Ligases

Ligases are a class of enzymes that catalyze the joining of two molecules to form a single covalent bond, a process that normally requires energy input. Most ligases accomplish this by using energy from ATP, though some can utilize other nucleotide cofactors such as NAD+. The reaction typically involves forming a high-energy intermediate on one substrate before the second substrate is united, resulting in a new bond and the release of a pyrophosphate or similar leaving group.

Within biology, ligases perform diverse bonding tasks. DNA ligases seal nicks in the DNA backbone during replication and repair, using ATP or NAD+ as a cofactor depending on the organism. RNA ligases participate in RNA processing and repair, joining RNA fragments. Protein ubiquitin ligases (E3 ligases) catalyze the attachment of ubiquitin to substrate proteins, targeting them for degradation or altering their activity. Metabolic ligases such as acyl-CoA synthetases activate fatty acids and other carboxylic acids by attaching them to coenzyme A, forming acyl-CoA derivatives through an ATP-dependent process.

The study of ligases spans structural biology, biochemistry, and biotechnology. In molecular cloning and genetic engineering, DNA ligase is used to join DNA fragments. In cell biology, ubiquitin ligases regulate protein turnover and signaling pathways. Mechanistically, many ligases operate via enzyme–substrate intermediates, such as adenylated substrates or enzyme-bound thioester intermediates, before completing the bond-forming step.

Overall, ligases are essential for building and remodeling macromolecules, coordinating repair and metabolism, and enabling various biotechnological applications.