Activation of ubiquitin and ubiquitin-like proteins.

Attachment of ubiquitin and ubiquitin-like proteins to cellular targets represents a fundamental regulatory strategy within eukaryotes and exhibits remarkably pleiotropic effects on cell function. These posttranslational modifications share a common mechanism comprised of three steps: an activating enzyme to couple ATP hydrolysis to formation of a high-energy intermediate at the carboxyl terminus of ubiquitin or the ubiquitin-like protein, a ligase to couple aminolysis of the activated polypeptide to formation of the new peptide bond and a carrier protein to link the two half reactions. The activating enzymes play pivotal roles in defining pathway specificity for ubiquitin or the ubiquitin-like protein and for target protein specificity in charging the cognate carrier protein supporting downstream ligation steps. Therefore, the family of activating enzymes are critical components of cell regulation that have only recently been recognized as important pharmacological targets.