NMNAT1

Last updated

NMNAT1
Protein NMNAT1 PDB 1gzu.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases NMNAT1 , LCA9, NMNAT, PNAT1, nicotinamide nucleotide adenylyltransferase 1, SHILCA
External IDs OMIM: 608700; MGI: 1913704; HomoloGene: 39074; GeneCards: NMNAT1; OMA:NMNAT1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
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 Chr 4: 149.55 – 149.57 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) is an enzyme that in humans is encoded by the nmnat1 gene. [5] [6] [7] It is a member of the nicotinamide-nucleotide adenylyltransferases (NMNATs) which catalyze nicotinamide adenine dinucleotide (NAD) synthesis. [8]

Contents

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. [7]

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. [9] 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. Other tumors such as osteosarcoma, however, increase the expression of NMNAT1 upon exposure to DNA damaging agents and inactivation of the nmnat1 gene renders these cells more sensitive to chemotherapy with cisplatin. [10] This latter effect involves lowered nuclear NAD levels in NMNAT1 knockout cells and impaired DNA damage sensing by the NAD-dependent DNA break responsive enzyme poly (ADP-ribose) polymerase-1 (PARP1). [10] The dependence of osteosarcoma cells on NMNAT1-derived NAD for the PARP1-dependent DNA repair and survival is not restricted to cisplatin-treated cancer cells but has also been reported to occur in actinomycine D-treated tumor cell lines, as well. [11] These data suggest that nuclear NAD synthesis by NMNAT1 may represent a therapeutic target in osteosarcoma and possibly in other tumors, as well. [10] [11]

NMNAT enzymatic activity is probably essential at the cellular level, as complete ablation of NMNAT activity in model organisms leads to cellular inviability. [12]

NMNAT1 enhancement opposes the actions of SARM1 which would lead to axon degeneration, [13] but this effect is not due to preventing SARM1 depletion of NAD+. [8]

Clinical relevance

Mutations in this gene have been shown associated to the LCA9 form of the retinal degeneration pathology Leber's congenital amaurosis. [14] [8] [15]

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+). [16] All NMNAT gene isoform products also decline with age in mice in kidneys, oocytes, and colons. [16]

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000173614 Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000028992 Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Schweiger M, Hennig K, Lerner F, Niere M, Hirsch-Kauffmann M, Specht T, et al. (Mar 2001). "Characterization of recombinant human nicotinamide mononucleotide adenylyl transferase (NMNAT), a nuclear enzyme essential for NAD synthesis". FEBS Letters. 492 (1–2): 95–100. doi: 10.1016/S0014-5793(01)02180-9 . PMID   11248244.
  6. Emanuelli M, Carnevali F, Saccucci F, Pierella F, Amici A, Raffaelli N, et al. (Feb 2001). "Molecular cloning, chromosomal localization, tissue mRNA levels, bacterial expression, and enzymatic properties of human NMN adenylyltransferase". Journal of Biological Chemistry. 276 (1): 406–412. doi: 10.1074/jbc.M008700200 . PMID   11027696.
  7. 1 2 "Entrez Gene: NMNAT1 nicotinamide nucleotide adenylyltransferase 1".
  8. 1 2 3 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.
  9. Fletcher RS, Lavery GG (2018). "The emergence of the nicotinamide riboside kinases in the regulation of NAD+ metabolism". Journal of Molecular Endocrinology. 61 (3): R107 –R121. doi:10.1530/JME-18-0085. PMC   6145238 . PMID   30307159.
  10. 1 2 3 Kiss A, Raduly AP, Regdon Z, Polgar Z, Tarapcsak S, Sturniolo I, et al. (2020-05-07). "Targeting Nuclear NAD+ Synthesis Inhibits DNA Repair, Impairs Metabolic Adaptation and Increases Chemosensitivity of U-2OS Osteosarcoma Cells". Cancers. 12 (5): E1180. doi: 10.3390/cancers12051180 . ISSN   2072-6694. PMC   7281559 . PMID   32392755.
  11. 1 2 Kiss A, Csikos C, Regdon Z, Polgar Z, Virag L, Hegedus C (2021-08-18). "NMNAT1 Is a Survival Factor in Actinomycin D-Induced Osteosarcoma Cell Death". International Journal of Molecular Sciences. 22 (16): 8869. doi: 10.3390/ijms22168869 . ISSN   1422-0067. PMC   8396190 . PMID   34445574.
  12. Muller FL, Colla S, Aquilanti E, Manzo VE, Genovese G, Lee J, et al. (August 2012). "Passenger deletions generate therapeutic vulnerabilities in cancer". Nature. 488 (7411): 337–342. Bibcode:2012Natur.488..337M. doi:10.1038/nature11331. PMC   3712624 . PMID   22895339.
  13. Sasaki Y, Nakagawa T, Mao X, DiAntonio A, Milbrandt J (October 2016). "+ depletion". eLife. 5. doi: 10.7554/eLife.19749 . PMC   5063586 . PMID   27735788.
  14. Koenekoop RK, Wang H, Majewski J, Wang X, Lopez I, Ren H, et al. (September 2012). "Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration". Nature Genetics. 44 (9). Finding of Rare Disease Genes (FORGE) Canada Consortium: 1035–1039. doi:10.1038/ng.2356. PMC   3657614 . PMID   22842230.
  15. 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.
  16. 1 2 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