Nicotinamide mononucleotide adenylyltransferase 3 (NMNAT3) (NMNAT3)

Nicotinamide mononucleotide adenylyltransferase 3 (NMNAT3) is a critical enzyme in the biosynthesis of nicotinamide adenine dinucleotide (NAD+), a vital coenzyme for energy metabolism and cellular signaling (UniProt Q96T66). It catalyzes the final step of both the salvage and de novo pathways, converting nicotinamide mononucleotide (NMN) or nicotinic acid mononucleotide (NaMN) and ATP into NAD+ or deamido-NAD+, respectively (PubMed: 16118205). Unlike its isoforms NMNAT1 and NMNAT2, NMNAT3 is primarily localized within the mitochondria and the cytoplasm of mature erythrocytes (PubMed: 24732012). In red blood cells, NMNAT3 is essential for maintaining the NAD+ pool required for glycolysis; its deficiency leads to ATP depletion and hereditary hemolytic anemia (Wikipedia, 2026). In other tissues, NMNAT3 supports mitochondrial function and regulates the activity of NAD+-dependent enzymes like SIRT3, which influences metabolic health and aging (PubMed: 29411466). Therapeutic interest in NMNAT3 focuses on its activation to treat metabolic disorders, such as insulin resistance, and its role in neuroprotection by maintaining axonal integrity (PubMed: 28236542). Conversely, its inhibition is explored in oncology, as many cancer cells rely on high NAD+ levels for survival and proliferation (PubMed: 34199012).

Other names

Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 3Nicotinamide-nucleotide adenylyltransferase 3Nicotinate-nucleotide adenylyltransferase 3Pyridine nucleotide adenylyltransferase 3PNAT-3FKSG76

NMNAT3 catalyzes the reversible transfer of an adenylyl group from ATP to nicotinamide mononucleotide (NMN) or nicotinic acid mononucleotide (NaMN) to produce NAD+ or deamido-NAD+ and pyrophosphate (UniProt Q96T66). This reaction is the final and rate-limiting step in all known NAD+ biosynthetic pathways in humans (PubMed: 16118205). Drugs targeting this enzyme typically act as allosteric activators to boost NAD+ levels or as competitive inhibitors to deplete NAD+ in cancer cells (PubMed: 34199012).