HomoloGene: 39074 GeneCards: NMNAT1
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1p36.22 Start 9,943,428 bp[1] End 9,985,501 bp[1]
Gene ontology Molecular function • transferase activity • nucleotide binding • nucleotidyltransferase activity • GO:0001948 protein binding • ATP binding • catalytic activity • nicotinamide-nucleotide adenylyltransferase activity • nicotinate-nucleotide adenylyltransferase activity • identical protein binding Cellular component • cell nucleus • nucleoplasm • nuclear body • cytoplasm Biological process • pyridine nucleotide biosynthetic process • NAD metabolic process • NAD biosynthetic process • biosynthetic process • 'de novo' NAD biosynthetic process from aspartate • response to wounding • ATP generation from poly-ADP-D-ribose • positive regulation of MAPK cascade • negative regulation of neuron apoptotic process • negative regulation of apoptotic DNA fragmentation • nucleotide biosynthetic process Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	64802	66454
Ensembl	ENSG00000173614	ENSMUSG00000028992
UniProt	Q9HAN9	Q9EPA7
RefSeq (mRNA)	NM_001297778 NM_001297779 NM_022787	NM_133435 NM_001356357
RefSeq (protein)	NP_001284707 NP_001284708 NP_073624	NP_597679 NP_001343286
Location (UCSC)	Chr 1: 9.94 – 9.99 Mb	n/a
PubMed search	[2]	[3]
Wikidata
View/Edit Human View/Edit Mouse

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.[6]

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.[8] 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.[9]

NMNAT1 enhancement opposes the actions of SARM1 which would lead to axon degeneration,[10] but this effect is not due to preventing SARM1 depletion of NAD+.[7]

Clinical relevance

Mutations in this gene have been shown associated to the LCA9 form of the retinal degeneration pathology Leber's congenital amaurosis.[11][7][12]

Aging

Aged mice show a significant reduction of NMNAT1 gene products in the liver (which is the main site of de novo synthesis of NAD+).[13] All NMNAT gene isoform products also decline with age in mice in kidneys, oocytes, and colons.[13]

References

1. GRCh38: Ensembl release 89: ENSG00000173614 - Ensembl, May 2017
2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
3. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. 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.
5. 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.
6. "Entrez Gene: NMNAT1 nicotinamide nucleotide adenylyltransferase 1".
7. Brazill JM, Li C, Zhu Y, Zhai RG (2017). "NMNAT: It's an NAD + Synthase… It's a Chaperone… It's a Neuroprotector". Current Opinion in Genetics & Development. 44: 156–162. doi:10.1016/j.gde.2017.03.014. PMC 5515290. PMID 28445802.
8. Fletcher RS, Lavery GG (2018). "The emergence of the nicotinamide riboside kinases in the regulation of NAD+ metabolism". Journal of Molecular Endocrinology. 61: R107–R121. doi:10.1530/JME-18-0085. PMC 6145238. PMID 30307159.
9. Muller FL, Colla S, Aquilanti E, et al. (August 2012). "Passenger deletions generate therapeutic vulnerabilities in cancer". Nature. 488 (7411): 337–42. Bibcode:2012Natur.488..337M. doi:10.1038/nature11331. PMC 3712624. PMID 22895339.
10. Sasaki Y, Nakagawa T, Mao X, DiAntonio A, Milbrandt J (October 2016). "+ depletion". eLife. 5. doi:10.7554/eLife.19749. PMC 5063586. PMID 27735788.
11. 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 (September 2012). Finding of Rare Disease Genes (FORGE) Canada Consortium. "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.
12. Jadeja RN, Thounaojam MC, Martin PM (2020). "Implications of NAD + Metabolism in the Aging Retina and Retinal Degeneration". Oxidative Medicine and Cellular Longevity. 2020: 2692794. doi:10.1155/2020/2692794. PMC 7238357. PMID 32454935.
13. McReynolds MR, Chellappa K, Baur JA (2020). "Age-related NAD + decline". Experimental Gerontology. 134: 110888. doi:10.1016/j.exger.2020.110888. PMC 7442590. PMID 32097708.

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. 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. S2CID 7827573.
• 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. Bibcode:2007PNAS..104.3765B. doi:10.1073/pnas.0609211104. PMC 1820658. PMID 17360427.