NAD⁺ synthetase (NH₃-dependent) (NAD synthetase (or NAD⁺ synthetase))

NAD⁺ synthetase (NH₃-dependent) is an enzyme that catalyzes the final step in the biosynthesis of nicotinamide adenine dinucleotide (NAD⁺), converting deamido-NAD⁺ to NAD⁺ using ATP and ammonia as substrates[8]. This ligase (EC 6.3.1.5) forms a carbon-nitrogen bond between deamido-NAD⁺ and ammonia, releasing AMP and pyrophosphate[8]. In prokaryotes and some eukaryotes, there are two forms: an ammonia-dependent (NH₃-dependent) and a glutamine-dependent synthetase, with the NH₃-dependent form relying solely on free ammonia as the nitrogen donor[4][8]. Structural and mechanistic studies demonstrate a homodimeric enzyme with an ATP-binding site and a catalytically essential “P-loop”—features conserved across species[1][7]. NAD⁺ synthetase is critical for cellular metabolism and redox balance. In bacteria, it is indispensable and represents a validated target for antibiotic development, as interfering with NAD⁺ biosynthesis is lethal to many pathogens[2][3][4]. Human cells also express ammonia-dependent NAD⁺ synthetase isoforms (NADsyn2), but therapeutic targeting is challenging due to the central metabolic role of NAD⁺ in all cells[4][5]. The enzyme has no known clinical inhibitors, but its essentiality and unique prokaryotic structures make it a focus for antimicrobial discovery.

Other names

NH₃-dependent NAD⁺ synthetaseNAD synthetaseNAD⁺ synthaseDeamido-NAD⁺:ammonia ligase (AMP-forming)Nicotinamide adenine dinucleotide synthetaseDiphosphopyridine nucleotide synthetase

Inhibition of NAD⁺ synthetase leads to depletion of NAD⁺, impairing vital redox reactions and energy metabolism in target organisms[2][4].