NMNAT1

Description

The NMNAT1 (nicotinamide nucleotide adenylyltransferase 1) is a protein-coding gene located on chromosome 1.

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

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. 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. 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. 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). 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.

NMNAT1 catalyzes the synthesis of NAD+ from nicotinamide mononucleotide (NMN) and ATP. It can also use the deamidated form, nicotinic acid mononucleotide (NaMN), as a substrate with the same efficiency. Additionally, NMNAT1 can use triazofurin monophosphate (TrMP) as a substrate. It also catalyzes the reverse reaction, the pyrophosphorolytic cleavage of NAD+. NMNAT1 prefers NAD+ and NaAD as substrates for this reverse reaction, but degrades NADH, nicotinic acid adenine dinucleotide phosphate (NHD) and nicotinamide guanine dinucleotide (NGD) less effectively. NMNAT1 is involved in the synthesis of ATP in the nucleus, together with PARP1, PARG and NUDT5. Nuclear ATP generation is required for extensive chromatin remodeling events, which are energy-consuming. NMNAT1 also acts as a cofactor for glutamate and aspartate ADP-ribosylation by directing PARP1 catalytic activity to glutamate and aspartate residues on histones. NMNAT1 fails to cleave phosphorylated dinucleotides NADP+, NADPH and NaADP+. It protects against axonal degeneration following mechanical or toxic insults.

NMNAT1 is also known as LCA9, NMNAT, PNAT1, SHILCA.

Associated Diseases

Comprehensive carrier screening

WES Whole Exome Sequencing

Clinical Exome Sequencing