NAD synthetase 1 (NADSYN1)

NAD synthetase 1 (NADSYN1) is an enzyme that catalyzes the final step in the de novo biosynthesis of nicotinamide adenine dinucleotide (NAD⁺), an essential coenzyme in cellular energy metabolism and signaling[1][4][6]. NADSYN1 primarily uses glutamine as an amide donor—differentiating it from the related synthetase (NADSYN2), which is ammonia-specific[2]. NADSYN1 is expressed in multiple tissues and has crucial roles in vitamin D metabolism and broader metabolic regulation[1][4][7]. Genome-wide studies have shown NADSYN1 genetic variants influence vitamin D status and are associated with conditions including rickets, osteoporosis, cardiovascular disease, neurodegenerative disease, abnormal growth, and autoimmune disorders like rheumatoid arthritis[1]. Biallelic pathogenic variants result in Congenital NAD Deficiency Disorders with severe, often multisystem developmental anomalies, particularly affecting the vertebrae, heart, kidneys, and limbs—often leading to perinatal lethality or severe developmental delay[3][1]. The enzyme’s physiological role and tissue-specificity are essential for maintaining metabolic and developmental homeostasis[6][4][5]. No direct pharmacological agents targeting NADSYN1 are currently in clinical use, but loss-of-function mutations and NAD+ metabolite levels serve as genetic and biochemical biomarkers for related disorders[3][1]. Essential safety concerns relate to the severe phenotypes seen in congenital absence of enzymatic activity and the enzyme’s non-redundant function in central metabolism and development[3].

Other names

Glutamine-dependent NAD(+) synthetaseNAD(+) synthase (glutamine-hydrolyzing)EC 6.3.5.1

Not applicable (as of available evidence—enzyme replacement or modulation not therapeutically established)