NAD+-dependent DNA ligase (LigA)

NAD+-dependent DNA ligase (LigA) is an essential bacterial enzyme required for the maintenance of genomic stability through the sealing of single-strand nicks in double-stranded DNA. It is a critical component of DNA replication, specifically in the joining of Okazaki fragments, as well as in various DNA repair pathways such as base excision repair and nucleotide excision repair (UniProt: P06238). Unlike eukaryotic DNA ligases, which are ATP-dependent, LigA utilizes nicotinamide adenine dinucleotide (NAD+) as a cofactor to form the enzyme-adenylate intermediate (PubMed: 12114524). This fundamental difference in cofactor usage makes LigA an ideal target for the development of selective antibacterial agents that do not cross-react with human ligases. Experimental inhibitors, such as pyrido[2,3-d]pyrimidines and various adenosine analogues, have demonstrated potent antibacterial activity by blocking the NAD+ binding site or preventing the adenylation of the enzyme (PubMed: 22403118). Because LigA is conserved across nearly all bacterial species and is essential for viability, it remains a high-interest target for addressing the global challenge of antibiotic resistance. The enzyme's mechanism involves three distinct nucleotidyl transfer steps, providing multiple sites for potential small-molecule intervention (NCBI: Gene ID 946905). Despite its validation as a target, no LigA-specific inhibitors have yet reached clinical approval, primarily due to challenges in balancing potency with favorable pharmacokinetic properties.

Other names

Bacterial DNA ligaseNAD-ligasePolydeoxyribonucleotide synthase (NAD+)DNA ligase (NAD+)ligA

Inhibition of the DNA ligation process by competing with the NAD+ cofactor or preventing the formation of the enzyme-AMP intermediate, leading to unrepaired DNA nicks and bacterial cell death (PubMed: 12114524).