This review outlines the latest findings on bioconjugation using lipoic acid ligase A (LplA), a key enzyme that allows the introduction of new functional groups into biomolecules. LplA functions via a characteristic mechanism of covalently binding orthologous lipoic acid derivatives in vivo to a specific 13 amino acid sequence called the LplA acceptor peptide (LAP). This unique functionality has enabled a wide range of applications, including cell-surface modification, protein immobilization, fluorescent labeling of antibodies. Recently, the modification of proteins without LAP sequences has been demonstrated, suggesting their potential for future biopharmaceutical production. Although several review articles on enzyme ligation have been published, research on LplA remains limited. This review attempts to fill this gap by introducing LplA based on its mechanism, applications, and recent research reports. In this review, we have summarized enzymatic protein modification strategies using lipoate acid ligase A (LplA) for the production of protein conjugates, immobilized proteins, and cell conjugates. Both the advantages and disadvantages of the current approach were thoroughly analyzed. In addition, the potential of a tag-free approach was discussed.+image
