NADSYN1 (Glutamine-Dependent NAD+ Synthetase 1 De Novo & Preiss-Handler Gene)
NADSYN1 (NAD synthetase 1; HGNC:29832, NCBI Gene ID 55191) is a human locus mapped to chromosome band 11q13.4 that encodes homohomododecameric glutamine-dependent NAD+ synthetase 1 (706 aa; EC 6.3.5.1). NADSYN1 acts in terminal step of the Preiss-Handler (nicotinic acid) & de novo kynurenine (tryptophan) NAD+ synthesis pathways, together with NAMPT (NAD+ Salvage Rate-Limiting Enzyme Gene), CD38 (NAD+ Glycohydrolase Gene), and SIRT1 (NAD+-Dependent Deacetylase Gene). Encodes glutamine-dependent NAD+ synthetase 1, catalyzing the final amidation of nicotinic acid adenine dinucleotide (NAAD) into NAD+.
Terminal step of the Preiss-Handler (nicotinic acid) & de novo kynurenine (tryptophan) NAD+ synthesis pathways
Clinical / Therapeutic Role
Biallelic LoF mutations cause congenital vertebral, cardiac, and renal VACTERL-like NAD+ deficiency malformation syndrome
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 21-exon gene on chromosome 11q13.4 encoding a 706-amino-acid bifunctional two-domain enzyme comprising an N-terminal nitrilase-like glutaminase domain and a C-terminal ATP-pyrophosphatase NAD+ synthetase domain connected by an internal ammonia tunnel.
Cellular & Tissue Expression Profile: Expressed predominantly in the liver, kidneys, small intestine, and embryonic mesoderm—the tissues capable of synthesizing NAD+ de novo from dietary L-tryptophan (via the kynurenine pathway) or from nicotinic acid (niacin) via the Preiss-Handler pathway.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Hydrolyzes L-glutamine to L-glutamate in its N-terminal domain, channels nascent ammonia internally to the C-terminal active site, and uses ATP cleavage (yielding AMP + PPi) to amidate the carboxylate group of nicotinic acid adenine dinucleotide (deamido-NAD+ / NAAD) into mature nicotinamide adenine dinucleotide (NAD+).
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Biallelic loss-of-function mutations in NADSYN1 cause congenital NAD+ deficiency disorder, an autosomal recessive embryopathy characterized by vertebral segmentation defects, congenital heart defects (hypoplastic left heart), renal agenesis, and limb anomalies (VACTERL-spectrum malformations), while common SNPs at the NADSYN1/DHCR7 locus on 11q13.4 are the strongest genome-wide determinant of circulating 25-hydroxyvitamin D levels.
Therapeutic & Clinical Pharmacology: Because nicotinamide (via NAMPT) and nicotinamide riboside bypass NADSYN1 to enter the salvage pathway directly as NMN, maternal dietary supplementation with salvage-pathway NAD+ precursors rescues embryonic NAD+ deficiency in preclinical NADSYN1 models.