NAD synthetase (NADSYN)

NAD synthetase (NADSYN) is a key enzyme in the de novo biosynthesis pathway of nicotinamide adenine dinucleotide (NAD+), an essential coenzyme central to cellular metabolism and physiology. NADSYN catalyzes the final step in the de novo pathway, amidating nicotinic acid adenine dinucleotide (NaAD) to form NAD+, using glutamine as a nitrogen donor[1]. NAD+ is crucial as a hydride acceptor and donor in redox reactions (glycolysis, TCA cycle, fatty acid oxidation), and as a substrate for enzymes involved in DNA repair, chromatin remodeling, and stress responses (e.g., sirtuins, PARPs)[1][3].\nNAD+ can be synthesized de novo from tryptophan—mainly in the liver—or via salvage pathways from nicotinamide (NAM), nicotinic acid (NA), and nicotinamide riboside (NR)[1][3][5]. While most tissues rely on salvage, the de novo pathway (involving NADSYN) is particularly important when salvage is insufficient, such as in certain dietary deficiencies or metabolic disorders[1].\nReduced cellular NAD+ levels are implicated in a spectrum of diseases, including metabolic syndromes, cancer, aging, and neurodegeneration, making enzymes in the NAD biosynthesis pathway, including NADSYN, potential therapeutic targets for modulating NAD+ metabolism[1][3]. However, given the essential and ubiquitous role of NAD+, targeting NADSYN carries the risk of systemic toxicity, highlighting the need for tissue-specific or context-dependent modulation strategies.\nCurrently, there are no specific drugs clinically approved to target NADSYN directly, but indirect modulation via NAD+ precursors (e.g., NR, NMN) shows promise in preclinical models of age-related and metabolic diseases[3]. Biomarkers for NADSYN pathway activity include plasma and cellular NAD+ and related metabolites (NAM, NMN), as well as downstream effects on sirtuin and PARP activity[1].\nIn summary, NAD synthetase is a pivotal enzyme in NAD+ biosynthesis, with broad implications for cellular metabolism, stress responses, and disease, representing a high-priority but also high-risk target for therapeutic intervention in metabolic and age-related disorders.

Other names

Nicotinamide adenine dinucleotide synthetaseNAD synthaseNAD+ synthetase

Inhibition or activation of NAD biosynthesis, modulation of cellular NAD+ levels, indirect regulation of sirtuin and PARP activity