Ammonia-dependent NAD+ synthetase (NadE)

Ammonia-dependent NAD+ synthetase (NadE) is an essential bacterial enzyme that catalyzes the final step in the biosynthesis of nicotinamide adenine dinucleotide (NAD+) (UniProt: P0A706). It facilitates the ATP-dependent amidation of nicotinic acid adenine dinucleotide (NaAD) using ammonia as the nitrogen source (PubMed: 12484756). As NAD+ is a vital cofactor for energy metabolism, redox reactions, and DNA repair, its production is critical for bacterial viability (PubMed: 22403110). NadE is a validated target for the development of novel antibiotics, particularly for treating infections caused by multidrug-resistant organisms like Mycobacterium tuberculosis and Staphylococcus aureus (PubMed: 17439231). The enzyme is highly conserved across many bacterial species but differs significantly from the human version, which typically utilizes glutamine as a nitrogen donor (PubMed: 25664371). This structural and functional divergence allows for the design of selective inhibitors that target the bacterial enzyme without affecting human NAD+ synthesis (PubMed: 19105613). Experimental inhibitors often target the ATP-binding site or the NaAD-binding pocket to prevent the formation of the enzyme-adenylate intermediate. While several potent small-molecule inhibitors have been identified in laboratory settings, none have yet progressed to clinical use.

Other names

NadENH3-dependent NAD synthetaseNicotinamide adenine dinucleotide synthetaseDeamido-NAD+ ammonia ligase

Inhibition of the ATP-dependent amidation of nicotinic acid adenine dinucleotide (NaAD) to NAD+, leading to cofactor depletion and bacterial death.