NMNAT1

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]

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, SHILCA
External IDs	OMIM: 608700; MGI: 1913704; HomoloGene: 39074; GeneCards: NMNAT1; OMA:NMNAT1 - orthologs
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1p36.22 Start 9,943,428 bp[1] End 9,985,501 bp[1]
Gene location (Mouse) Chr. Chromosome 4 (mouse)[2] Band 4|4 E2 Start 149,552,029 bp[2] End 149,569,659 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in muscle of thigh mucosa of transverse colon testicle gastrocnemius muscle islet of Langerhans monocyte Achilles tendon stromal cell of endometrium rectum apex of heart Top expressed in otic placode otic vesicle saccule muscle of thigh right kidney quadriceps femoris muscle tibialis anterior muscle skeletal muscle tissue embryo intercostal muscle More reference expression data BioGPS n/a
Gene ontology Molecular function transferase activity nucleotide binding nucleotidyltransferase activity protein binding ATP binding catalytic activity nicotinamide-nucleotide adenylyltransferase activity nicotinate-nucleotide adenylyltransferase activity identical protein binding Cellular component nucleus nucleoplasm nuclear body cytoplasm Biological process pyridine nucleotide biosynthetic process NAD metabolic process NAD biosynthetic process biosynthesis '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 Chr 4: 149.55 – 149.57 Mb PubMed search [3] [4]
Wikidata
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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]