E1 (activating enzyme), E2 (conjugating enzyme), and E3 (ligating enzyme) are key enzymes in the process of ubiquitination, responsible for the tagging and degradation of proteins. The E1 enzyme activates ubiquitin and transfers it to the E2 enzyme, which then cooperates with the E3 enzyme to attach ubiquitin to the target protein. This series of reactions play a central role in cellular processes such as protein homeostasis, signal transduction, and cell cycle control. The E1, E2, and E3 enzyme families consist of numerous members, each with unique substrate specificities and tissue expression patterns. Mutations or dysregulation in specific genes are closely associated with various diseases, including cancer, neurodegenerative diseases, and autoimmune disorders.